Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7]C2CCCCC2)[CH2:6][CH2:5][CH2:4]CC1.C(O[C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27]([OH:29])=[O:28])=O)C1C=CC=CC=1.COC(=O)C[N:42]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:34]([O:33][C:31]([NH:30][CH:26]([CH2:25][NH:24][C:22]1[C:4]([NH2:42])=[CH:5][CH:6]=[CH:1][N:7]=1)[C:27]([OH:29])=[O:28])=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1N)C(=O)O

Procedure:
(2S) 2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)propionic acid was prepared by a similar method to (2S) 2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1.[CH3:33]O>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:3]([CH3:33])(=[O:5])=[O:2])[N:20]=2)=[CH:12][CH:13]=1
Reactant: CSc1nccc(-c2[nH]c(-c3ccccc3)nc2-c2ccc(F)cc2)n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Product: CS(=O)(=O)c1nccc(-c2[nH]c(-c3ccccc3)nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
An aqueous solution (40 mL) of Oxone (10.4 g) is added dropwise to a stirred ice-cold solution of 4-(4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl)-2-(methylthio)pyrimidine, 75 (2.1 g) in methanol (40 mL). After stirring for 4 h at room temperature, the methanol is evaporated, the solution diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. Evaporation of the solvent furnishes the title compound, 76 (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[NH2:19]/[C:20](/[CH3:36])=[CH:21]\[C:22]([O:24][CH2:25][CH2:26][N:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28])=[O:23]>CC(O)C>[CH3:36][C:20]1[NH:19][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[Cl:1])[C:21]=1[C:22]([O:24][CH2:25][CH2:26][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:28])=[O:23]
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(F)c1Cl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc(F)c1Cl
Yield: 60.9 %

Procedure:
A mixture of 460 mg of 2-chloro-3-fluorobenzaldehyde, 360 mg of methyl 3-aminocrotonate and 820 mg of 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate in 4 ml of 2-propanol was refluxed for 8 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel to provide 860 mg of the desired compound (110).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[CH2:19][O:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-].O>CCO>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (500 mg, 1.3 mmol), NaN3 (111 mg, 1.7 mmol), NH4Cl (91 mg, 1.7 mmol), were combined in 4 ml of EtOH and 1 ml of H2O and heated to 80° C. overnight. Upon completion, the EtOH was evaporated and the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4 and concentrated. The material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C@@H:4]([OH:21])[CH2:3][C@H:2]([NH:1][C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][CH3:35])=[O:38])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](N)Cc1ccc(-c2ccccn2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A solution of the product of Example 1E (1.7 g) in THF (33 mL) was treated with the product of Example 1F (0.81 g, 4.3 mmol), DEPBT (1.5 g, 5.0 mmol), and N,N-diisopropylethylamine (2.9 mL, 16.6 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (1.55 g, 74% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCC=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.25 g (4.32 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.39 ml (4.32 mmol) of 1-butanal in 20 ml of ethanol, 0.036 ml (0.43 mmol) of pyrrolidine was added at 60° C., followed by refluxing for 19 hours (1 and 2 hours later, 0.39 ml (4.32 mmol) was further added; 3 hours later, 0.39 ml (4.32 mmol) of 1-butanal and 0.036 ml (0.43 mmol) of pyrrolidine were further added). After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4), after which the solvent was distilled off, to yield 0.17 g (11.5%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH:19]([CH3:30])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:18]([CH:19]([CH3:30])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:3]([CH2:2][Cl:1])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2cc(Br)ccc12
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: CC(CCO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.2 %

