Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][NH:11][CH2:12]3)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:11]2[CH2:12][CH:13]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Clc1cccnc1N1C2CCC1CNC2
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2CC3CCC(C2)N3c2ncccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (102 mg, 456 μmol) and 1-tert-butyl-4-isocyanatobenzene (80 mg, 456 μmol) were combined in dry dichloromethane (4.5 mL) and stirred overnight at room temperature. The mixture was concentrated and the residue was purified by chromatography on silica gel (7:3, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 399 (M+H)+; 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 1.73 (m, 2H), 1.85 (m, 2H), 3.20 (dd, 2H), 3.92 (dd, 2H), 4.51 (dd, 2H), 6.94 (dd, 1H), 7.24 (d, 2H), 7.37 (d, 2H), 7.79 (dd, 1H), 8.17 (dd, 1H), 8.30 (s, 1H).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH3:10][C:11]([C@@H:45]([OH:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][SH:56])=[O:52])=[O:47])([CH2:13][O:14][P:15]([O:18][P:19]([O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])([OH:21])=[O:20])([OH:17])=[O:16])[CH3:12].C[O:59][C:60]1C(O)=C(OC)[CH:63]=[C:62](/C=C/C(O)=O)[CH:61]=1>FC(F)(F)C(O)=O.C(#N)C>[C:60]([S:56][CH2:55][CH2:54][NH:53][C:51](=[O:52])[CH2:50][CH2:49][NH:48][C:46](=[O:47])[C@H:45]([OH:57])[C:11]([CH3:10])([CH3:12])[CH2:13][O:14][P:15]([OH:17])(=[O:16])[O:18][P:19]([OH:21])(=[O:20])[O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])(=[O:59])/[CH:61]=[CH:62]/[CH3:63]
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1O
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The assay mixture contained 50 mM Tris-HCl (pH 7.5), 1 mM CoA ester, and about 1 μg cell free extract. Reactions were allowed to proceed at room temperature and were stopped by adding 1 volume 10% trifluroacetic acid (TFA). The reaction mixtures were purified prior to MALDI-TOF MS analysis using Sep Pak Vac C18 50 mg columns (Waters, Inc.). The columns were conditioned with 1 mL methanol and then equilibrated with two washes of 1 mL 0.1% TFA. The sample was applied to the column, and the flow through was discarded. The column was washed twice with 1 mL 0.1% TFA. The sample was eluted in 200 μL 40% acetonitrile, 0.1% TFA. The acetonitrile was removed by centrifugation in vacuo. Samples were prepared for MALDI-TOF MS analysis by mixing 1:1 with 110 mM sinapinic acid in 0.1% TFA, 67% acetonitrile. The samples were allowed to air dry.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H]>CN(C)C=O.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]2=3)=[CH:22][CH:23]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2cccnc2Cl)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
1.44 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 3.69 g (0.010 mol) N-(2-chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)methyl]amino]-3-pyridinecarboxamide in 100 ml of dimethylformamide. After the evolution of hydrogen stopped, the mixture was heated (110° C.) for 16 hours and then refluxed for eight hours. After the mixture had cooled, the excess sodium hydride was decomposed by the slow addition of ice. The mixture was further diluted with water, and the product was extracted with ether and concentrated. The crystallized residue was filtered and washed with ether to give 1.60 g of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (50% of theory) as an off-white powder, m.p. 209°-210° C.
