Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32](OC)=O)=[CH:25][C:24]=2[O:23]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]3[NH:21][C:19](=[O:20])[C:3]4[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)=[CH:25][C:24]=2[O:23]1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 26.8 %

Procedure:
10 mg (0.034 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.103 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4 mg (48%) of a solid, Rf=0.68 (dichloromethane/methanol=15:1).
Reaction SMILES: [C:1]1([C:7]2([CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]32[O:12][CH2:11][CH2:10][O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]32[O:12][CH2:11][CH2:10][O:9]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCC1(c2ccccc2)CCCCC12OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC1(c2ccccc2)CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution of methyl 4-(6-phenyl-1,4-dioxaspiro[4.5]decan-6-yl)butanoate (0.137 g, 0.43 mmol) in MeOH (3 mL) was added 1N sodium hydroxide (1.290 mL, 1.290 mmol), and the mixture was stirred at room temp for 4 hrs. It was made acidic with 1.4 mL of 1N HCl and the product was extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4 and evaporated to give a solid residue (128 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].F[B-](F)(F)F.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].CN(C=O)C>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:2]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-(2-bromo-4-(trifluoromethyl)phenyl)acetate (A57) (1.60 g, 5.38 mmol), PdCl2(PPh3)2 (189 mg, 269 μmmol), t-Bu3PH.BF4 (78.1 mg, 269 μmmol), CuI (51.3 mg, 269 μmol) and TMS-acetylene (1.52 mL, 10.8 mmol) in Et3N (10 mL) and anhydrous, degassed DMF (10 mL) was stirred at 80° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A58 as an orange liquid (1.56 g, 92%); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.87 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-A: rt 6.979 min; m/z 315 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([CH:12]([O:14]C(=O)C)[CH3:13])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:14][CH:12]([C:6]1[N:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:4](=[O:24])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=1)[CH3:13]
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc2nc(C(C)O)n(-c3ccccc3)c(=O)c12
Reaction time: 0.33 h

Procedure:
Compound 180 (0.011 g, 0.034 mmol) was dissolved in methanol (2 mL), and potassium carbonate (0.012 g, 0.085 mmol) was added. The reaction mixture was stirred for 20 min, and then water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts were washed with saturated brine (10 mL). The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure to give compound 181. ESI-MS m/z=281 (MH+). The reaction described above and compound 181 are shown below,
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[Cl:36]>O1CCCC1>[Cl:33][C:32]1[CH:31]=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([Cl:36])[C:27]=1[CH2:26][CH:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:12]1=[O:16]
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in tetrahydrofuran (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS (m+1) 414.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccs1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1cccs1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-thiophenecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Cl
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: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (168 mg, 0.597 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μL, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 18 hr. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0), silica gel column chromatography (30 g, ethyl acetate/hexane=0/100→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (101 mg, 37%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]2[C:7]([CH3:10])=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>O1CCOCC1>[Cl:13][C:12]1[C:3]([N:2]2[CH:16]=[CH:20][CH:19]=[CH:18]2)=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: Cc1coc2cc(N)c(Cl)cc12
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1coc2cc(-n3cccc3)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7 ml of 5N hydrochloric acid are added to a mixture of 9.1 g (50 mmole) of 6-amino-5-chloro-3-methylbenzofuran, 10 ml (78 mmole) of 2,5-dimethoxytetrahydrofuran and 200 ml of dioxane and the whole is stirred at room temperature for 16 hours. The whole is subsequently concentrated by evaporation in vacuo and the residue is chromatographed over silica gel with petroleum ether/methylene chloride. Crystallisation of the resulting product from petroleum ether yields 5-chloro-3-methyl-6-(pyrrol-1-yl)-benzofuran having a melting point of 49°-52°.
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=S)N2CCN(c3ccccc3F)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8][CH2:9]2)=[CH:14][C:15]=1[F:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1

Procedure:
4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-fluoro-phenylamine (0.85 g, 2.4 mmol) was dissolved in DCM (20 mL). To this solution was transferred a solution of CbzCl (560 mg, 3.28 mmol, 1.3 equiv.) in 5 mL of DCM, followed by addition of powder anhydrous K2CO3 (0.99 g, 7.2 mmol, 3 equiv.). The reaction mixture was stirred at 0° C. to rt. overnight. The reaction was quenched by dilution with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered and the filtrate was concentrated in vacuo to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1>CN(C)C=O>[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][N:64]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:5])[CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1
Reactant: C1CC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCC2)CC1
Reaction time: 2 h
Yield: 5.8 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.20 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL), and to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-cyclobutoxypiperidine (14) (0.104 g, 0.67 mmol). The reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white solid (0.017 g, 5.82%); 1H NMR (400.132 MHz, CDCl3) δ 1.56-1.44 (2H, m), 1.72-1.64 (2H, m), 2.00-1.84 (4H, m), 2.23-2.14 (2H, m), 3.14-3.04 (1H, m), 3.48-3.41 (2H, m), 3.58-3.52 (1H, m), 4.00 (1H, quintet), 4.10-4.03 (1H, m), 4.26 (2H, s), 7.01 (1H, t), 7.31-7.24 (2H, m), 7.77-7.70 (3H, m), 8.47-8.44 (1H, m), 9.90 (1H, s); m/z (LC-MS, ESI+), RT=2.15 (M+H 436).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.2 mmol) was coupled with (2R,6S)-2,6-dimethyl-piperazine (50 mg, 0.2 mmol), HOBt (36 mg, 1.1 eq.), EDAC.HCl (40 mg, 1.1 eq.) and TEA (76 mg) in DMF (25 mL) at 75° C. for 2 hours to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH3:17][NH:18][CH2:19][CH:20]=[CH2:21]>C1COCC1>[CH2:19]([N:18]([CH3:17])[C:7]([C:6]1[C:5]([I:12])=[C:4]([C:3]([I:16])=[C:2]([NH2:1])[C:10]=1[I:11])[C:13]([Cl:15])=[O:14])=[O:8])[CH:20]=[CH2:21]
Reactant: C=CCNC
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: C1CCOC1
Product: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reaction time: 8 h