Procedure:
A solution of chloroacetyl chloride (16.1 g, 142 mmol) in chloroform (120 mL) was added dropwise to a solution of 7-bromo-N4-[3-(tert-butyldimethylsilanyloxy)-1-methylpropyl]quinoline-3,4-diamine (54.96 g, 129.5 mmol) in chloroform (500 mL), and the reaction was stirred for three days at room temperature. The solvent was removed under reduced pressure, and the intermediate amide was heated at reflux for two hours in glacial acetic acid (600 mL). The acetic acid was removed under reduced pressure, and the residue was passed through a plug of silica gel (eluting with dichloromethane) to provide 9.53 g of 7-bromo-1-[3-(tert-butyldimethylsilanyloxy)-1-methylpropyl]-2-chloromethyl-1H-imidazo[4,5-c]quinoline and a mixture of three other products. The mixture of products was dissolved in glacial acetic acid and heated at reflux for two days. The acetic acid was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 0% to 5% 2 M methanolic ammonia in dichloromethane) to provide 9.14 g of 3-{2-[(acetyloxy)methyl]-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl}butyl acetate.
Reaction SMILES: [CH2:1]([S:3]([N:6]([CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])(=[O:5])=[O:4])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52]([N:54]([CH2:57][CH2:58][NH2:59])[CH2:55][CH3:56])[CH3:53]>CN(C=O)C.CC(=O)OCC.O>[CH2:52]([N:54]([CH2:55][CH3:56])[CH2:57][CH2:58][NH:59][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)[CH3:53]
Reactant: CCS(=O)(=O)N(CCCCC(=O)O)C1CC(C)(C)Oc2ccc(C)cc21
Reactant: CCN(CC)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)CCCCN(C1CC(C)(C)Oc2ccc(C)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of 0.3 g (0.78 mmol) of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid, 0.11 g (0.78 mmol) of HOBT and 0.18 g (0.86 mmol) of DCC in 4 ml of DMF is stirred at 0° C. for 1 h. 0.09 g (0.78 mmol) of diethylaminoethylamine is then added and the mixture is stirred overnight at RT. It is treated with 50 ml of water and 50 ml of EA, and the organic phase is washed twice with 25 ml each of saturated sodium bicarbonate solution and additionally twice with water. After drying over magnesium sulfate and concentrating in vacuo, 0.3 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid (2-diethylaminoethyl)amide is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][P:5]([OH:40])([O:7][C@@H:8]([CH3:39])[C:9]([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)=[O:10])=[O:6].[CH3:41][N:42]([CH3:44])[CH3:43]>C1(C)C=CC=CC=1>[OH-:4].[CH3:27][CH:26]([CH2:25][CH2:24][CH2:23][C@H:22]([C@@H:21]1[C@:30]2([CH3:38])[C@H:18]([C@H:17]3[C@H:33]([CH2:32][CH2:31]2)[C@:34]2([CH3:37])[C:14]([CH2:13][C@@H:12]([O:11][C:9]([C@@H:8]([O:7][P:5]([OH:40])([O:4][CH2:3][CH2:2][N+:42]([CH3:44])([CH3:43])[CH3:41])=[O:6])[CH3:39])=[O:10])[CH2:36][CH2:35]2)=[CH:15][CH2:16]3)[CH2:19][CH2:20]1)[CH3:29])[CH3:28]
Reactant: CN(C)C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)[C@H](C)OP(=O)(O)OCCBr)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)[C@H](C)OP(=O)(O)OCC[N+](C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Product: [OH-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.7 g of cholest-5-en-3β-yl (S)-2-[[(2-bromoethoxy)hydroxyphosphinyl]oxy]propionate in 15 ml of toluene is treated with 15 ml of trimethylamine in a dry-ice bath. The mixture is heated to 60° C. for 30 hours. After cooling the reaction mixture is taken up in toluene and concentrated. The residue is taken up in 30 ml of methanol, treated with 2 g of silver carbonate and stirred at 50° C. for 0.5 hour. The precipitate is filtered off, concentrated and there is obtained 0.6 g of O-[[(S)-1-[(cholest-5-en-3β-yloxy)carbonyl]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt, MS: 624 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:51]=[C:52]([CH3:54])[CH3:53]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:18]([C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([C:14]([F:24])([F:23])[F:13])[CH:16]=1)[CH2:51][C:52]2([CH3:54])[CH3:53])=[O:12])[CH3:2]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(F)(F)F)c1)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of 4-aminobenzoic acid ethyl ester (3.3 g, 20 mmol), 3-trifluoromethyl benzaldehyde (3.48 g, 20 mmol) and ytterbium(III) triflate hydrate (1.86 g, 3 mmol) in acetonitrile (150 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (5.6 g, 100 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 40%) as a white solid: MS (ESI) M+1=378.3.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:43][C:44](=[O:46])[CH3:45].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH2:43][C:44](=[O:46])[CH3:45])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CCCN3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN1CCN(CCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 50 °C
Yield: 12.9 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with K2CO3 (33 mg, 0.24 mmol) followed by the addition of chloroacetone (15 μL, 0.19 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (10.8 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.29 (m, 5H), 7.13 (d, 1H), 6.59 (s, 1H), 5.64 (s, 2H), 3.27 to 3.24 (m, 1H), 3.09 (s, 2H), 2.87 (t, 2H), 2.36 to 2.23 (m, 9H), 2.04 (s, 3H), 1.88 to 1.79 (m, 2H); ES-MS m/z 523.2 [M+H]+, RT (min) 2.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(Cl)(=[O:16])CCCC.N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:19]([O:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=[C:2]([OH:1])[CH:7]=1)(=[O:16])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COc1cc(O)cc(O)c1
Reactant: c1ccncc1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Oc1cc(O)cc(OC)c1