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([CH3:9])([CH3:8])[CH3:7].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:6]([CH3:7])([CH3:8])[CH3:9])=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Cl)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
tert-Butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (Example 1, 466 mg, 1.70 mmol) was dissolved in dry THF (10 mL). (4-Chlorophenyl)magnesium bromide (CAS 873-77-8, 1.0 M in THF, 6.79 mL, 6.79 mmol) was then added dropwise at rt. After stirring at rt overnight the reaction was quenched with NH4Cl and extracted with EtOAc (2×50 mL). The combined organic phases were washed once with water, dried over MgSO4 and filtered. After removal of the solvent the product was purified on a silica gel column eluted with heptane:EtOAc 10-20% to give tert-butyl 1-(4-chlorophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (137 mg, 25%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22](=[O:23])[CH:21]=[CH:17][C:12]([C:13]#[N:18])=[C:19]1[S-:20].[Na+:10]
Reactant: S=C=Nc1ccccc1Cl
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#Cc1ccc(=O)n(-c2ccccc2Cl)c1[S-]
Temperature: 25 °C
Yield: 88 %

Procedure:
NaHMDS (13.2 mL, 1.0M in THF, 13.2 mmol) was added slowly to a solution of 2-chlorophenyl isothiocyanate (1.02 g, 6.0 mmol) in THF (50 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (841 mg, 6.0 mmol) and EtOH (75 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in hot EtOH (10 mL). Et2O (˜100 mL) was added slowly to precipitate out the product. The solid was filtered off, washed with Et2O (2×30 mL) and dried to give the title compound (1.5 g, 88%) (v. hygroscopic). δH (DMSO-d6) 7.35-7.32 (1H, m), 7.25-7.20 (2H, m), 7.15 (1H, d, J 9.1 Hz), 7.05-7.01 (1H, m), 5.85 (1H, br s), 5.58 (1H, d, J 9.1 Hz). LCMS (ES+) RT 3.06 minutes, 285 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: NS(=O)(=O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Into a solution of 2,6-dichlorobenzenesulfonamide (7.8 g, 34.5 mmol) in 30 mL of concentrated sulfuric acid at 0°, nitric acid (1.74 mL, 41.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hours, then 200 mL of water was added to produce a precipitate. The resulting mixture was filtered. The white solid was collected, washed with water and dried in vacuo to give the desired product (7.17 g, 76%). 1H NMR (DMSO-d6): δ8.25 (s, 2H), 8.20 (d, 1H), 7.92 (d, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.44 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Br)ccc1OCc1ccccc1
Yield: 90.9 %

Procedure:
To a 100 ml acetone solution of 4-bromo-2-propylphenol 5.4 g (25.1 mmol) and benzyl bromide 5.6 g (32.7 mmol) was added potassium carbonate 5.2 g (37.6 mmo). Resulting suspension was stirred under reflux temperature for overnight. Acetone was removed under reduced pressure, diluted with ethyl acetate and water. Organic phase was separated. Aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on silica gel (hexanes:t-butyl methyl ether) to give 6.96 g of benzyl 4-bromo-2-propylphenyl ether as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(C(C)N(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 56 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (50 mg, 0.116 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.173 mmol) to afford the desired product (33 mg, 56%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD) δ 8.74 (s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.07-7.97 (m, 2H), 7.32 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.55 (d, J=12.2 Hz, 2H), 3.19 (dd, J=19.9, 7.2 Hz, 2H), 2.64-2.58 (m, 1H), 2.58-2.50 (m, 1H), 2.40 (s, 6H), 2.03 (d, J=12.7 Hz, 1H), 1.95-1.78 (m, 3H), 1.73-1.61 (m, 2H), 1.33-1.28 (m, 2H), 1.26-1.20 (m, 2H), 1.11 (d, J=6.6 Hz, 3H); ESI MS m/z 508 [C29H34ClN3O3+H]+; HPLC 97.0% (AUC), tR=10.04 min.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@@H:8]([CH2:9]O)[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:40]([CH2:9][C@H:8]1[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5][C@@H:4]1[O:3][CH2:1][CH3:2])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CO
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of 1.40 g of 2'-deoxy-3'-O-ethyl-5-ethyluridine, 1.3 g of triphenylphosphine, 1.59 g of sodium azide and 1.66 g of carbon tetrabromide in 19 ml of dimethylformamide was stirred at room temperature for 20 hours. 11 ml of methanol were added, the mixture was stirred for 30 minutes and then evaporated. The residue was suspended in 110 ml of water and extracted three times with 70 ml of ethyl acetate each time. The combined ethyl acetate extracts were evaporated and the residue was subject to flash chromatography on a column of silica gel using ethyl acetate/hexane (2:1) for the elution, there being obtained 1.26 g of 5'-azido-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of a colorless oil.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([CH3:15])[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[N:2][NH:1][C:3]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Solvent: CCO
