Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[C:9]=2[CH:18]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole (9.61 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.8 g compound (I-56) with a yield of 63.4%. ESI-MS [M+H]+: m/z 461.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1.[CH3:15]I>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:15])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1
Reactant: CI
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Product: C=CCc1cc(C(=O)OC)ccc1OC

Procedure:
3-Allyl-4-methoxybenzoic acid methyl ester was prepared from 3-Allyl-4-hydroxybenzoic acid methyl ester according to Method C using methyl iodide as an alkylating agent in quantative yield. This product was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1>O1CCOCC1>[Cl:51][C:48]1[N:47]=[CH:46][C:45]([CH2:44][NH:43][C:2]2[N:3]=[C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:5]=[C:6]([NH:8][N:9]=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[N:7]=2)=[CH:50][CH:49]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
{4-Chloro-6-[N′-(4-trifluoromethoxybenzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)amine (XXI) (2.54 g, 5.14 mmol) was dissolved in dioxane (25 mL). To this solution was added diisopropylethylamine (1.8 mL, 10.3 mL) followed by 3-aminomethyl-6-chloropyridine (0.52 mL, 5.17 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue dissolved in ethyl ether (40 mL). This solution was rinsed with brine, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil which was purified by column chromatography (silica, gel, hexane/EtOAc), to afford desired product 2 (0.93 g, 32% yield).
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:10])[S-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15]>C(O)C>[CH3:19][C:13]1([CH3:20])[S:10][C:8](=[S:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:14]1=[O:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: S=C([S-])Nc1ccccc1
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)SC(=S)N(c2ccccc2)C1=O

Procedure:
Ammonium phenyldithiocarbamate (93 g, 0.5 mole) and ethyl 2-bromoisobutyrate (98 g, 0.5 mole) were dissolved in ethanol (100 mL) and heated at reflux overnight. The ethanol was distilled off and the residue poured into ice water. The solid was filtered and recrystallized in 95% ethanol. The product had a final weight of 31.4 g and an M.P. of 107-108 degrees.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][CH2:13][O:12][C:3]1[CH:4]=[C:5]([O:8][CH2:9][O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(B(O)O)c(OCOC)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
To a solution of 1-bromo-2,4-bismethoxymethoxybenzene in hexane (250 ml) and tetrahydrofuran (110 ml) was added triisopropyl borate (45 g, 238 mmol), and the mixture was cooled to −78° C. A solution (151 ml, 238 mmol) of 1.58M n-butyllithium in hexane was added dropwise and the mixture was stirred for 5 hr. 1N Hydrochloric acid (240 ml) was added under ice-cooling, and the mixture was stirred for 15 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,4-bismethoxymethoxyphenylboronic acid (13.6 g, yield 35%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][S:26]2)[S:21][C:20]=1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([NH:44][C:45](=[O:47])[CH3:46])=[CH:42][CH:41]=1>>[CH2:12]([N:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][S:26]2)[S:21][C:20]1=[N:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44][C:45](=[O:47])[CH3:46])=[CH:48][CH:49]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSC1=[N+](Cc2ccccc2)C(=O)C(=C2SC=C(c3ccccc3)N2C)S1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)Nc1ccc(N=C2SC(=C3SC=C(c4ccccc4)N3C)C(=O)N2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3′-benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazolyliden-3′-ium p-toluenesulfonate and 4′-aminoacetanilide in a manner similar to that described in Example 1. 1H-NMR (CDCl3): δ 7.56 (2H, d), 7.42–7.47 (5H, m), 7.24–7.34 (5H, m), 7.12 (1H, s), 6.97 (2H, d), 6.30 (1H, s), 5.15 (2H, s), 3.49 (3H, s), 2.17 (3H, s); MS(ESI): 513 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:8]=1.[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:11]([C:10]4[CH:15]=[CH:16][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:23])=[CH:8][C:9]=4[N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[O:12])[CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCC2=O)CC1
Yield: 4.1 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxopyrrolidin-1-yl)benzoate (131 mg) described in Preparation Example 33 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (84 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (8.3 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11])([O-])=O.O1CCOCC1.[H][H]>[Ni].CO>[NH2:1][C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: [H][H]
Reactant: CSc1cc(C)nc(SC)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: CSc1cc(C)nc(SC)c1N
Yield: 85 %

