Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[C:12]1([CH3:26])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23].C(O)(C)C>N1C=CC=CC=1>[NH2:25][C:24]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:20]([C:13]2[C:12]([CH3:26])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[CH3:19])[C:21]=1[C:22]#[N:23]
Reactant: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2c(N)c(C#N)c(-c3c(C)cc(C)cc3C)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 155 mg (1 mmol) of 3-amino-4-carbethoxypyrazole and 196 mg (1 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 3 mL of anhydrous pyridine was stirred at reflux under air for 3 days and then cooled and concentrated in vacuo. Because LC-MS indicated the presence of considerable dihydro intermediate, 112 mg (0.49 mmol) of 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and 3 mL of isopropanol were added to the residue, and the mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (elution with 2% methanol in dichloromethane) to give the title compound as an orange solid. LC-MS 350 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:43])[CH2:41][CH3:42]>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:43][CH2:40][CH2:41][CH3:42])=[N:34][C:35]#[N:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCCNC(=NC#N)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and propylamine.
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)=[O:4].C(O)(=O)C.C(OCC)(=O)C.[ClH:26]>C(O)C.[Fe]>[ClH:26].[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:15])=[CH2:1])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1ccc(N)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 114 g of 2-methyl-N-(4-nitro phenyl) acrylamide (0.55 mol) and 92.6 g of Fe powder (1.65 mol=3 mol equiv.) was refluxed in 420 ml of ethanol. While refluxing, 400 ml of acetic acid (6.6 mol=12 mol equiv.) was added. A proper cooling and a safe gas separation were ensured. During the first reaction step a very strong exothermic gas release occurred. After completing of the addition of acetic acid, stirring while refluxing was continued for 60 min. After TLC inspection, 300 ml of ethyl acetate was added and the Fe salts were suction-filtered. The salts were then washed with 1.9 liter of ethyl acetate. While stirring, 138 ml of concentrated HCl (1.65 mol=3 equiv.) was added to the filtrate. The mixture was cooled to 5° C. while stirring. The precipitate was suction-filtered and washed with ethyl acetate. After drying at 40° C., 85 g of N-(4-amino phenyl)-2-methyl acrylamide hydrochloride was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21](C(Cl)=O)=[CH:20][CH:19]=1.[N:33]1[C:42]2[C:37](=[CH:38][C:39]([NH2:43])=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[C:27]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]2[C:15]([NH:43][C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:33]=[CH:34][CH:35]=[CH:36]3)=[O:17])=[O:7])=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: O=C(Nc1ccc2ncccc2c1)[C@@H]1CC(=CCl)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbo-nyl chloride, and 6-quinolinamine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=468.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(C2CC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(C2CC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a suspension of compound 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.5 g, 3.9 mmol) and K2CO3 (1.6 mg, 7.8 mmol) in DMF (15 mL) was added dropwise CH3I (1.1 mg, 7.8 mmol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 2 hours. After concentration in vacuum, the residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O, brine and dried over Na2SO4. The mixture was filtered and concentrated to give the product of compound 5-bromo-2-cyclopropyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 65%). 1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.98 (s, 1H), 5.63 (s, 1H), 3.05 (s, 3H), 2.79 (s, 6H), 2.39˜2.43 (m, 1H), 0.95˜0.97 (m, 2H), 0.89˜0.91 (m, 2H). MS (M+H)+: 401/403.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2N)[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32]([O:34][C:35](=[O:39])[CH:36](Br)[CH3:37])[CH3:33].C[N:41](C=O)C>>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:41][CH:36]([CH3:37])[C:35]([O:34][CH2:32][CH3:33])=[O:39])=[CH:21][CH:20]=2)[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)Br
Reactant: CCc1nc(-c2ccccc2)cc(=O)n1CCOc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)Nc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-ethyl-6-oxo-4-phenyl-1,6-dihydro-1-pyrimidinyl]-2-(aminophenoxy)ethane (1.9 g, 5.67 mmol) (Ref. U.S. Pat. No. 6,310,069) in dry DMF (20 mL) was added K2CO3 and stirred at RT for 30 min. To this ethyl-2-bromopropanoate (1.54 g, 8.51 mmol), was added and the mixture was stirred at 50° C. for 14 h. The reaction mixture was filtered, washed with EtOAc and the combined filtrates were washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated the solvent and the crude compound was purified by column chromatography by eluting with 25% EtOAc:pet. ether to give the title compound as a brownish low melting solid (mp: 40° C., 1.867 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[C:13](=[O:16])([O-])[O-:14].[K+].[K+].C(OC([CH2:26][NH:27][C@@H:28]1[CH2:33][CH2:32][C@H:31](OS(C)(=O)=O)[CH2:30][CH2:29]1)=O)(C)(C)C>CN(C=O)C>[C:4]([O:14][C:13](=[O:16])[N:27]([CH3:26])[C@H:28]1[CH2:29][CH2:30][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:32][CH2:33]1)([CH3:9])([CH3:5])[CH3:3]
Reactant: O=c1[nH]ccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)CN[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
suspension of 6-Hydroxy-2H-isoquinolin-1-one (410 mg, 2.52 mmol) and potassium carbonate (420 mg, 3.03 mmol) in DMF (7 ml) was heated to 110° C. and a solution of methanesulfonic acid cis-4-(tert-butoxycarbonylmethylamino)cyclohexyl ester (930 mg, 3.03 mmol) in DMF (3 ml) was added dropwise. Heating was continued at 110° C. for 16 hours and the solvent removed in vacuo. The residue was taken up in chloroform/isopropanol (3:1) and washed with aqueous sodium hydrogen carbonate. The organics were collected through a hydrophobic frit and concentrated to afford crude product. The residue was purified by flash chromatography on silica (eluent: dichloromethane followed by 2M ammonia in methanol) to give trans-methyl[4-(1-oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester (400 mg, 42%), EI-MS: m/z=373.1 [M+H]+.
