Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:10])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:18])[N:3]=1.[CH3:24][C:25]([NH2:31])([C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:26]>>[CH3:24][C:25]([NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:10])([CH3:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:18])[C:19]([CH3:22])([CH3:20])[CH3:21])[N:3]=1)([CH3:26])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Reactant: CC(C)(C)C(C)(C)N
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(NC(C)(C)C(C)(C)C)n1
Temperature: 185 °C

Procedure:
3.3 g. (9.6 mmole) of 2-chloro-4,6-di(2,3,3-trimethyl-2-butyl)amino-s-triazine and 3.3 g. (30 mmoles) of 2,3,3-trimethyl-2-butylamine are heated at reflux (oil bath 185° C.) for 21 hours. Thin layer chromatography of a sample of the reaction mixture indicates a mixture of starting material and product in a ratio of 3:7. Heating is terminated and the reaction mixture is treated with excess aqueous NaOH. Filtration affords a 4.9 g. of crude beige product. This is digested with 15 ml. of hot acetone, filtered and 2.6 g. of beige solid collected, m.p. 278° C. dec. Recrystallization of this product from hot ethanol gives the pure product, m.p. 317°-321° C. dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 94 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylate (Example 2.3; 4.05 mmol) in methanol (8 ml) and water (8 ml) at rt was added sodium hydroxide (16.2 mmol). The reaction was heated at 50° C. Ethyl acetate was added and the aquous phase was treated with HCl 1N until pH=6-7. Ethyl acetate was added again, the layers were separated and the organic phase was dried with MgSO4 and concentrated. The crude product was obtained in 94% yield, and used in the next step without further purification.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([S:22][CH3:23])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.C[O:25]CCO>>[CH3:23][S:22]([C:21]1[N:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)[C:18]3[C:13]([C:12]2=[N:19][N:20]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:25]
Reactant: COc1ccc(-c2nn3c(SC)nnc3c3ccccc23)cc1
Reactant: COCCO
Product: CS(=O)c1nnc2c3ccccc3c(-c3ccccc3)nn12

Procedure:
This compound is obtained by following the procedure of the foregoing example but substituting 6-phenyl-3-methylthio-1,2,4-triazolo[3,4-a]phthalazine for 6-(4-methoxyphenyl)-3-methylthio-1,2,4-triazolo[3,4-a]phthalazine. M.p. 215°-217° C. (Methylcellosolve®).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][Br:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OCCBr)c(Cl)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A portion (2.3 g, 9.18 mmol) of the 1-(4-amino-2-chlorophenoxy)-2-bromoethane produced in (6) above was dissolved in pyridine (10 ml) and the resulting solution was cooled to 0° C., followed by dripping of methanesulfonyl chloride (1.43 ml, 0.018 mol) and stirring at room temperature for 2 h. Thereafter, the solvent was evaporated and the residue was diluted with an aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried with sodium sulfate and the solvent was evaporated, with the residue being thereafter purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (6.6%) to yield the end compound 1-(2-chloro-4-methanesulfonamidophenoxy)-2-bromoethane (2.78 g) as a pale yellow solid mass.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([CH:33]2[CH2:37][CH2:36][N:35]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[S:17][CH:18]=[CH:19][N:20]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCC(c4ccccc4)C3)nccc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-Chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (from Example 73, step 2; 0.050 g, 0.153 mmol) and potassium carbonate (0.106 g, 0.767 mmol) were dissolved in DMF (1.023 ml). 3-Phenyl-pyrrolidine (0.032 ml, 0.230 mmol) was added and the reaction was stirred overnight at 110° C. The reaction was filtered through a syringe filter and purified via HPLC (25 to 70% MeCN:H2O with 0.1% TFA modifier). The product fractions were combined and concentrated. The material was dissolved in methanol and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed with methanol, then the product was liberated by flushing the column with 2 M ammonia in methanol. The filtrate was combined to afford 1-(3-phenylpyrrolidin-1-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.34 (d, J=8.9 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.71 (dd, J=1.9, 8.9 Hz, 1H), 7.40-7.31 (m, 4H), 7.28-7.22 (m, 1H), 7.19 (d, J=5.6 Hz, 1H), 7.11 (d, J=4.2 Hz, 1H), 6.67 (d, J=4.3 Hz, 1H), 4.12-3.97 (m, 2H), 3.94-3.77 (m, 2H), 3.55-3.42 (m, 1H), 2.42-2.27 (m, 1H), 2.19-2.04 (m, 1H). m/z (ESI) 437.2 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([P:15](OCC)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:14]>C(O)C>[CH2:11]([O:10][C:1]([CH:2]([P:15]([O:16][CH2:17][CH3:18])([CH2:13][CH3:14])=[O:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: CCOP(=O)(CC)OCC
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)P(=O)(CC)OCC
Yield: 90.9 %

