Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N+:11]([O-])=O.[Cl-].[NH4+].CO>[Zn].O>[NH2:11][C:3]1[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH:8]=[CH2:9])[C:2]=1[Cl:1]
Reactant: C=CCn1nc(C)c([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: C=CCn1nc(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A mixture of 0.5 g (0.00248 mole) of 5-chloro-3-methyl-4-nitro-1-(2-propenyl)-1H-pyrazole (XX), 1.6 g (0.0198 mole) of ammonium chloride, 1.6 g of zinc powder, 20 mL of methanol and 20 mL of water was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with ethyl acetate-hexane (1:1) gave 0.10 g of 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), which was identical to the material prepared in Example 88 (method 1) above.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[N-:5]=[N+:6]=[N-:7].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([C:17]#[CH:18])[C:13]([NH2:16])=[N:14][CH:15]=1>CC(O)(C)C.O.CCOC(C)=O.[Cu]I>[Br:9][C:10]1[CH:11]=[C:12]([C:17]2[N:5]=[N:6][N:7]([CH:1]([CH3:3])[CH3:2])[CH:18]=2)[C:13]([NH2:16])=[N:14][CH:15]=1
Reactant: CC(C)Br
Reactant: C#Cc1cc(Br)cnc1N
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of isopropyl bromide (5.0 g, 40.65 mmol) and sodium azide (2.6 g, 40.65 mmol) in t-BuOH/water (1:2) (50 mL) was stirred for 2 h at 80° C. Then the reaction mixture was cooled to room temperature, to which was added 5-bromo-3-ethynyl-pyridin-2-ylamine (0.8 g, 4.065 mmol) and CuI (catalytic amount). The reaction mixture was stirred for 16 h at 80° C. The reaction mixture was cooled to RT, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was washed with diethyl ether to afford the title compound as ash colour solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:12][C:5]1[C:6]2[C:7](=[O:9])[N:40]([CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17](=[O:23])[NH:1][C:2]=2[S:3][CH:4]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc2[nH]c(=O)n(CCc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution (150 mL) of ethyl 2-amino-4-methylthiophene-3-carboxylate (2 g) in methylene chloride were added triphosgene (1.39 g) and triethylamine (2.38 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (4.09 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (80 mL), sodium methoxide (5.2 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (3.09 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1Cl
Reactant: OC1CCOCC1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOCC3)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[1-(3-chloro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 458.5 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][C:16]3=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[CH2:20]([NH:27][CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:18]=2)[CH2:13][CH2:14][CH2:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2ccc(OCc3ccncc3)cc21
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(CNC2CCCc3ccc(OCc4ccncc4)cc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A solution of Compound 1 (820 mg, 3.24 mmol) and benzyl amine (354 L, 3.24 mmol) in benzene (10 mL) was heated to reflux under azeotropic conditions. After the calculated amount of water was collected, the reaction was cooled and concentrated in vacuo. The residue was taken-up into ethanol (5 mL) and added to a slurry of sodium boroydride (246 mg, 6.48 mmol) in ethanol (15 mL). The reaction was heated to 80° C., stirred for 30 min, cooled and concentrated in vacuo. The residue was diluted with ethyl acetate followed by the slow addition of 1N hydrochloric acid. The layers were separated. The aqueous phase was adjusted to pH 7 with 2N sodium hydroxide and extracted with methylene chloride (2×). The organics were combined, washed with brine, dried over anh. magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (elution with 5% methanol:methylene chloride) provided 1.09 g of Compound 12 as an oil.
Reaction SMILES: [NH2-].[Na+].[NH2:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:18](#[N:22])[CH:19]([CH3:21])[CH3:20]>CCOCC>[NH2:22][C:18]1[C:19]([CH3:21])([CH3:20])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[C:5]2[C:4](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)C#N
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium amide (15 g.) was added portionwise to a stirred solution of 2-aminobenzophenone(19.7g., 0.1 mole) and isobutyronitrile (20.7g., 0.3 mole) in dry ether (500 ml.). The mixture was stirred for 1 hour at room temperature and then heated under reflux for 21/2 hours. After cooling, the mixture was poured onto ice, extracted with ether and the combined extracts washed and dried (MgSO4). The solvent was removed and the residue crystallised from toluene to give a product (10.76g., m.p. 157° - 160° C). Recrystallisation from toluene gave the pure title compound, 9.17g., m.p. 161° - 163° C. [Found: C. 76.75, H, 6.9, N, 10.5%. C17H18N2O requires C, 76.65, H, 6.8, N, 10.5%].
