Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[CH:19][N:18](C(OC(C)(C)C)=O)[N:17]=4)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:28]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:20]=[CH:19][NH:18][N:17]=4)=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(-c3nc4cc(I)ccc4o3)cc2)n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2oc(-c3ccc(-c4cc[nH]n4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Subsequently, tert-butyl 3-[4-(5-iodo-1,3-benzoxazol-2-yl)phenyl]-1H-1-pyrazolecarboxylate (14.6 mg) was dissolved in chloroform (500 μL), and trifluoroacetic acid (231 μL) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by drying. The thus-obtained white solid was dissolved in chloroform, and the solution was washed sequentially with 1N aqueous sodium hydroxide, water, and saturated saline, followed by drying over magnesium sulfate. The solvent was evaporated under reduce pressure, and the solid was recovered through filtration by use of isopropyl ether, followed by drying under reduced pressure, to thereby yield the title compound (9.8 mg).
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[C:16]1([C:22]2(OC)[CH2:26][CH2:25][C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(OC)O2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[N:2]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:12]=3[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]4)[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC1(c2ccccc2)CCC(OC)(c2ccccc2)O1
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Agent: [Cl-]
Product: O=c1[nH]c2cc(Cl)c(-n3c(-c4ccccc4)ccc3-c3ccccc3)cc2[nH]c1=O

Procedure:
16.5 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 16.5 mmol of 2,5-diphenyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C.CC(C)=O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)=[C:17]([S:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:5]([NH:4][CH2:3][CH2:2][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:6])[CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:22]=1)#[N:24]
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCCl)CC2)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCN3CCOCC3)CC2)c1
Reaction time: 3 h
Yield: 65.5 %

Procedure:
1-(2-chloroethyl)-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)-phenylsulfonyl)piperidin-4-yl)urea (838 mg), potassium carbonate (655 mg, 3.0 eq.) and morpholine (413 mg, 3.0 eq.) were dissolved in acetonitrile (25 mL) and heated to reflux. After three hours, the reaction was complete (confirmed by HPLC). The mixture was then concentrated in vacuo, the solid triturated with dichlormethane and isopropyl ether to obtain a white powder. The powder was suspended in hot acetone, cooled in an ice bath, filtered, and washed with water to obtain the product as a white powder (601 mg, 65% yield, 97% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].CN1C=CN=C1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: C=CC(C)=O
Agent: Cn1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 70 °C
Reaction time: 11 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (600 mg, 1.69 mmol) and methyl vinyl ketone (0.42 ml, 5.18 mmol) were added to a solution of 1-methylimidazole (7 μl, 0.085 mmol) in DMSO (6 ml). The reaction mixture was stirred at 70° C. for 11 h. Then water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-98:2) to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.21 (3H, d), 2.16 (3H, s), 2.92 (2H, t), 4.26 (2H, t), 4.28 (1H, distorted dd), 4.39 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (1H, d), 7.50 (1H, d), 7.52 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](O)=[O:34])[C:27]=2[O:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[C:27]4[O:26][CH2:25][O:24][C:28]=4[CH:29]=[CH:30][CH:31]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1OCO2
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=481.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][Li])=[CH:5][CH:4]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: [Li]CSc1ccc(OC)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Using the apparatus and procedure of Example I, 100 ml. of an approximately one-molar solution of (p-methoxyphenylthio)methyllithium in hexane-THF solvent is added dropwise with stirring to 0.1 mole of tributyltin chloride dissolved in THF. The temperature is maintained by means of an ice bath in the range of from 0° C to 10° C. Following the complete addition over a one-quarter hour period, the reaction mixture is stirred for two hours at room temperature and hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by vacuum distillation yields the desired product, (p-methoxyphenylthiomethyl)tributyltin.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:36])([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:25][CH:26](Cl)[CH3:27].C(O)(C)C.CCCCCC.[K+].[Br-]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCOC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCCCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 11, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl hexyl carbonate (2.85 g, 13.6 mmol) were converted to chromatographed title product, isolated as a yellow solid which was crystallized from isopropyl alcohol/hexane (280 mg, 0.5 mmol, 6.1%): mp 86°-87° C.; IR (KBr) 1764, 1678 cm-1 ; 1H NMR (CCl3) delta 0.87 (t, J=7 Hz, 3H), 1.05-1.39 (m, 6H), 1.41-1.60 (m, 2H), 1.75 (d, J=6 Hz, 3H), 3.10 (s, 3H), 4.00 (t, J=7 Hz, 2H), 6.36 (q, J=6 Hz, 1H), 7.06-7.17 (m, 1H), 7.63-7.86 (m, 5H), 8.31-8.42 (m, 2H), 9.39 (br s, 1H); precise mass calcd for C24H29N3O7S m/e 503.1737, found 503.1761.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])O[CH2:7][CH2:6]2.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[O:35][CH3:36])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]3=[O:13])=[CH:30][C:29]=2[O:35][CH3:36])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccc2c(c1)CCOC2=O
Reactant: COc1cc(N)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)c(OC)c1)C2=O