Procedure:
172 g of diethyl fumarate are slowly added at 65°-70° C. under nitrogen to a mixture of 140 g of diethyl ethanephosphonate in 46 g of ethanol. After a further 3 hours the solvent (excess ethanol and diethyl ether) is removed by vacuum distillation; the crude product is obtained in a yield of 285 g with a 95.7% purity, which corresponds to a theoretical yield of 90.9%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:17][CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:21][CH2:20][C:19]([N:16]1[CH2:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14][CH2:15]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (S)-(−)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 39, 475 mg) and anhydrous potassium carbonate (303 mg) in methanol (44 mL) is stirred under N2 at ambient temperature for 1.5 hours and then adjusted to pH 7 with aqueous hydrochloric acid (1M) and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 40 g), eluting with a gradient of methanol/chloroform (5/95-10/90), and those fractions with an Rf=0.21 by TLC (methanol/chloroform, 10/90) are pooled and concentrated under reduced pressure. The resulting foam is then triturated with methylene chloride/diethyl ether and the precipitate filtered to give the title compound, Anal. calcd for C19H22N3O5F: C, 58.31; H, 5.67; N, 10.74. Found: C, 58.15; H, 5.64; N, 10.72.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH3:16][NH:17][C:18](NC)=[O:19]>>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:18]([NH:17][CH3:16])=[O:19])=[CH:15][CH:14]=1)#[N:13]
Reactant: N#Cc1ccc(OCCNCCO)cc1
Reactant: CNC(=O)NC
Product: CNC(=O)N(CCO)CCOc1ccc(C#N)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
4-[2-(2-Hydroxyethylamino)ethoxy]benzonitrile (1 g, 0.009 mol; see Preparation C, step (ii) above) and N,N′-dimethylurea (0.43 g, 0.0049 mol) were heated with stirring at 130° C. for 4 h. The reaction was directly purified by column chromatography to yield 0.7 g of the sub-title product as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 0 °C
Yield: 98.9 %

Procedure:
A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromomethyl-benzene (2.01 g, 11.5 mmol), potassium carbonate (1.65 g, 12.0 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Afterwards, ice water (10 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound (3.0 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cc(Br)ccc2n1
Temperature: 90 °C
Yield: 73.8 %

