Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:26])[C:9]=2[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:26])[C:9]=2[C@H:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1 g, 2 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine (0.11 g, 0.4 mmol) in toluene (7 mL) cooled to −20° C. was added a solution of freshly distilled catecholborane (0.29 mL, 2.6 mmol) in toluene (3 mL). After 3 h, saturated Na2CO3 (10 mL) was added, the mixture allowed to warm to room temperature and the layers separated. Following extraction with EtOAc, the combined organic layers were washed with additional saturated Na2CO3 (15 mL portions) until the washing was no longer colored and then once with saturated NH4Cl (15 mL). After drying over anhydrous MgSO4, the solution was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (10-65% EtOAc/Hex) to afford 0.61 g (61%, 98% ee) of the title compound as a colorless amorphous solid. 1H-NMR: 400 MHz, (CDCl3) δ: 7.72 (s, 1H); 7.69 (d, J=2.4 Hz, 1H); 7.50 (m, 2H); 7.37 (d, J=9.2 Hz, 1H); 7.30 (m, 2H); 7.19 (dd, J=9.2, 2.4 Hz, 1H); 5.21 (d, J=2 Hz, 1H); 4.21 (m, 2H); 3.25 (d, J=2 Hz, 1H); 2.53 (s, 3H); 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.Cl.[OH-].[NH4+]>[Fe].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1N
Reaction time: 2 h

Procedure:
2.44 G. of 1-amino-4-benzyloxy-2-nitrobenzene is stirred in 100 ml. methanol and 100 ml. 20% hydrochloric acid with 1.0 g. iron powder at room temperature. After two hours, the mixture is poured into excess ammonium hydroxide solution, the residue extracted with chloroform, filtered under nitrogen, dried over magnesium sulfate, filtered once again, and evaporated to dryness to give 1,2-diamino-4-benzyloxybenzene.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N+:18]([O-])=O)=[N:6][CH2:5]1.O.NN>C(O)C.O1CCCC1.[C].[Pd]>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[NH2:18])=[N:6][CH2:5]1
Reactant: COC(OC)C1CN=C(c2cc3cccc([N+](=O)[O-])c3[nH]2)S1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)C1CN=C(c2cc3cccc(N)c3[nH]2)S1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a solution of 2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-nitro-1H-indole (16.25 g) in ethanol (200 mL) and tetrahydrofuran (100 mL) was added 10% palladium carbon (50% containing water, 2 g) under nitrogen atmosphere, and hydrazine monohydrate (14.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at 80° C. for 20 min, and allowed to cool to room temperature. The palladium carbon was removed by the filtration, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (11.2 g, yield 76%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (50:50, volume ratio). MS: 292 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][SH:3].Cl.[OH-].[K+].Cl[C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:23])[C:11]=2[CH:10]=1.CN1C(=O)N(C)CCC1.Cl>C1(C)C=CC=CC=1.O>[NH2:4][CH2:1][CH2:2][S:3][C:15]1[CH:16]=[CH:17][C:18]2[S:19][C:20]3[C:11](=[CH:10][CH:9]=[CH:22][CH:21]=3)[C:12](=[O:23])[C:13]=2[CH:14]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: NCCSc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
17.0 g. (0.15 mol) of cysteaminium chloride and 19.8 g. (0.3 mol) of potassium hydroxide are boiled for 3 hours on a water separator in 180 ml. of toluene. 24.6 g. (0.1 mol) of 2-chlorothioxanthone and 180 mol of dimethylpropyleneurea are added to the evaporated residue, and the mixture is stirred for 20 hours at 100° C. The reaction mixture is poured into 1 l of 2N hydrochloric acid and the aqueous phase is extracted with ethyl acetate. The aqueous phase then adjusted to pH 10 and extracted with ethyl acetate. Work-up of the organic phase gives 24.0 g. of the analytically pure compound IIIb.
Reaction SMILES: CCCCCC.[H-].[K+].[CH3:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=1[Cl:25]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([N:12]2[CH:13]=[CH:14][C:10]([CH3:9])=[N:11]2)=[CH:20][C:19]=1[Cl:25]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Temperature: 130 °C
Yield: 82.8 %