Procedure:
6-Methoxy-isochroman-1-one and 4-(4-amino-2-methoxyphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester were reacted according to Method AC. In this way the product was obtained with molecular weight 481.60 (C27H35N3O5); MS (ESI): 482 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][CH:46]([F:48])[F:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:47][CH:46]([F:48])[CH2:45][NH:44][C:42]([CH2:41][NH:40][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:29])([F:27])[F:28])[O:14][N:13]=2)=[C:16]2[CH2:25][CH2:24][CH2:23][C:17]=12)=[O:21])=[O:43]
Reactant: NCC(=O)NCC(F)F
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of compound 3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (3 g, 6.4 mmol) in acetonitrile (30 mL) is added N,N-diisopropylethylamine (2.5 g, 19 mmol), 2-amino-N-(2,2-difluoro-ethyl)-acetamide hydrochloride (1.34 g, 7.7 mmol) and HATU (3.7 g, 9.6 mmol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (3 g, 88%). MS (m/z): 588.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[N:39]=[CH:38][C:37]([F:43])=[CH:36]4)=[CH:29][C:28]=2[CH3:44])[C:23]([F:26])([F:25])[F:24])[N:3]=1.Br[C:46]1C=CC(C(O)=O)=C(CC)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[N:39]=[CH:38][C:37]([F:43])=[CH:36]4)=[CH:29][C:28]=2[CH2:44][CH3:46])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: Cc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F
Reactant: CCc1cc(Br)ccc1C(=O)O
Product: CCc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 59c) starting with 4-bromo-2-ethylbenzoic acid in place of 4-bromo-2-methylbenzoic acid.
Reaction SMILES: [H-].[K+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][C:18]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[O:19])[C:11](=[O:15])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C1CN(c2ccncc2)CCN1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dispersion of potassium hydride in mineral oil (35% w/w, 0.63 g) was added to a stirred suspension of 4-(4-pyridyl)piperazin-2-one (0.885 g) in DMF (10 ml) and the mixture was stirr-ed at room temperature for 2 hours. To the anion thus formed, was added methyl 4-bromoacetylphenoxyacetate (1.44 g) and the mixture was stirred at room temperature for 20 hours. Solvent was evaporated and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography, the product being eluted with 1/9/0.1 v:v:v methanol/dichloromethane/0.88 S.G aqueous ammonia. Recrystallisation from ethyl acetate gave the title compound, m.p. 164°-165° C.; NMR (d6DMSO) δ 8.2(2H,d), 7.97(2H,d), 7.08(2H,d), 6.83(2H,d), 4.93(4H,d), 4.02(2H,s), 3.71(3H,s), 3.7(2H,m), 3.52(2H,m); m/e 384 (M+H)+ ; calculated for C20H21N3O5 : C, 62.7; H, 5.52; N, 11.0. Found: C, 62.6; H, 5.6; N, 10.9%.
Reaction SMILES: [C:1]([C:3](=[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)SC)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:27][NH2:28]>CCO>[NH2:2][C:1]1[NH:28][N:27]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(Nc1ccc(N2CCN(C(C)C)CC2)cc1)=C(C#N)C(N)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(Nc3n[nH]c(N)c3C(N)=O)cc2)CC1
Temperature: 75 °C

Procedure:
2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamide was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a purple powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)[Cl:27]>Cl>[ClH:27].[F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Reactant: ClCCl
Agent: Cl
Product: Fc1cc(F)c(C(F)(F)F)c(C2CCNCC2)c1
Yield: 63 %