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[Br:15][CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:40]2N=C[CH:43]=[CH:44][C:39]=2N=N1>C(#N)C>[Br:15][CH:16]([C:20]1[CH:21]=[CH:43][CH:44]=[CH:39][CH:40]=1)[C:17]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[CH:6][N:7]=1)=[O:19]
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC(Br)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (0.484 g, 2.16 mmol) and 2-bromo-butyric acid (0.360 g, 2.16 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (302 μL, 2.16 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.15 g, 3.02 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography. ESI-MS m/z calc. 372.0, found 373.2 (M+1)+ Retention time 3.41 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([F:11])[S:7]1(=[O:13])=[O:12].C([Li])CCC.[F:25]NS(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([F:25])([F:11])[S:7]1(=[O:13])=[O:12]
Reactant: COc1ccc(CN2CCC(F)S2(=O)=O)c(OC)c1
Reactant: O=S(=O)(NF)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(F)(F)S2(=O)=O)c(OC)c1
Reaction time: 1 h
Yield: 1.8 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-5-fluoroisothiazolidine-1,1-dioxide (5.700 g, 19.7 mmol) in anhydrous tetrahydrofuran (225 mL), cooled to −78° C., was slowly added n-butyl lithium (14.973 mL of a 2.5 N solution in hexanes, 37.4 mmol) and the resulting dark orange/red solution stirred for 1 hr. A solution of N-fluorobenzene sulfonamide (14.6 g, 46.3 mmol) in anhydrous tetrahydrofuran (60 mL) was added slowly over 30 mins, stirring at −78° C. for 3 hrs and at room temperature for 2.5 hrs. The reaction was poured into saturated aqueous ammonium chloride, diluted with ethyl acetate, and the organic layer isolated. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was suspended in methylene chloride and filtered through a pad of silica gel, washing with methylene chloride, and concentrating the solution. The crude material was purified by silica gel chromatography (20-75% ethyl acetate/hexanes) and then by preparative HPLC (C18, 32-95% acetonitrile/water over 17 mins) to give a tan oil (0.106 g, 2%). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.18 (d, 1H, J=8.4 Hz), 6.49-6.45 (m, 2H), 4.28 (s, 2H), 3.82 (s, 3H), 3.14 (s, 3H), 3.19-3.15 (m, 2H), 2.70-2.55 (m, 2H).
Reaction SMILES: O[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([F:10])([F:9])[F:8].Cl[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:15]=[C:14]([CH3:28])[CH:13]=1.C([O-])([O-])=[O:30].[K+].[K+]>CN(C)C=O.O>[CH3:28][C:14]1[CH:13]=[C:12]([O:30][C:6]2[CH:2]=[C:3]([C:7]([F:10])([F:9])[F:8])[S:4][CH:5]=2)[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:15]=1
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: Oc1ccsc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2csc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 3-hydroxy-2-(trifluoromethyl)thiophene (0.50 g, 2.98 mmol) and 6-chloro-4-methyl-2-(α,α,α-trifluoro-p-tolyl)pyrimidine (0.31g, 2.98 mmol) in dimethylformamide is treated with K2CO3 (0.62 g, 4.47 mmol), heated at 100° C. for 17 hours, cooled to room temperature and diluted with water. The resultant reaction mixture is extracted with ether. The ether extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a brown solid residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 20/80) to give the title product as a light yellow solid, 0.88 g (73% yield), mp 83.5-85° C., identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH:22][CH3:23])[O:20][CH:21]=2)=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH3:23][NH:22][C:19]1[O:20][CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH2:9])=[CH:12][CH:13]=2)[N:18]=1
