Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[N:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[N:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (652 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (522 mg, yield: 85%). This was recrystallized from ethanol-hexane. Melting point: 144–145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[C:30]([O:37][CH3:38])(=[O:36])[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][CH:31]([C:30]([O:37][CH3:38])=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine (100 g) in dry dimethylformamide (500 ml), dimethyl malonate (43.16 ml) and 28% (w/w) methanolic solution of sodium methoxide (60.77 g) were added, and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate, washed with water and dried over magnesium sulfate. Removal of the solvent gave (2R,4R)-1-benzyloxycarbonyl-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsiloxypyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)cn2)n1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 2-amino-5-fluoropyridine instead of 2-chloro-4-aminopyridine to yield [2-(5-Fluoro-pyridin-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester as a white solid. MS (ISP): m/e=347.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide as a light yellow solid, MS (ISP): m/e=247.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light yellow solid, MS (ISP): m/e=324.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([CH:12]([NH2:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C2(C#N)CCC2)CC1
Reactant: [Li]c1ccccc1
Product: CN1CCN(C2(C(N)c3ccccc3)CCC2)CC1

Procedure:
The title compound, yellow liquid, MS: m/e=260.2 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-(4-methyl-piperazin-1-yl)-cyclobutanecarbonitrile (intermediate V) and phenyllithium.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[NH:25][N:24]=2)=[N:9][C:10]([C:13]2[S:14][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][CH:17]=2)=[N:11][CH:12]=1)(=O)C.[OH-].[Na+].O>CO>[CH:28]1([C:26]2[NH:25][N:24]=[C:23]([NH:22][C:8]3[C:7]([CH2:6][CH2:5][OH:4])=[CH:12][N:11]=[C:10]([C:13]4[S:14][C:15]([S:18]([NH2:19])(=[O:21])=[O:20])=[CH:16][CH:17]=4)[N:9]=3)[CH:27]=2)[CH2:30][CH2:29]1
Reactant: CC(=O)OCCc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2ncc(CCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 65.6 %

Procedure:
A solution of 2-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(5-sulfamoylthiophen-2-yl)pyrimidin-5-yl)ethyl acetate (Compound 313) (200 mg, 0.45 mmol, 1.0 equiv.) and NaOH.aq (2 mL) in MeOH (5 mL) was stirred for 1 h at rt. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to yield 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(2-hydroxyethyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 239) (120 mg, 66%). LC-MS (m/z)=407.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.81 (m, 2H), 1.01-1.06 (m, 2H), 1.97-2.01 (m, 1H), 2.89 (t, J=5.6 Hz, 2H), 3.69 (d, J=5.6 Hz, 2H), 6.47 (s, 1H), 7.69 (d, J=4.0 Hz, 1H), 7.98 (s, 2H), 8.23 (s, 1H), 8.34 (d, J=3.2 Hz, 1H), 10.67 (s, 1H)
Reaction SMILES: [CH2:1]([C@@H:8]1[O:10][C@@H:9]1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.O.Cl>[CH2:1]([C@@H:8]1[O:10][C@@H:9]1[C:11]([OH:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@@H]1O[C@@H]1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC[C@@H]1O[C@@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 500 mg (2.50 mmole) of (2R-cis)-3-heptyloxiranemethanol in 50 ml of DMF was added 3.30 g (8.75 mmole) of pyridinium dichromate. The reaction was allowed to stir overnight under argon. The mixture was then diluted with 150 ml H2O and 20 ml 0.1M HCl and washed three times with 50 ml of Et2O. The combined Et2O layers were dried over MgSO4, filtered and evaporated to afford a white powder. This residue was crystallized from petroleum ether to afford 39 mg of white power, mp 62°-3° C. 1H NMR (CDCl3) δ3.59 (d, 1, J=5 Hz), 3.24 (m, 1), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M+(19.1)186.1, M-45(42.3)141.1, M(100)95.1.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](OC)=[O:8])[C@H:4]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccsc2)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl(+−)-trans-4-methylene-2-(3-thienyl)cyclopentanoate (6.0 g, 27 mmol) prepared as in Step B in THF (70 mL) under nitrogen and cooled to −10° C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) in THF (54 mL). After 1 h, the bath was removed and the reaction was stirred at rt for 3 h. The reaction was cooled in an ice/methanol bath and the excess LAH was quenched by dropwise addition of water/1N potassium hydroxide/water and the salts were removed by filtration through celite. The filtrate was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated to afford the crude title product (4.09 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[C:13](Br)[C:12]1=[O:18]>CO>[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[C:13]([NH:4][CH2:1][CH2:2][CH3:3])[C:12]1=[O:18]