Procedure:
Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, 2-chloro-4-fluorobenzoic acid methyl ester (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130° C. for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 16 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][N:21]3[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[N:14][CH:13]=1.C([N-]CC)C>CS(C)=O>[Cl:26][C:24]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[S:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])=[C:17]([C:15]2[O:16][C:12]([CH2:11][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:13][N:14]=2)[CH:25]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Reactant: CC(C)N1CCNCC1
Agent: CC[N-]CC
Solvent: CS(C)=O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
DMSO (7 vols, 70 ml) and isopropylpiperazine (1.5 eq, 0.387 wt, 0.431 vol, 4.31 ml, 3.87 g) are charged to a clean vessel. 5-(Bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (1.0 eq, 10 g (9.13 g corrected for assay), 1 wt) is added in 5 portions at 20° C. over 1 hr and the mixture stirred for 1 hr. The mixture is heated to 50° C. and aged for 1 hr, then checked for consumption of starting material by HPLC. Diethylamide (1.2 eq, 0.244 wt, 0.336 vol, 2.44 g, 3.36 ml) is added over 10 mins and the mixture aged for 30 mins, then cooled to 20° C. over 1 hr and further aged for 2 hrs. The thick slurry is filtered and washed with DMSO (2×1.5 vols, 2×15 ml) followed by acetone:water 1:2 (3×2 vols, 3×20 ml). The resultant solid is blown dry on the filter and dried at 60° C. in vacuo to constant weight/temperature to afford 2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole as an off-white solid.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A mixture of triflouroacetaldehyde ethyl hemiacetal (2.58 ml), 2-nitropropane (1.81 ml) and potassium carbonate (111 mg) is stirred at 65° C. (oil bath temperature) for 6 hours followed by 2.5 days at room temperature. The reaction mixture is diluted with water (100 ml) and extracted with methylene chloride (100 ml+5×50 ml). The combined organic layers are dried over sodium sulphate and the solvent is evaporated under reduced pressure. Purification of the liquid residue by flash chromatography on silica gel (eluant n-hexane/ethylacetate 85:15) affords 3-methyl-3-nitro-1,1,1-trifluorobutan-2-ol as an oil (2.005 g)
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=C(N)[N:5]=1.[H-].[Na+].[CH3:14][N:15]([CH:17]=O)[CH3:16]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:17]([N:15]([CH3:16])[CH3:14])[N:5]=1
Reactant: CN(C)C=O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
MeI (0.46 ml, 1.04 g, 7.32 mmol, 2.4 eq) was added to a stirred solution of 4,6-dichloropyrimidin-2-amine (Aldrich, 0.5 g, 3.05 mmol, 1 eq) in 10 ml anhydrous DMF under Ar. After cooling to 0° C., NaH (0.27 g, 6.71 mmol, 2.2 eq) was added. The reaction was stirred at 0° C. to room temperature overnight. The reaction was quenched with water and extracted with Et2O (×1). The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.4947 g (2.58 mmol, 84% yield) of 4,6-dichloro-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: [Cl:1][CH:2]1[CH2:10][CH2:9][C:8]2[C:7](=[NH:11])[NH:6][C:5](=N)[C:4]=2[CH2:3]1.Cl.[C:14]([N:18]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]1[S:20][CH2:21][C:22](=[NH:24])[N:23]=1)([CH3:17])([CH3:16])[CH3:15].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[NH:11]=[C:7]1[C:8]2[CH2:9][CH2:10][CH:2]([Cl:1])[CH2:3][C:4]=2[C:5](=[C:21]2[S:20][C:19]([N:18]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([CH3:15])([CH3:16])[CH3:17])=[N:23][C:22]2=[NH:24])[NH:6]1
Reactant: CC(C)(C)N(C1=NC(=N)CS1)C(C)(C)C
Reactant: N=C1NC(=N)C2=C1CCC(Cl)C2
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CC(C)(C)N(C1=NC(=N)C(=C2NC(=N)C3=C2CC(Cl)CC3)S1)C(C)(C)C