Reactant: CNc1nc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)co1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(-c2ccc(CN)cc2)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Add 4N hydrogen chloride in dioxane (10.5 mL) to a solution of N-(tert-butoxycarbonyl)-4-(2-methylamino-oxazol-4-yl)-benzylamine (624 mg, 1.6 mmol) in DCM (250 mL). Stir the solution at room temperature for 16 h in a sealed flask. Concentrate the mixture in vacuo to a solid. Slurry the solid in excess of diethyl ether and filter. Collect the white solid to obtain the title compound (1.48 g, 95%). MS (ES+) m/z: 204.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1c(Br)cncc1Br
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2c(Br)cncc2Br)CC1
Yield: 44.4 %

Procedure:
General procedure C was followed using 3,5-dibromo-4-chloropyridine 18 (50 mg, 0.18 mmol), isonipecotamide (24 mg, 0.18 mmol), NMP (2 mL) and triethylamine (51 μL, 0.37 mmol). The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a pale yellow solid (29 mg, 43%), m.p. 158-160° C.; umax (CHCl3)/cm−1 3053, 2985, 1687, 1591; m/z (ESI) C11H14Br2N3O requires 361.9498 found [M+H]+ 361.9500.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-])=O)[C:14]([N+:20]([O-])=O)=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:19][CH:17]([C:16]3[CH:15]=[C:14]([NH2:20])[C:13]([NH2:23])=[CH:12][C:11]=32)[CH2:18]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc(N)c(N)cc12

Procedure:
4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (1.9 g, 5.44 mmol) was hydrogenated in methanol under a H2 atmosphere (45 psi) over 10% Pd/C (100 mg) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (1.57 g, 100%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.14).
Reaction SMILES: [CH:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1C2CCCC1CCC2.B(O)O.Br[C:23]1[CH:56]=[CH:55][C:26]([CH2:27][C:28]2[N:29]([C:41]3[CH:42]=[C:43]([N:47]4[S:51](=[O:53])(=[O:52])[NH:50][C:49](=[O:54])[CH2:48]4)[CH:44]=[CH:45][CH:46]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[N:32]=2)=[CH:25][CH:24]=1>C1COCC1>[CH:1]1([CH2:7][CH:8]=[CH:9][C:23]2[CH:56]=[CH:55][C:26]([CH2:27][C:28]3[N:29]([C:41]4[CH:42]=[C:43]([N:47]5[S:51](=[O:52])(=[O:53])[NH:50][C:49](=[O:54])[CH2:48]5)[CH:44]=[CH:45][CH:46]=4)[CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[N:32]=3)=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCC1CCCCC1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Agent: B1C2CCCC1CCC2
Agent: OBO
Solvent: C1CCOC1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCC4CCCCC4)cc3)c2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-cyclohexyl-1-propyne (145 μL, 1 mmol) in 2 mL dry THF at 0° C. was added 2 mL 0.5 M 9-BBN solution in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hr. Then it was condensed under vacuum and used as boronic acid derivative according to general procedure G, reacting with 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) to give 5-{3-[2-[4-(3-cyclohexyl-propenyl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[C@H:27]([OH:33])[CH2:26]1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Temperature: 40 °C
Yield: 58.1 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 27C, 2.35 g, 8.42 mmol) in dichloromethane (15 mL) was added at room temperature to a suspension of (S)-6-((S)-3-amino-4-hydroxy-butyl)-6-aza-spiro[2.5]octan-4-ol (1.81 g, 8.42 mmol), sodium triacetoxyborohyride (2.21 g, 1.01 mmol) and acetic acid (1.01 g, 16.8 mmol) in dichloromethane (15 mL). The reaction mixture was heated at 40° C. for 72 h, then partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (2.18 g, 58%). White foam, MS (ISP)=446.