Reactant: CN1C(=O)C=C(Br)C1=O
Reactant: CCCN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCNC1=CC(=O)N(C)C1=O
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To propylamine (52 μL, 0.78 mmol) and sodium acetate (64 mg, 0.78 mmol) in methanol (30 mL) was added N-methylmonobromomaleimide (150 mg, 0.78 mmol) dropwise in methanol (30 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (41 mg, 0.24 mmol) in 31% yield. δH (500 MHz, CDCl3) 5.43 (s, 1H, NH), 4.80 (s, 1H, H-2), 3.16-3.13 (m, 2H, H2-9), 2.98 (s, 3H, H3-6), 1.71-1.64 (m, 2H, H2-8), 0.99 (t, J=7.5, H3-7); δC (125 MHz, CDCl3) 172.71 (C═O), 167.66 (C═O), 149.51 (C3), 83.84 (C2), 46.01 (C9), 23.44 (C6), 21.87 (C8), 11.38 (C7); IR (film, cm−1) 3317 (m), 2944 (w), 1698 (s), 1651 (s); MS (EI) m/z (relative intensity): 168 (M+, 70), 139 (100), 111 (40); Exact Mass Calcd for [C8H12N2O2]+ requires m/z 168.0893 Found 168.0887 (EI); UV (Acetonitrile) ε210=15900, ε240=2800, ε283=500 and ε368=500 cm−1M−1 d3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:58])([F:57])[O:46][C:47]1[CH:48]=[C:49]([CH2:53][C:54](O)=[O:55])[CH:50]=[CH:51][CH:52]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][C:45]([F:57])([F:44])[F:58])[CH:48]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(OC(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-trifluoromethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-trifluoromethoxy-phenyl)-acetamide (0.8 g, 74%) as a white solid: mp 178-180° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.32 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.83 (s, 2H), 4.72 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.23-8.10 (m, 7H), 8.74 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.84, 48.83, 118.96, 121.43, 121.93, 127.15, 128.29, 130.07, 131.53, 133.15, 134.61, 138.80, 139.00, 148.24, 166.88, 167.41, 169.77, 169.96, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.44; H, 3.44; N, 8.46; F, 11.89.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[N:15]1([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Cn2ccnc2)c2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
A mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (3.45 g; 15 mmol), imidazole (1.02 g; 15 mmol) and diisopropylethylamine (5.25 ml; 30 mmol) in CHCl3 (60 ml) was stirred for 24 h at room temperature and then for 3 h at 60° C. After cooling, the mixture was evaporated, washed with ethyl acetate (50 ml) and then hexane (50 ml). The residue was crystallized from a mixture of toluene and ethanol (abs.) to give 0.83 g (29%) of title product. M.p. 182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11](=[O:12])[NH:10][N:9]=[CH:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C)C=O>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]2[C:11](=[O:12])[N:7]([C:5]3[S:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[CH:6]=3)[CH:8]=[N:9]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate (0.15 g, 0.59 mmol), potassium carbonate (0.16 g, 1.19 mmol) and 4-fluorobenzyl bromide (0.11 mL, 0.90 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature, then partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-40% ethyl acetate in hexanes to afford the title compound as a cream solid in 81% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.42-7.36 (m, 2H), 7.08-7.01 (m, 2H), 6.93 (s, 1H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 362.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]1([N:16]2[CH:20]=[C:19]([CH:21]=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:21]([C:19]3[N:18]=[N:17][N:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:20]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1cn(-c2ccccc2)nn1
Product: Brc1cnc2[nH]c(-c3cn(-c4ccccc4)nn3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 1-phenyl-1H-1,2,3-triazole-4-carboxaldehyde.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:34]([NH:24][CH2:23][C:22]([N:20]([C:15]1[C:14]([Cl:26])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:27])[N:4]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:21])=[O:25])(=[O:36])[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) were added pyridine (17 mg), 4-dimethylaminopyridine (10 mg) and acetic anhydride (32 mg), and the mixture was stirred for 1.5 hours. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=5:1, V/V) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (74 mg).