Product: CC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine (300 mg, 1.5 mmol) and 1-(4-Chloro-phenyl)-ethanone (136 μL, 1.05 mmol) in 8.0 mL of ethanol by a procedure similar to example 1, step 4 yielding 190 mg (38%) of an off-white solid. HPLC Purity: 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(C(=O)N[C@H](CN)CC2CCCCC2)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 61.4 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml) at 25° C. was added hydrazine (0.14 ml, 4.40 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (br. s., 1H) 7.97 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H) 2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61 1.64 (m, 4H) 1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]1([CH:19]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:42]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:37][CH2:38][N:39]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:40][CH2:41]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)=[O:24])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCC(N(CCC(c3ccccc3)c3ccccc3)C(=O)Nc3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen in anhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5 mg, 0.075 mmol, 1.5 eq.) then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. The aminomethyl (20 mg) and SAX ion exchange resins are added and the mixture is agitated overnight. The resins are filtered and rinsed with dichloromethane. The oil obtained after evaporation is passed through a silica gel cartridge (500 mg, Interchim) eluting with ethyl acetate in order to obtain 18 mg (yield=56%) of a white solid after concentration.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.Cl.[OH:12][NH2:13].[OH-].[Na+].Cl.ON>C(O)C.O>[CH3:1]/[C:2](/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[N:13]/[OH:12]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=N/O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
15.5 grams (approximately 0.1 mole) of 4-chloroacetophenone were dissolved in 50 cc of ethyl alcohol in a 250 cc beaker. Thereafter, a solution consisting of 15 grams (0.214 mole) of hydroxyl amine hydrochloride dissolved in 30 cc of water were added to the beaker. Then, another solution consisting of 10 grams (0.25 mole) of sodium hydroxide dissolved in 30 cc of water were added to the beaker and the resultant solution was heated for 10 minutes on a hot plate. The reaction mixture was cooled to room temperature and poured into another beaker containing about 250 cc of cold water. The resultant mixture was acidified to a pH of 3 to 5 with strong hydrochloric acid to dissolve any unreacted hydroxyl amine. The white solid product was removed by filtration and after washing and drying, 15.6 grams of crude 4-chloroacetophenone oxime product were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].C(O)(=O)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)OCc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CC(O)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
N-(Benzyloxycarbonyl)-3-amino-1-cyclobutanone (3.51 g, 16.0 mmol) from Step A was dissolved in 100 mL of THF and the THF solution was cooled to -78° C. with stirring under a nitrogen atmosphere. To the solution was added 17.6 mL (17.6 mmol) of potassium tri-sec-butylborohydride (sold by Aldrich Chemical Company as a 1 M solution in THF under the registered trademark K-Selectride®) and stirring was continued for 10 minutes. The reaction mixture was allowed to warm to 0° C. and then quenched with 1.16 mL (1 equivalent) of glacial acetic acid. The reaction mixture was then filtered through Celite filter aid and concentrated in vacuo. The residue (3.1 g) was dissolved in ~10 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5 psi with 250 mL of acetone:hexane (1:2 v/v), followed by 200 mL of acetone:hexane (1:1 v/v) to give 2.22 g (63% yield) of the title compound; MS DCI-NH3M/Z: 222 (M+H)+, 239 (M+NH4)+ ; 1H NMR (CD3OD) δ 1.81 (m, 2H), 2.62 (m, 2H), 3.60 (m, 1H), 3.90 (m, 1H), 5.09 (s, 2H), 7.25-7.40 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(C)cc1B(O)O
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Product: COc1ccc(C)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 65.2 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2-methoxy-5-methyl-phenyl boronic acid (187 mg) were reacted to afford the title compound (128 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.18 (d, 1H), 8.50 (m, 1H), 7.71 (m, 1H), 7.24 (m, 1H), 7.07 (m, 1H), 7.03 (m, 1H), 4.49 (m, 1H), 3.61 (s, 3H), 2.29 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=381 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2-(bromoacetamido)benzoic acid from Example 41 (10 g, 0.03 mol), aniline (8 g, 7.8 mL, 250 mol %) and DMF (60 mL) was heated at 100-110° C. for 4 h. The reaction mixture was poured into ice-water (200 mL) and the resulting solid product was solubilized by adding 5% KOH (40 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the aqueous layer was acidified with 5% HBr to pH=3 and extracted with EtOAc (3×200 mL). The EtOAc washings were dried (Na2SO4), filtered and concentrated to afford, after drying under vacuum, 7.8 g (75%) of the title compound as a white solid, mp 210-212° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.96 (s, 1H, COOH), 8.75 (d, 1H, J=8), 7.87 (d, 1H, J=2.8), 7.68 (d, 1H, J=2.4), 7.65 (d, 1H, J=2.8), 7.10 (t, 2H, J=7.6), 6.61 (m, 4H), 3.84 (s, 2H); 13C NMR (DMSO-d6) δ 171.08, 167.81, 148.05, 139.36, 133.81, 130.25, 128.97, 126.20, 121.25, 117.77, 117.14, 112.45, 48.90; MS (EI, m/z) 304 (M+)