Procedure:
One equivalent of 3,5-dihydroxyanisole was reacted with one equivalent of valeroyl chloride in pyridine as solvent for a period of one hour by the reaction scheme shown in FIG. 2. The solvent pyridine was removed from the reaction mixture to give 3-hydroxy-5-methoxyphenyl valerate (the monoester) and 5-methoxyphenyl-1,3-divalerate (the diester) in approximately equal amounts.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOCC>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of phenol (1.88 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.39 g of the product 430.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:27]([N:35]=[C:36]=[O:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[C:27]([NH:35][C:36](=[O:37])[NH:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCOC(=O)c1c(N)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(NC(=O)NC(=O)c2ccccc2)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
To a solution of ethyl 2-amino-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (38.9 mg, 0.1 mmol) in toluene (5 mL) was added benzoyl isocyanate (14.7 mg, 0.1 mmol). The reaction was stirred at RT for 2 h then diluted with EA (5 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give ethyl 2-(3-benzoylureido)-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (12 mg, 22% yield) as a white solid. 1H NMR (DMSO-d6) δ: 12.41 (s, 1H), 11.51 (s, 1H), 8.10 (d, J=7.4 Hz, 2H), 7.75 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.7 Hz, 2H), 7.60-7.51 (m, 3H), 7.48 (d, J=6.9 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H). LCMS: MH+ 537 and TR=2.962 min.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:14][C:15]([C:17]1[CH:45]=[C:20]2[N:21]=[C:22]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[N:19]2[N:18]=1)=[O:16])[CH2:8][O:9]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:22]2[CH:23]=[C:24]([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][CH:30]=3)[N:19]3[N:18]=[C:17]([C:15]([NH:14][CH:7]([CH2:8][OH:9])[C:6]([OH:46])=[O:5])=[O:16])[CH:45]=[C:20]3[N:21]=2)=[CH:39][CH:40]=1
Reactant: CC(C)(C)OCC(NC(=O)c1cc2nc(-c3ccc(Cl)cc3)cc(-c3ccc(Oc4ccccc4)cc3)n2n1)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CO)C(=O)O)c1cc2nc(-c3ccc(Cl)cc3)cc(-c3ccc(Oc4ccccc4)cc3)n2n1
Yield: 93 %

Procedure:
A sample of 3-tert-butoxy-2-{[5-(4-chloro-phenyl)-7-(4-phenoxy-phenyl)-pyrazolo[1,5-α]pyrimidine-2-carbonyl]-amino}-propionic acid tert-butyl ester was treated with 1 mL of 95:5 trifluoroacetic acid (TFA):H2O, and the resulting solution was stirred at rt for 1.5 h, after which time it was quenched by the addition of 2 mL of 1:1 acetonitrile:water. The mixture was then concentrated and lyophilized to afford 11.2 mg (93% yield over 2 steps) of desired 2-{[5-(4-chloro-phenyl)-7-(4-phenoxy-phenyl)-pyrazolo[1,5-α]pyrimidine-2-carbonyl]-amino}-3-hydroxy-propionic acid, as a solid whose 1H NMR spectrum was consistent with its structure. For entry 260: LC-MS calcd. for C28H21ClN4O5 [M+H]+: 529.12; found: 529.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[S:21]>C(O)(=O)C.C(OCC)(=O)C.CCOCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:7](=[O:9])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[NH:11][C:20]1=[S:21]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: S=C=Nc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Yield: 71.9 %

Procedure:
A solution of 1.04 g (6.71 mmol) of 5-fluoroanthranilic acid and 1.13 g (6.71 mmol) of 2-chlorophenylisothiocyanate in 10 ml of glacial acetic acid was refluxed for 2.5 hours. The reaction mixture was cooled and the acetic acid was evaporated to give a yellow solid residue, which was taken up in ethyl acetate and ether. The solid was filtered off and washed with ether and air dried to give 1.48 g (72%) of the desired product, m.p. 295-297° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(N)n1

Procedure:
2,4,6-triamino-5-nitrosopyrimidine was prepared by dissolving 1.0 mole of 2,4,6-triaminopyrimidine in 1040 ml of water and 1.5 moles of acetic acid, maintaining the temperature in the range of about 0°-16° C. Then 1.0 mole of sodium nitrite was added to the reaction mixture while controlling the reaction temperature in the range of 0°-20° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1O[CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:27])[C:18](=[O:26])[N:19]([CH3:25])[C:20](=[O:24])[C:21]=1[CH2:22][CH3:23].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(Cl)Cl.C(OCC)(=O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([O:33][CH:2]([CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:27])[C:18](=[O:26])[N:19]([CH3:25])[C:20](=[O:24])[C:21]=1[CH2:22][CH3:23])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:32]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCc1c(NCCN)n(C)c(=O)n(C)c1=O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1c(NCCNCC(COc2ccccc2)OC(=O)/C=C/C(=O)O)n(C)c(=O)n(C)c1=O
Reaction time: 24 h

Procedure:
3.3 g. Phenyl glycidyl ether and 10 g. 4-(2-aminoethylamino)-1,3-dimethyl-5-ethylpyrimidine-2,6(1H,3H)-dione are mixed and left to stand for 24 hours at ambient temperature. The reaction mixture is dissolved in methylene chloride and purified chromatographically with silica gel, using the elution agent methylene chloride-ammonia-saturated methanol (9:1 v/v). By evaporation of the pure fractions, there are obtained 5.5 g. of a yellowish oil. This is dissolved in ethyl acetate, whereafter a solution of 1.7 g. fumaric acid in ethyl acetate is added thereto. After crystallization has taken place, the crystals are filtered off with suction and recrystallized from ethanol. There are obtained 2.8 g. (26% of theory) of the desired product in the form of colorless crystals; m.p. 138°-139° C. (bubble formation).