Procedure:
A mixture of 18.9 g (0.082 mol) 3-nitro-2,4-bis(methylthio)-6-methylpyridine and 18.9 g Raney nickel in 600 ml. 1,4-dioxane and 300 ml methanol was shaken with hydrogen (15 psi) in a Parr hydrogenation apparatus for 3.5 hours. The catalyst was filtered and the filtrate was concentrated to dryness in vacuo. The solid residue was chromatographed on silica gel (650 g), eluting with 9:1 hexane/ethyl acetate to yield 14.0 g. (85% yield) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4].[O-2].[Mg+2].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][O:19][C:20](N=[N+]=[N-])=[O:21])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH:9][C:20]([O:19][CH2:18][C:17]1[CH:25]=[CH:26][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:21])[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Reactant: C=C(CCCN)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.4 %

Procedure:
To a solution of 8.8 g of 2-methylene-5-aminopentanoic acid hydrochloric in 100 ml of water is added with stirring 6.36 g of magnesium oxide, followed by a solution of 12.2 g of p-methoxybenzyloxycarbonyl azide in 100 ml of dioxane, and the resulting mixture is stirred at room temperature for two days. The reaction mixture is filtered, and the filtrate diluted with 200 ml of ethyl acetate, two equivalents of Dowex 50 ion exchange resin is added, and the mixture is stirred at room temperature for two hours. The resin is then filtered off and washed with water. The layers in the filtrate are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried and concentrated in vacuo to give 18.2 g of 2-methylene-5-(p-methoxybenzyloxycarbonyl)aminopentanoic acid as an amber oil which crystallizes on standing. This is used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:13]=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20](O)=[O:21])[CH:16]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:27]([C:31]1[CH:32]=[CH:33][C:34]([S:38]([CH3:40])=[O:39])=[C:35]([NH2:37])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([S:38]([CH3:40])=[O:39])=[C:35]([NH:37][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:17]([N:15]3[CH:16]=[C:12]([C:9]4[CH:10]=[N:11][C:6]([NH:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:7][CH:8]=4)[N:13]=[N:14]3)[CH:18]=2)[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CS(=O)c1ccc(C(C)(C)C)cc1N
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)ccc2S(C)=O)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1

Procedure:
Example 6 was prepared by coupling 3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoic acid with 5-tert-butyl-2-methanesulfinyl-phenylamine (see U.S. provisional application 60/526,569) in the same manner as Example 1. ESI MS m/z 543 [C30H34N6O2S+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][C:30]([CH3:33])([CH3:32])[O:29][C:27](=[O:28])[NH:22][CH2:23][C:24](=[O:25])[NH:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[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: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of L-Lys(Z)OMe 40 (1.05 g, 2.6 mmol) in dry DMF (40 mL) was added Boc-GlyOH (494 mg, 2.8 mmol), HATU (977 mg, 2.57 mmol), and DIEA (2.03 mL, 11.7 mmol). The mixture was stirred at rt overnight. The solvent was then removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (960 mg, yield 90%). Intermediate 41 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.12 (t, 1H), 7.98 (t, 1H), 7.47-7.38 (m, 5H), 6.98 (t, 1H), 5.13 (s, 2H), 4.56 (m, 1H), 4.05 (d, 2H), 3.65 (s, 3H), 3.02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:20])[N:10]([OH:19])[C:11](=[O:18])[C:12]3[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=3>C(O)C>[OH:19][N:10]1[C:9](=[O:20])[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:16]3[C:17]=2[C:12](=[CH:13][CH:14]=[CH:15]3)[C:11]1=[O:18]
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 77.1 %