Procedure:
2-Amino-5-bromopyridine (10 g, 57.8 mmol) was dissolved in ethanol (100 mL) and chloroacetone (9.3 mL, 115.59 mmol) was added. The mixture was heated to reflux at 90° C. for 16 h. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography, eluting with a gradient of 0-20% methanol in DCM, to afford the title compound (9 g, 66.4%) as a yellow solid. δH (500 MHz, CD3OD) 9.03 (s, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.79 (d, J 9.4 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17](Cl)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH2:28][O:27][C:26](=[O:29])[CH:25]=1.O>O1CCCC1>[O:29]=[C:26]1[O:27][CH2:28][C:24]([NH:23][C:17](=[O:18])[C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:20])=[CH:25]1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: NC1=CC(=O)OC1
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (0.45 g) and 4-amino-5H-furan-2-one (0.30 g) in dry tetrahydrofuran (10 ml) is refluxed for 2 h. After cooling at room temperature, the reaction mixture is poured into water (200 ml) and the resulting suspension is left under stirring for 1 h. The solid is filtered off and resuspended in methanol (4.3 ml) under stirring for 1 h, then collected by filtration to give N-(5-oxo-2,5-dihydrofuran-3-yl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide (0.27 g).
Reaction SMILES: CC1C=[C:5](C)[N:4]([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH3:24][O:25][CH2:26][CH2:27][C:28]1[O:32]C(N)=[N:30][N:29]=1>>[CH3:24][O:25][CH2:26][CH2:27][C:28]1[O:32][C:5]([NH:4][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:30][N:29]=1
Reactant: COCCc1nnc(N)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Product: COCCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 204° C. and MS: m/e=351.1 (M+H+) was prepared in accordance with the general method of example 44a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:21][CH2:20]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(Cl)nn1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 6-chloropyridazin-3-amine (2.58 g, 20 mmol) and N-Boc-piperazine (22.3 g, 120 mmol). The reaction mixture was heated at 140° C. and stirred for 2 h. It was then cooled to room temperature and the resulting solid was washed with ethyl acetate (100 mL), and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 330a as a yellow solid (3.5 g, 60%). MS: [M+H]+ 280.
Reaction SMILES: [C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3]Cl.[I-:12].[Na+].O>C(#N)C>[C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3][I:12]
Reactant: COCCCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCOC(=O)OCI
Temperature: 55 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Chloromethyl [3-(methoxy)propyl] carbonate (3.7 g) was dissolved in acetonitrile (12 ml), and sodium iodide (12.0 g) was added. The mixture was stirred at 55° C. for 4 hours under an argon atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml) and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain iodomethyl [3-(methoxy)propyl] carbonate (5.0 g) as a pale yellow liquid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[CH2:18]([Sn](CCCC)(CCCC)C#CC)[CH2:19][CH2:20]C>CN(C=O)C.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>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:18]#[C:19][CH3:20])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (Compound 1) (280 mg, 0.79 mmol) and Pd(PPh3)2Cl2 (56 mg, 0.08 mmol) were dissolved in DMF (7.9 ml), followed by addition of tributyl(1-propynyl)tin (481 μl, 1.6 mmol). The reaction mixture was heated at 100° C. for 1.5 hours, concentrated and then purified on a silica gel column (CH2Cl2:MeOH, 50:1, v/v) and by HPLC (34%-35% CH3CN, 13 minutes) to give Compound 2 (125 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])=[CH:20][CH:19]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][O:15][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH:28]=[CH:27][N:26]=[C:25]4[CH3:29])=[CH:22][CH:23]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: Nc1cccc(N2CCNC(CO)C2)c1
Product: Cc1nccn1-c1ccc(COCC2CN(c3cccc(N)c3)CCN2)cc1

Procedure:
In a manner similar to Preparation 19, react 4-(3-aminophenyl)-2-piperazinemethanol with 1-[4-(chloromethyl)phenyl]-2-methyl-1H-imidazole to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:53])[NH:10][CH2:11][C:12]1([C:15]([NH:17][C@@H:18]([CH2:41][C:42]2[CH:47]=[CH:46]C(OC(C)(C)C)=[CH:44][CH:43]=2)[C:19]([N:21]([CH2:33][CH:34](OCC)OCC)[CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:54]([OH:56])=O.O>>[CH2:1]([NH:8][C:9]([N:10]1[CH2:11][C:12]2([CH2:14][CH2:13]2)[C:15](=[O:16])[N:17]2[CH:18]([CH2:41][C:42]3[CH:43]=[CH:44][C:54]([OH:56])=[CH:46][CH:47]=3)[C:19](=[O:20])[N:21]([CH2:22][C:23]3[C:32]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:33][CH:34]12)=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Solvent: O
Product: O=C1C(Cc2ccc(O)cc2)N2C(=O)C3(CC3)CN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To (S)-1-((3-benzylureido)methyl)-N-(3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)cyclopropanecarboxamide (Compound II-1) (188 mg, 0.26 mmol) was added 10%-HCOOH/water (2.0 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 90:10) to obtain the title compound (47 mg, 29%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(=O)C1C(=CC=CC=1)O.C(N(CCCC)CCCC)CCC>[C:11]([OH:13])(=[O:12])[C:4]1[CH:3]=[CH:2][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Solvent: O=Cc1ccccc1O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(O)c1cccc(C(=O)O)c1

