Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=O)(O)O.C([CH:7](CC)[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[O:9])C.[H-].[Na+].[F:21][C:22]([F:38])([F:37])[C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.C(OCC)C>C1COCC1.O>[CH:11]([N:10]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:9])[CH:7]=[C:25]([C:24]1[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=1[C:22]([F:38])([F:37])[F:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:13])[CH3:12]
Reactant: CCC(CC)C(=O)N(C(C)C)C(C)C
Reactant: O=C(c1ccccc1)c1ccccc1C(F)(F)F
Agent: O=[PH](O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)N(C(=O)C=C(c1ccccc1)c1ccccc1C(F)(F)F)C(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of diethyl N,N-diisopropylacetamide phosphonate (8.4 g, 30 mmol) in THF (20 mL) was added dropwise to sodium hydride (80%, 0.85 g, 29 mmol) during 30 min, keeping the temperature below 30° C. A solution of 2-trifluoromethyl-benzophenone (5.0 g, 20 mmol) in THF (20 mL) was added and the reaction mixture was heated to 50° C. and kept at that temperature for 16 h. A second portion of the phosphorous ylide (15 mmol), prepared as above, was added. After another 24 h at 50° C. the mixture was partioned between diethyl ether and water. The etheral layer was evaporated and the residue chromatographed on silica (toluene-ethyl acetate 9:1) yielding 3.0 g (41%) as a mixture of the E- and Z-isomers. Labels a and b refer to the different isomers. 1H NMR (CDCl3-d) δ0.80 (d, 6Ha), 1.08 (d, 3Hb), 1.24 (t, 6Hb), 1.31 (d, 3Hb), 1.44 (d, 6Ha), 3.32 (m, 1Ha), 3.34 (m, 1Hb), 4.19 (m, 1Hb), 4.32 (m, 1Ha), 6.04 (s, 1Ha), 6.65 (s, 1Hb) and 7.18-7.75 (m, 9Ha, 9Hb).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:20])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.3 %

Procedure:
To a solution of 5-bromo-2-methoxybenzaldehyde (2.4 g, 11.2 mmol) in 50 mL CH2Cl2, m-chloroperbenzoic acid (70-75%, 7 g, 28.4 mmol pure m-CPBA,) was added and the mixture was stirred at ambient temperature for 2 days. The reaction was quenched with aqueous saturated NaHCO3 solution and extracted with ethyl acetate (50 mL×3). The organic extract was dried with anhydrous sodium sulfate and filtered through a silica gel bed. Evaporation of the solvent gave compound 35 (2.1 g) in 92% yield; mp 62-64° C.; 1H NMR (CDCl3) δ3.87 (3H, s), 6.71 (1H, d, J=8.6), 6.97 (1H, dd, J1=8.6, J2=2.4), 7.07 (1H, d, J=2.4); 13C NMR δ56.59, 112.36, 113.75, 118.33, 123.29, 146.37, 146.98.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10])=[O:4].I[C@@:14]1([N:23]2[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]2=[O:25])[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17](O)[C@H:15]1O.CO>ClCCl>[F:1][C:2]([F:11])([F:12])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:29]1[C:27](=[O:28])[NH:26][C:24](=[O:25])[N:23]([CH:30]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[CH2:17][CH2:15]1)=[O:4]
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C#CCCCNC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
5-Trifluroacetamido-1-pentyne (59) was coupled for 4 h to 5-iodo-2',3'-dideoxyuridine (47, prepared as described in Example 2A) according to the general procedure described in Example 1C. Chromatography on silica gel (100 g) with a 0-5% methanol in dichloromethane gradient afforded 647.7 mg of alkynylamino nucleoside 58 as a light tan foam. This material was homogeneous by TLC and NMR except for the presence of about 16 mole % of dimethylformamide. Correcting for the presence of dimethylformamide, the yield of desired product was 80%.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CC(C)CSc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCN(CC=C)C(=O)n1cnc(SCC(C)C)n1

Procedure:
A mixture of 7.85 g. 3-isobutylthio-1,2,4-triazole, 10.97 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 11 ml. dry triethylamine was refluxed under anhydrous conditions for 48 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride. An oily residue was obtained which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-isobutylthio-1,2,4-triazole, b.p. 116° - 118°C./0.5 mm. (96.0% 1-isomer by GLC assay).
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH:18][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC(=O)NCc1ccc(F)c(F)c1