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:8][CH2:7][C:6](OC)([O:9]C)[CH2:5]1)([CH3:3])[CH3:2].O>Cl.O1CCOCC1>[CH:1]([C:4]1([C:13]([OH:15])=[O:14])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C1(C(=O)O)CCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (8.32 g, 30.5 mmol) was dissolved in 4N anhydrous HCl in dioxane (50 mL) and water (10 mL) was added. The reaction mixture was stirred at rt overnight, then was concentrated. The residue was dissolved in DCM, dried over anhydrous MgSO4, filtered, and concentrated to give 1-isopropyl-3-oxocyclopentanecarboxylic acid (used without purification). 1H NMR (500 MHz, CDCl3) δ 2.70 (d, J=18.1 Hz, 1H), 2.44-2.39 (m, 1H), 2.30-2.15 (m, 2H), 2.14 (dd, J=18.1, 1.0 Hz, 1H), 2.06 (p, J=6.9 Hz, 1H), 1.98 (m, 1H), 0.98 (dd, J=11.4, 6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.Cl[C:11]1[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1>CO>[CH3:1][NH:3][C:11]1[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: CN
Solvent: CO
Product: CNc1ccc(C(=O)Nc2ccc(OC)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Methanol (20 mL), triethylamine (1.59 mL, 11.4 mmol) and monomethylamine (2.0 M in MeOH, 19 mL, 38.0 mmol) were added to a pressure tube containing 6-chloro-N-(4-methoxyphenyl)nicotinamide (37, 2.0 g, 7.61 mmol) obtained in step 1. After agitating at 100° C. overnight and then cooling to room temperature, the product was removed by filtration. Removal of the solvent under reduced pressure yielded the target compound 6-(N-monomethylamino)-N-(4-methoxyphenyl)nicotinamide (38, 1.76 g, 90%) without further purification.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>CC(N=NC(C#N)(C)C)(C#N)C>[CH3:17][Si:16]([CH3:19])([CH3:18])/[CH:14]=[CH:15]/[Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Temperature: 80 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
Tributyltin hydride (2.0 mL, 7.3 mmol, 1.0 equiv) and ethynyltrimethylsilane (2.1 mL, 15 mmol, 2.0 equiv) were combined, AIBN (60 mg, 0.36 mmol, 0.05 equiv) was added, and the resulting colorless neat solution was heated to 80° C. Upon heating, the reaction exothermed to −110° C. The reaction mixture was cooled back to 80° C. and stirred for 20 h. The reaction mixture was cooled to 23° C. to afford the crude title compound as a pale yellow oil (2.8 g, 99% crude yield): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=22.5 Hz, 1H), 6.60 (d, J=22.5 Hz, 1H), 1.44-1.54 (m, 6H), 1.23-1.35 (m, 6H), 0.82-0.91 (m, 15H), 0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 581.2 (M+H+).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+].O>CN1CCN(C)C1=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Methyl 4-fluoro-3-nitrobenzoate (13.6 g) was added over 10 minutes to a stirred solution of sodium thiomethoxide (4.8 g) in 1,3-dimethyl-2-imidazolidinone (100 ml). The dark brown solution was stirred for 2 hours and was then heated on a steam bath for 2.5 hours. After cooling, the solution was poured into water (1.0 liter) and was extracted with diethyl ether (300 ml and then 2×200 ml). The ether solution was washed with water (2×250 ml), was dried over magnesium sulphate and was then concentrated in vacuo to leave an orange slurry. Crystallization from methanol provided methyl 4-methylthio-3-nitrobenzoate (3.45 g), m.p. 118°-120° C. [Elemental analysis: C,47.8; H,3.9; N,6.2; S,13.7%; calculated: C,47.58; H,3.96; N,6.17; S,14.1%].
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O1CCCC1>[N:6]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Bromoacetic acid (2 g, 14.4 mole) was dissolved in tetrahydrofuran (50 mL) and added dropwise to a stirred solution of morpholine (3.76 g, 43.2 mole) in tetrahydrofuran (THF, 20 mL). The solution was stirred at room temperature for three days. The white solid (4.17 g) was filtered, washed with THF (100 mL), and recrystallised from hot ethanol (EtOH), Yield: 2.59 g: IR: 1740 cm-1. For the two different isobaric versions of morpholine acetic acid, either bromoacetic-1-13C acid (Aldrich PN 27,933-1) or bromoacetic-2-13C acid (Aldrich PN 27,935-8) was substituted for bromoacetic acid.