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(N(CC)CC)C>C(O)CCC>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:1]([C:3]2[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=2)(=[O:10])=[O:2])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: NCCCN1CCCC1=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)NCCCN2CCCC2=O)cc1

Procedure:
Sulphanilyl fluoride (6.5 g, 37.1 mmol), 3-(pyrrolidin-2-on-1-yl)propylamine (5.79 g, 40.8 mmol) and triethylamine (5.69 ml, 40.8 mmol) in n-butanol (15 ml) was heated at reflux for 10 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/MeOH (100:0) increasing in polarity to (90:10) to give the title compound m/z: 297.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19]1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: c1cc[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-n2cccc2)cc1
Temperature: 195 °C

Procedure:
To a solution of 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) (100 mg, 0.33 mmol) in DMF (5 mL) was added 1-H-pyrrole (0.66 mmol, 44 mg), K2CO3 (2.4 eq., 115 mg) and catalytic CuI (3 mg). The reaction tube was sealed, and heated in a microwave at 195° C. for 3 hours. The solution was extracted with ethyl acetate and washed with cold water. The product was purified twice by reverse phase HPLC (10 to 95% acetonitrile/water). The compound was re-dissolved in ethanol and evaporated to dryness. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (d, 6H)), 1.48 (s, 6H), 1.70 (m, 1H), 2.85 (t, 2H), 6.1 (d, 2H), 7.3 (m, 5H), 7.5 (d,2H). MS: M+H=285.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].C(N(CC)C(C)C)(C)C.[NH2:27][C@@H:28]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]([F:51])([F:50])[F:49])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:27][C@@H:28]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([F:51])([F:49])[F:50])[CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (284 mg, 0.74 mmol) [prepared according to Preparation 6] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414 mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[BH3-]C#N.[Na+]>CCO.CO>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2c3ccccc3nc(C)n2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of Example XXXVI (14.0 g, 0.0436 m) was dissolved in EtOH (1.5 lit) and the pH was adjusted to 4 with methanolic HCl. A solution of NaBH3CN (18.0 g, 0.272 m) in MeOH (300 ml) was added. The pH was readjusted to 4 at 5 min intervals for 20 min. After this time, the pH remained at 4. The reaction mixture was stirred at ambient temperature for 2 hr. The solvent was removed and the residue slurried in H2O (250 ml) and treated with 1N NaOH until basic. The mixture was extracted with CH2Cl2 (2 × 200 ml). The organic extract was dried over Na2SO4, filtered, and the solvent removed to give a white solid; m.p. 102°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([CH:37]([CH3:39])[CH3:38])[CH:27]=1)=[O:24].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:51][NH2:52]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:52][CH3:51])=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([CH:37]([CH3:39])[CH3:38])[CH:27]=1)=[O:24]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccccc3)c1)C2
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccccc3)c1)C2
Yield: 74 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and treated with methylamine to provide 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.13 (dd, J=8, 2.5 Hz, 1H), 7.96 (brs, 1H), 7.52 (m, 4H), 7.42 (m, 1H), 7.25 (dd, J=12.9 Hz, 1H), 7.00 (m, 2H), 6.34 (s, 1H), 4.56 (s, 2H), 3.25 (brs, 3H), 2.86 (m, 1H), 2.78 (d, J=5 Hz, 3H), 1.20 (d, J=6 Hz, 6H); MS (EST) m/z: 530.2 (M+H+).