Procedure:
A solution of ethyl4,4-dimethyl-3-oxopentanoate (Alfa Aesar, 2.4 g, 14 mmol) and 3,4-difluorobenzylamine (Aldrich, 2.0 g, 14 mmol) in toluene (15 ml) was refluxed for 24 h. The solvent was removed to yield the title compound as an off-white wax. Used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[CH2:22]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:37][CH:38]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH2:31][CH2:30][O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:34]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: CC1(C)OB(c2cccc(OCCOCc3ccccc3)c2)OC1(C)C
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3cccc(OCCOCc4ccccc4)c3)cn2)C1
Yield: 28 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (example 7, step 1) (600 mg, 1.15 mmol) was reacted with 2-[3-(2-benzyloxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.5 equiv). Crude product purified by flash chromatography on silica gel eluting with 4:1 ethyl acetate:hexane to afford title compound (214 mg, 28%) as a brown foam.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#N)[CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:31].[OH2:35]>CS(C)=O>[CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:31])=[O:35])[CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Solvent: CS(C)=O
Product: O=C(O)c1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Yield: 58 %

Procedure:
To a solution of 3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (120 mg, 0.32 mmol, prepared in Example 53) in DMSO (15 ml) was added 50% sulfuric acid (5 ml), and the mixture was heated under reflux for 2.5 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-benzyl-5-(3-carboxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (73 mg, 58%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8]>>[Cl-:5].[C:7]([C:6]([S:3][C:2]([NH2:4])=[NH2+:1])([CH3:11])[CH3:10])([OH:9])=[O:8]
Reactant: NC(N)=S
Reactant: CC(C)(Cl)C(=O)O
Product: CC(C)(SC(N)=[NH2+])C(=O)O
Product: [Cl-]
Yield: 74 %

Procedure:
Example 1 was repeated with thiourea and 2-chloro-2-methylpropionic acid, affording the title compound in a yield of 74%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[NH:13][N:12]=[CH:11][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>C(#N)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:8]([F:7])([F:19])[F:20])=[N:13]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Yield: 99.9 %

Procedure:
According to Scheme 1, Step 1: K2CO3 (11.5 mmol, 1.59 g) was added to a solution of ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (7.69 mmol, 1.60 g) in acetonitrile (24 mL) followed by 1-(chloromethyl)-4-methoxybenzene (8.46 mmol, 1.15 mL) and the reaction mixture was heated under reflux for 4.5 hours. After evaporation of the solvent, the reaction mixture was diluted with brine and EtOAc. The aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (7.68 mmol, 2.52 g, 100%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[O:31][CH2:32][CH:33]([F:35])[F:34])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:35][CH:33]([F:34])[CH2:32][O:31][C:18]1[C:19]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:36])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 0.450 mmol of 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, and the crude acid was recrystallized from acetonitrile to afford 192 mg (0.378 mmol, yield: 58%) of 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid was isolated as a white solid. 1H NMR (CDCl3), δ: 7.81 (dd, J=7.3, 1.5 Hz, 1H), 7.45 (m, 4H), 7.21 (d, J=2.4 Hz, 1H), 6.33 (s, 1H), 5.19 (dt, J=55.5, 4.3 Hz, 1H), 3.51 (m, 2H), 2.59 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: O=S(=O)(Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The potassium salt of fluorobenzene-2,4-disulfonic acid can be obtained in accordance with the following working procedure: 93.3 ml (1 mol) of fluorobenzene were added dropwise to 200 ml of chlorosulfonic acid over one hour. When the evolution of hydrogen chloride had ceased, the reaction mixture was stirred at room temperature for 2 hours and then poured onto 300 g of ice. It was extracted with chloroform, and the organic phase was washed with 50 ml of water and saturated sodium hydrogen carbonate solution. Distillation of the organic phase in vacuo gave 175 g (90% of theory) of p-FC6H4SO2Cl (boiling point: 86 to 88° C. at 0.1 mbar; melting point: 35 to 38° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 88.3 %