Procedure:
A solution of tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (27, 0.590 g, 1.61 mmol) in CH2Cl2 (10 mL) and HCl (2.0 N solution in Et2O, 10 mL) stirred at ambient temperature for 18 h. The resulting solids were filtered to afford 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (28) as a white solid (0.309 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.01-6.94 (m, 1H), 6.94-6.76 (m, 1H), 3.82-3.60 (m, 2H), 3.42-3.02 (m, 3H), 2.22-1.99 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][C:37]=1[CH3:51]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:49])([CH3:50])[CH2:46][O:47][CH3:48])=[CH:38][C:37]=2[CH3:51])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COCC(C)(C)COc1cc(C)c(Br)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COCC(C)(C)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-5-(3-methoxy-2,2-dimethylpropoxy)-1,3-dimethylbenzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=1.12 min; Mass spectrum (ESI+): m/z=563 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)=[O:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:23]4[CH:22]=[C:21]5[C:26](=[CH:25][CH:24]=4)[NH:18][CH:19]=[CH:20]5)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]ccc5c4)cc3)[nH]c2c1

Procedure:
Compound 661 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:30]4([CH2:29][CH2:28][O:27][CH3:26])[CH2:32][CH2:31]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4OC)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 159 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ 0.58-0.74 (m, 4 H) 1.80 (t, J=6.9 Hz, 2 H) 3.14 (s, 4 H) 3.39 (t, J=7.1 Hz, 2 H) 3.89 (s, 3 H) 7.32-7.44 (m, 2 H) 8.27-8.35 (m, 2 H) 8.42 (d, J=8.8 Hz, 1 H) 8.57 (d, J=7.6 Hz, 1 H) 8.76 (s, 1 H) 8.80 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 434.5.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[CH3:33])[N:26]([CH3:34])[CH:25]=2)[C:19]2[C:14]1=[N:15][C:16]([CH:35]1[CH2:37][CH2:36]1)=[N:17][CH:18]=2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[Li+].[OH-].Cl>C1COCC1.O>[CH:35]1([C:16]2[N:15]=[C:14]3[C:19]([N:20]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[CH3:33])[N:26]([CH3:34])[CH:25]=4)[C:21](=[O:22])[N:13]3[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:38])=[O:3])=[CH:18][N:17]=2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C3CC3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](CC(=O)O)c3ccccc3)c3nc(C4CC4)ncc31)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
(R)-3-[2-Cyclopropyl-7-(1,4-dimethyl-1H-indol-3-ylmethyl)-8-oxo-7,8-dihydro-purin-9-yl]-3-phenyl-propionic acid ethyl ester (130 mg, 0.255 mmol) was dissolved in THF (3 ml). To the solution a concentrated solution of LiOH in water (2 ml) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction mixture was neutralized with 1N HCl, and then extracted with ethyl acetate 3×. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The white solid obtained was purified by prep TLC, eluded with 10% methanol in dichloromethane to give the title compound (52 mg, 43%). LCMS, M++1, m/z: 481.54
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[O:38][CH:39]=[CH:40][N:41]=4)=[CH:33][C:32]=3[CH2:42][NH:43][CH3:44])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[O:17][N:16]=1.CN1CCOCC1.[F:52][C:53]([F:59])([F:58])[CH2:54][C:55](O)=[O:56].OC1C2N=NNC=2C=CC=1>CN(C=O)C>[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:38][CH:39]=[CH:40][N:41]=3)=[CH:33][C:32]=2[CH2:42][N:43]([CH3:44])[C:55](=[O:56])[CH2:54][C:53]([F:59])([F:58])[F:52])(=[O:24])=[O:23])[O:17][N:16]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(F)(F)F)c1C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC, 50 mg; 0.26 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg; 0.21 mmol, prepared as in Step (A) of Example 28), N-methylmorpholine (0.80 ml; 0.73 mmol), 3,3,3-trifluoropropionic acid (33 mg; 0.26 mmol), and hydroxybenzotriazole (HOBT, 40 mg; 0.26 mmol) in DMF at 0° C. After 18 hours at room temperature, the reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with saturated KHSO4 (2×30 ml), water (30 ml), brine (30 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 2.5×12 cm silica gel column using 1000 ml EtOAc:Hex, 3:1 and 500 ml EtOAc as the mobile phase. The pure fractions were concentrated to afford 49 mg (43%) of the title compound of this Example as a white powder.