Procedure:
Typically 5-amino-2,4,6,triiodoisophthaloyl dichloride (1) (100 g, 168 mmol) was dissolved in anhydrous THF (500 ml), the N-methyl allylamine (25 ml) was dissolved in 50 ml THF, and added dropwise to the solution over 1 hour. The mixture was heated to 50 deg C. and stirred overnight. The crude mixture was analysed by LCMS and this confirmed that the reaction mixture contained the desired product, ‘bis-acid chloride’ and ‘bis-N-methyl-allylamide’. The reaction was also monitored by TLC (2% MeOH in DCM) on silica gel plates, bis-acid chloride had an Rf of ˜0.98, the mono-N-methylallylamide ˜0.73 and the bis-N-methylallylamide ˜0.25. Once the reaction was deemed complete, the solution was filtered, vacuumed to dryness, then dissolved in 500 ml of ethyl acetate this solution was then loaded onto silica and purified on a 750 g column using ethyl acetate (B) and petrol (A) (10%→100% B over ˜10 column volumes). The pure fractions were collected and identified by TLC, the desired fractions were then vacuumed to dryness. The structure was confirmed by 1H and 13C NMR and purity by LCMS.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OC)=[O:19].[CH3:22][CH:23]([SH:25])[CH3:24]>>[F:16][C:14]([F:15])([F:17])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[S:5][C:4]([CH2:18][OH:19])=[C:3]([CH2:2][S:25][CH:23]([CH3:24])[CH3:22])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: CC(C)S
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Product: CC(C)SCc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO

Procedure:
The title compound was prepared using methyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 132) and isopropylthiol.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH:3]=1.C(OO)(=[O:12])C>C(OCC)(=O)C>[CH3:1][C:2]12[O:12][CH:7]1[CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]2
Reactant: CC1=CCC(CO)CC1
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Product: CC12CCC(CO)CC1O2

Procedure:
Epoxidation of 12.6 g (0.1 mol) of (4-methylcyclohex-3-enyl)methanol was carried out with a 5 percent by weight solution of peracetic acid in ethyl acetate at 65° C. Purification of the product by distillation yielded 12 g of (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol with a purity of 98%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:7]4=[N:14][CH:13]=[CH:12][CH:11]=[C:8]4[C:9]([NH2:10])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: N#Cc1cccnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2ncccc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (102 μL, 0.164 mmol, Aldrich) was added dropwise to a solution of 2-bromonicotinonitrile (30 mg, 0.164 mmol, Aldrich) in THF (2 mL) at −95° C. under N2 atmosphere. After 1 min a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (55 mg, 0.127 mmol, example 1b) in THF (1 mL) was added. After 2 min aqueous, saturated NH4Cl solution was added and the reaction mixture was allowed to warm to RT. EtOAc was added and the organic phase was separated. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The remaining residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title compound as a light-yellow solid. MS m/z=432.8 [M+H]+. Calculated for C18H9BrClFN4O: 431.65
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=411.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and pentanoic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[NH:17][C:16](=O)[N:15]3[CH:19]=[CH:20][N:21]=[C:14]3[CH:13]=2)[CH:9]=[N:8]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:35]>C(Cl)Cl>[Cl:35][C:16]1[N:15]2[CH:19]=[CH:20][N:21]=[C:14]2[CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:23])([CH3:22])[CH3:1])[CH:11]=2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(=O)[nH]2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (Step B, 772 mg, 2.33 mmol) in dry DCM (15 mL) was added DIEA (1.22 mL, 6.99 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The mixture was cooled to 0° C. and POCl3 (855 μL, 9.32 mmol) was added. The mixture was stirred for 1 hour at 0° C. then at ambient temperature for 18 hours. The reaction mixture was concentrated and the residual syrup was dissolved in EtOAc (15 mL). The solution was added dropwise to stirred 1M K2CO3 (20 mL) cooled to 0° C. and stirred for 30 minutes. The mixture was allowed to reach ambient temperature and the EtOAc layer was removed. The remaining aqueous layer was extracted with EtOAc (2×) and the combined EtOAc fractions were washed with saturated NaCl. The EtOAc solution was dried over MgSO4/activated carbon, filtered through a packed Celite plug (EtOAc elution) and concentrated. The residual dark syrup was dissolved in Et2O, treated with activated carbon and filtered through a packed Celite pug (Et2O elution). The Et2O solution was concentrated to give a brittle tan foam that was pulverized to a flowing solid and dried in vacuum. This afforded the title compound (416 mg, 51.0% yield) as a light tan solid. MS (apci) m/z=350.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COCCOCCOCCO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: COCCOCCOCCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 74 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(2-(2-methoxyethoxy)ethoxy)ethanol according to Method E (yellow solid, 199 mg, 0.352 mmol, 74% yield). ES-HRMS m/z calc. for C31H36ClN3NaO5 (M+Na) 588.2241, found 588.2245.