Procedure:
Sodium thiomethoxide (0.9 g, 12.0 mmol) was added to a solution of 6-bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione (1.2 g, 4.0 mmol, from Example 4) in ethanol (200 mL). The mixture was refluxed for 48 hours and concentrated. The solid residue was dissolved in water and acidified with concentrated HCl to pH 4. The resulting precipitate was filtered, washed with water, and dried to give 0.8 g of the title compound, mp 301-306° C.;
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21]C)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(/C=C/C=C/C(=O)NCc2ccccc2)ccc1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/C=C/c1ccc(O)c(O)c1)NCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-hydroxy-3-methoxyphenyl)-penta-2,4-dienoic acid benzylamide (118 mg, 0.38 mmol) [Example 5] in 50 mL of dichloromethane, 100 μl of boron tribromide (0.95 mmol) was added dropwise at −78° C. The mixture was stirred for 15 min at −78° C. and for 1 h at room temperature. Water (100 mL) was added, the organic layer was separated, dried with Na2SO4 and evaporated.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:14]=1[CH2:22][CH2:23][CH:24]=O>>[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:14]=1[CH2:22][CH2:23][CH:24]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: CCc1nc(I)cn1CCN
Reactant: COc1cc(F)c(CCC=O)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(OC)cc1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (9.700 mmol) and 3-(2,5-difluoro-4-methoxy-phenyl)-propionaldehyde (2.135 g; 10.670 mmol) afforded 8-[2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.72 min.; [M+H]+=447.67 g/mol.
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH2:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1cc(C2CCC2)nn1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a stirred mixture of 3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 4.69 mmol) and potassium carbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., was added phenyl chloroformate (0.88 g, 5.62 mmol) dropwise. After stirring for a further 30 min at −5° C., the reaction mixture was warmed to rt and stirred for a further 15 h. The mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford an oil. Recrystallization from petroleum ether gave phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.30 g, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 6.53-7.53 (m, 12H), 3.57 (m, 1H), 2.26-2.38 (m, 4H), 1.64-2.07 (m, 2H); LC-MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=2)[C:14]1=[O:26].O=[C:46]1C2C(=CC=CC=2)CC(=O)N1CC(Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:43][C:6]1[CH:5]=[N+:4]([O-:44])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[CH2:46][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:26]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=C(Cl)CN1C(=O)Cc2ccccc2C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1C(=O)Cc2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (40 mg, 0.062 mmol) was dissolved in DCM (2 ml), and added with 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)acetyl chloride (163 mg, 0.686 mmol) and DMAP (84 mg, 0.686 mmol). The reaction was stirred at RT overnight and quenched by addition of HCl. The solution extracted with DCM and washed with NaHCO3 sat. sol., then dried over Na2SO4 and the solvent removed under reduced pressure. The crude was purified by preparative HPLC (Method 2) to yield the titled compound (30.0 mg, 52% yield).). 1H NMR (400 MHz, acetone) ppm 8.19 (s, 2H), 8.09-8.15 (m, 1H), 7.67-7.79 (m, 1H), 7.44-7.61 (m, 2H), 7.15-7.24 (m, 2H), 7.01-7.09 (m, 1H), 6.94 (t, J=75.00 Hz, 1H), 6.01-6.25 (m, 1H), 4.68 (s, 2H), 4.24 (s, 2H), 4.03 (dd, J=6.84, 2.87 Hz, 2H), 3.42-3.60 (m, 1H), 3.20-3.38 (m, 1H), 1.24-1.46 (m, 1H), 0.65 (dd, J=8.16, 1.54 Hz, 2H), 0.43 (d, J=5.73 Hz, 2H); MS/ESI+ 621.3 [MH]+
Reaction SMILES: [Na+].[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])=O.CN(C=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:19])(=[O:16])=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])c1ccc(OCC2CC2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspention of 100 g (399.6 mmol) of 4-cyclopropylmethoxy-benzenesulfonic acid sodium salt, 186.55 ml (2557.5 mmol) of thionyl chloride and 6.19 ml (80 mmol) of DMF are added dropwise at r.t. After stirring for 15 h, the mixture is poured into ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35-0.45 (m, 2H), 0.65-0.75 (m, 2H), 1.25-1.35 (m, 1H), 3.91 (d, 2H, J=7.04 Hz), 7.02 (d, 2H, J=9.04 Hz), 7.96 (d, 2H, J=9.04 Hz).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:15](Cl)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([O:8][C:15]1[C:10]([Cl:9])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([NH2:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(OCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 36.6 %

Procedure:
Benzyl alcohol (12.5 mL, 0.121 mol), 4,5-dichloro-2-nitro-phenylamine (5.00 g, 24.2 mmol), cesium carbonate (15.7 g, 48.3 mmol), and DMA (110 mL) were combined in a sealable pressure vessel. The vessel was purged with dry nitrogen, sealed, and heated at 80° C. for 17 h. The reaction mixture was poured into brine (400 mL) and cooled to 0° C. The resulting precipitate was collected and dissolved in EtOAc (400 mL). The organic layer was washed with water (50 mL) and brine (50 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (1-50% EtOAc/hexanes, dryloaded) to yield the titled compound (2.47 g, 37% yield). MS (ESI/CI): mass calcd. for C13H11ClN2O3, 278.1; m/z found, 279.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.50-7.30 (m, 5H), 6.23 (s, 1H), 6.19 (br s, 2H), 5.16 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:13][CH2:14][CH:15]=[CH2:16])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:13][CH2:14][CH:15]=[CH2:16])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CCCC(=C1C(=O)Nc2cc(Cl)ccc21)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCCC(c1cccc(Cl)c1)C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a yellow slurry of 6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one (Example 62, Step B) (12.81 g, 37.2 mmol) in MeOH (200 mL) at room temperature was slowly added sodium borohydride (1.689 g, 44.7 mmol). Evolution of gas was observed. The yellow reaction mixture was stirred at room temperature for 30 min. Additional sodium borohydride (1.689 g, 44.7 mmol) was slowly added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (200 mL). A precipitate formed and the mixture was sonicated for 15 min then filtered. The filtrate was concentrated under reduced pressure to 36 mL and then extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.