Procedure:
Preparation of example 152 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-fluorophenyl)propanoic acid (54 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (61 mg, 0.113 mmol) as a yellow powder in 88% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[NH:25][CH:24]=[CH:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH:23]=[CH:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2-[(1H-indole-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (57) (220 mg, 0.63 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (58) as an off white solid (186 mg, 92%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(C)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.1 g, 0.215 mmol, Preparation #K. 1) and TEA (0.2 mL, 1.4 mmol, Sd Fine Chem) in DCM (10 mL) was added acetyl chloride (0.022 g, 0.28 mmol, Spectrochem). The reaction mixture was slowly warmed to RT and stirred for about 10 min. The reaction mixture was diluted with water (10 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 50% EtOAc-hexane. The relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.05 g (45%): 1H NMR (400 MHz, DMSO): δ 9.469 (t, J=5.6 Hz, 1H), 8.139 (s, 1H), 7.176-7.114 (m, 2H), 6.885 (brs, 1H), 4.679-4.660 (m, 1H), 4.483-4.467 (d, J=6.4 Hz, 2H), 4.436-4.406 (m, 1H), 3.815 (s, 3H), 3.496-3.424 (m, 2H), 3.295-3.239 (m, 2H), 3.194-2.978 (m, 1H), 2.753 (s, 3H), 1.983 (s, 3H), 1.909-1.621 (m, 3H), 1.243-1.189 (m, 2H). LC/MS (Table 1, method c) Rt=1.76 min; MS m/z: 470.1 (M+H)+.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2]>CO>[OH2:2].[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: O
Temperature: 25 °C

Procedure:
An aliquot (1.5 g, 2.2 mmol) of the tosylate anhydrous form 1 salt form of the compound of Formula I prepared above was dissolved in 4.5 mL of methanol. The solution was concentrated to dryness after 3 days by vacuum distillation. The solids were slurried in 4.5 mL of 2-propanol which was shaken at 25° C. and 350 RPM for six days yielding precipitate. The solids were collected by vacuum filtration and dried under vacuum at room temperature over a 12 hour period. The resulting crystalline tosylate hydrate form 2 salt form of the compound of Formula I was analyzed by X-ray crystallography (FIG. 21), DSC (FIG. 22), and TGA (FIG. 23) in accordance with the procedures described above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:30])=[C:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].Cl>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:30])=[C:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cc1c(C)c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cn3)cc2oc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)c(=O)oc2cc(NS(=O)(=O)c3ccc([N+](=O)[O-])cn3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2b was dissolved in THF (4 ml), lithium hydroxide•monohydrate (24.4 mg, 0.58 mmol, 7.4 equivalents) dissolved in H2O (4 ml) was added under cooling on ice, and the mixture was stirred. After 30 min, the reaction mixture was warmed to room temperature and further stirred. After 3 hr, the disappearance of the starting materials was confirmed by TLC and the reaction mixture was acidified with 5% HCl and extracted with CHCl3. The organic layer was washed with saturated brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluate: 1% acetic acid-containing CHCl3:MeOH=20:1) (compound 3b: 29.9 mg, 0.07 mmol, 90%).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:42])([F:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:41])[F:42])=[CH:40][CH:39]=3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 4-trifluoromethylbenzyl bromide (478 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (176 mg, 37.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.13 (br. s., 1 H), 7.69 (d, J=8.08 Hz, 2 H), 7.51 (d, J=8.08 Hz, 2 H), 5.07 (s, 2 H), 4.64 (t, J=12.13 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.13-2.32 (m, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.50-1.72 (m, 3 H), 1.28 (q, 2 H), 1.11 (q, J=13.22 Hz, 1 H).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:15]2)=[CH:9]1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>ClCCl>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:26]2[CH2:25][CH2:24][CH:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:14]([CH2:13][C:10]4[CH:11]=[CH:12][O:8][CH:9]=4)[CH:15]=3)[CH2:28][CH2:27]2)[CH:33]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCC(c3cn(Cc4ccoc4)c4ncccc34)CC2)c1
Yield: 86.9 %

Procedure:
0.3 ml of triethylamine were added over a solution of 0.4 g (1.42 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine in 5 ml of dichloromethane. A solution of 0.39 g (1.71 mmol) of 3-bromomethyl-benzoic acid methyl ester in 2 ml of dichloromethane was added and the crude mixture was stirred at room temperature for 18 hours. The mixture was diluted with 25 ml of dichloromethane and it was washed with water and brine. The organic phase was dried over magnesium sulphate and after filtration and evaporation, 0.53 g of the crude residue were obtained. The crude mixture was purified by flash chromatography over silica gel affording 0.3 g (49% of yield) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:17][CH2:18][N:13]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:15]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 39.6 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.500 g), 4-(piperazin-1-yl)benzenesulfonamide (Example 2, Step 2; 0.630 g), triethylamine (0.477 g), and ethylene glycol (6 mL) give 0.40 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from methanol/dichloromethane; mp 255-256° C.; IR (mineral oil) 1153, 1327, 1322, 3306, 1106 cm-1. 1H NMR (DMSOd6) δ2.60, 3.29, 3.66, 7.01, 7.06, 7.25, 7.54, 7.60, 7.84, 8.80.