Procedure:
When equivalent amounts of 5-chloro-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-di-t-butylamino-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-5-chloro-4,5,6,7-tetrahydro-3-(2-di-t-butylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 0.905 mmol, 1 equiv), (S)-methyl 2-bromo-2-phenylacetate (207.4 mg, 0.905 mmol, 1 equiv) and potassium carbonate (312.7 mg, 2.26 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, 20% ethyl acetate/hexanes) to afford (S)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (183 mg, 42.3%). MS for C27H33N3O5 m/z 479.57 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.C(OC([N:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([N:32]3[CH2:39][C:36]4([CH2:38][CH2:37]4)[N:35]([S:40](=[O:43])(=[O:42])[NH2:41])[CH2:34][CH2:33]3)[C:26]=2[CH:25]=[CH:24]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:28]1[C:27]2[NH:23][CH:24]=[CH:25][C:26]=2[C:31]([N:32]2[CH2:33][CH2:34][N:35]([S:40]([NH:41][CH:1]=[O:3])(=[O:43])=[O:42])[C:36]3([CH2:38][CH2:37]3)[CH2:39]2)=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Reactant: O=CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=CNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Formic acid (0.24 mmol) was dissolved in dry THF (0.5 mL), added di(imidazol-1-yl)methanone (0.29 mmol) and then stirred at 50° C. for 30 min. before being cooled to rt and added 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (Intermediate 2) (0.24 mmol) and DBU (0.29 mmol). The reaction mixture was stirred at rt for 16 h. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([NH:32][C:33]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1)=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate, 0.061 ml (0.548 mmol) of butyl isocyanate and 5 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. The residue is digested in 5 ml of boiling methanol, cooled to 5° C. and filtered, yielding 3-[4-(n-butylamino-carbonylamino-methyl)-phenylamino]-4-(3-chloro-phenyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 217-218° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH:33]([NH:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][CH2:30][C:29]=2[C:39]=1[O:40][CH3:41]>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:34][CH:33]([NH:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][CH2:30][C:29]=3[C:39]=2[O:40][CH3:41])=[N:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine (110 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a tan foam. Mp: 79-82° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.59 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.61 (t, J=8 Hz, 1H), 7.51 (s, 1H), 7.27 (m, 1H), 6.86 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.63 (m, 2H), 3.29 (m, 4H), 3.00-2.67 (m, 7H) 2.05 (m, 1H), 1.80 (m, 8H), 1.60 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Fc1ccc(Cl)c(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3cc(F)ccc3Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.6 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Chloro-5-fluorobenzyl chloride (55 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-chloro-5-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (3.8 mg, 4%). LRMS (ESI+): m/z [M+CH3CN+H]+ 387.9.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:31]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=[O:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([C:40]([C@@H:39]5[CH2:43][CH2:44][CH2:45][N:38]5[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:41])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C2
Reaction time: 16 h
Yield: 78.7 %

Procedure:
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (50 mg, 0.12 mmol) was stirred in DMF (1 mL) and saturated Boc-L-proline (30 mg, 0.14 mmol), HATU (68 mg, 0.18 mmol) and Et3N (36 mg, 0.36 mmol) were added. After 16 h, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 25 mL/min) to provide the title compound (55 mg, 78%) as a colorless oil: ESI MS m/z 583 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[F:14][CH:2]([F:1])[C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccnc(C(F)F)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(C(F)F)c1F
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(difluoromethyl)-3-fluoroisonicotinate (0.44 g, 2.1 mmol, from Step 4) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.45 g, 11 mmol) in water (10 mL). The reaction was stirred for 2 hours. The reaction mixture was acidified by the addition of a solution of citric acid. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated to afford product, which was used without further purification in Step 6. H NMR (300 MHz, CD3OD): δ 8.57 (d, 1H), 7.99 (dd, 1H), 6.96 (t, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2cnc3ccccc3c2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 44 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoquinoline, the title compound was formed in 44% yield as a white solid, mp 205°-207° C. free base: 1H NMR (CDCl3, 300 MHz) 9.06 (d, J=3.6 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.68 (dd, J=6.0, 5.9 Hz, 1H), 7.54 (dd, J=8.5, 9.0 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 4H), 4.30 (s, 1H), 3.52 (s, 2H), 2.98 (m, 2H), 2.78 (m, 2H), 2.64 (d, J=1.4 Hz, 2H), 2.24 (dt, J=3.9, 11.6 Hz, 2H), 1.99 (s, 1H), 1.83 (m, 2H) MS (CI, CH4) m/z 433 (M+1.17), 415 (4), 211 (12), 89 (100), 79 (45), 73 (13) hydrochloride salt:
Reaction SMILES: [NH2:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[CH2:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13]=[C:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1>CO>[NH2:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[CH2:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:22]=[CH:21][C:12]([CH2:13][CH:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1

Procedure:
To a solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione (0.7 g, 1.6 mmol) in methanol (20 ml) dry Pd/C (0.15 g) was added. After hydrogenating at 60 psi at 40° C. over night, the solution was filtered with Celite and evaporated under reduced pressure to yield quantitatively the title compound. This compound did not show melting in DSC but changes to black colour, in capillary and shrinks at 97-133° C. Compound 2.