Procedure:
53 g (0.32 mol) of isophthalic acid, 53 g (0.27 mol) of trimellitic anhydride, 3 g (0.01 mol) of an azomethine obtained by reaction of 5-amino-isophthalic acid with salicylaldehyde, 0.85 g of tributylamine as catalyst, 196 g (0.7 mol) of 3.3'-dimethyl-4,4'-di-isocyanato-diphenylmethane and 700 g of N-methylprrolidone are stirred for 6 hours at 80° C. Subsequently, 43 g (0.1 mol) of 4,4'-bis-(ethoxalylamino)-diphenylmethane are stirred into the above mixture. The temperature is then raised to 195°C, and agitation is continued for a further 6 hours at this temperature. The fluorocarbon wax suspension as described in Example 2 is added to the trion resin solution so obtained in the same weight ratio.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O-:31])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:35])[F:34])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O[C:39]1C=CC(N2[C@@H](CC(OC)=O)[C@H](C)C(C(F)(F)F)=N2)=CC=1.ClC1C(N2CC[C@H](O)[C@H](C)C2)=CC(OC)=NC=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31][CH3:39])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:34])[F:35])=[N:24]4)=[CH:21][CH:22]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O)cc1
Reactant: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)[O-])cc3)[C@H](C)C2)c(Cl)cn1
Agent: CCCCP(CCCC)CCCC
Agent: COc1cc(N2CC[C@H](O)[C@H](C)C2)c(Cl)cn1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)cc1
Temperature: 50 °C
Yield: 64 %

Procedure:
2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of methyl 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (1J, 4.6 g, 15 mmol) and (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (3.4 g, 13 mmol) in toluene (166 mL) was added tributylphosphine (5.5 mL, 21 mmol). While stirring, (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (5.4 g, 21 mmol) was added portionwise to the reaction mixture, and the resulting mixture was heated at 50° C. for 120 min. The mixture was cooled to rt and 150 mL of hexanes was added to the mixture and a white precipitate formed. The mixture was filtered, and the filtrate was concentrated and was purified via silica gel chromatography to give methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (4.7 g, 8.5 mmol, 64% yield). LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1H), 7.15-7.04 (m, 2H), 7.01-6.89 (m, 2H), 6.30 (s, 1H), 4.49-4.36 (m, 1H), 3.91 (s, 4H), 3.73 (s, 3H), 3.62-3.49 (m, 2H), 3.28-3.15 (m, 1H), 2.95-2.85 (m, 1H), 2.82 (dd, J=16.2, 3.2 Hz, 1H), 2.67 (dd, J=12.3, 9.0 Hz, 1H), 2.43 (dd, J=16.1, 10.3 Hz, 1H), 2.26-2.12 (m, 2H), 1.91-1.78 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:23])[CH:15]=1
Reactant: COC(=O)c1c(Cl)ccnc1C
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Temperature: 100 °C
Yield: 16.6 %

Procedure:
A mixture of methyl 4-chloro-2-methylnicotinate (4 g, 21.55 mmol), (4-chloro-2-fluorophenyl)boronic acid (4.13 g, 23.71 mmol), tricyclohexylphosphine (1.813 g, 6.47 mmol), Pd(OAc)2 (0.484 g, 2.155 mmol) and Cs2CO3 (14.04 g, 43.1 mmol) in DMA (15 mL) was purged with nitrogen for 5 min and heated at 100° C. overnight (14 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®). DMA was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinate (1 g, 3.58 mmol, 17% yield) as a red oil. LC/MS, (ESI) m/z 280.1 [(M+H)+, calcd for C14H12ClFNO2 280.0]; LC/MS retention time (method D): tR=0.80 min.