Reaction SMILES: [C:1]([C:5](Cl)=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]1.CCN(CC)CC.O>C(Cl)Cl>[F:24][C:20]1([F:23])[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:14]2[CH:13]=[CH:12][C:11]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:10][C:9]=2[NH:8][C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:18][CH2:19]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(NC(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of t-BuCOCl (7.6 g, 0.063 mol) in DCM (150 mL) was slowly added to a solution of N-(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)ethanesulfonamide (22 g, 0.063 mol) and Et3N (9.7 mL, 0.069 mol) in DCM (500 mL) at 0° C. The reaction mixture was stirred for 3 hrs. at 0° C. DCM (300 mL) and water (200 mL) were added. The organic layer was separated and washed with water (3×200 mL), brine and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (EtOAc:hexane 1:1) to provide the title product (23.3 g) as beige solid.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].[CH2:19]([N:21]([CH2:24]C)[CH2:22]C)C.C(Cl)(=[O:28])N>C(Cl)Cl>[CH3:19][N:21]([CH3:24])[C:22]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)=[O:28]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CCN(CC)CC
Reactant: NC(=O)Cl
Solvent: O=[N+]([O-])O
Solvent: ClCCl
Product: CN(C)C(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (100 mg, 0.394 mmol) was dissolved CH2Cl2 and triethylamine (119 mg, 166 μL, 1.182 mmol, 3.0 eq) followed by carbamoyl chloride (46.4 mg, 39.7 μL, 0.433 mmol, 1.1 eq) were added. The reaction was stirred at room temperature for 4 hours and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-5% MeOH/CH2Cl2 as the eluting solvent to obtain 7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide as a light orange oil (88 mg, 85%). LCMS (m/e) 264 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01-7.95 (m, 2H), 7.26 (d, 1H, J=9.3 Hz), 3.45-3.39 (m, 4H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.83 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][CH2:37][O:38]C1CCCCO1>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:37][OH:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: OCCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 142, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran to give 179 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 9.86 (s, 1H); 8.44 (s, 1H); 8.29 (s, 1H); 7.84 (td, J=8.75, 5.94 Hz, 1H); 7.72 (td, J=9.64, 2.83 Hz, 1H); 7.43-7.37 (m, 1H); 7.21 (d, J=2.28 Hz, 1H); 7.09 (dd, J=8.45, 2.36 Hz, 1H); 6.96 (d, J=8.40 Hz, 1H); 5.37 (t, J=4.89 Hz, 1H); 4.21 (t, J=5.01 Hz, 2H); 3.83 (d, J=5.48 Hz, 2H); 3.65 (d, J=12.04 Hz, 2H); 3.23 (m, 2H); 3.10 (m, 4H); 2.69-2.60 (m, 1H); 2.01-1.80 (m, 4H). LCMS: RT=7.55 min, M+H+=493
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:34]=[C:35]([C:41](=[O:47])CCC(O)=O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:34]=[C:35]([CH:41]([OH:47])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(C(O)CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3-fluoro-4-methoxy-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH3:19][CH:20]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([C:33]#[N:34])[CH2:23][CH2:22][CH2:21]1.[O:35]=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[C:33]([C:24]1([C:36]2([OH:35])[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]2)[CH2:23][CH2:22][CH2:21][CH:20]([CH3:19])[N:25]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)#[N:34]
Reactant: CC1CCCC(C#N)N1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC1CCCC(C#N)(C2(O)CN(C(=O)OC(C)(C)C)C2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.8 %

Procedure:
To a solution of N,N-diisopropylamine (1.6 mL, 11.2 mmol) cooled to −78° C. in THF (15 mL) was added a 2.5 M solution of n-BuLi in hexane (4.5 mL, 11.2 mmol) dropwise over 5 minutes and the mixture was stirred at this temperature for an addition 15 minutes. 6-methyl-1-(phenylmethyl)piperidine-2-carbonitrile (2.4 g, 11.2 mmol) (prepared using procedures similar to those in Bonin et. al. Tet. Lett. 1982, 23(33), 3369-72) in THF (10 mL) was then added dropwise over 20 minutes and the reaction mixture was stirred for a further 30 minutes. Next a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (1.3 g, 7.5 mmoL), prepared using procedures similar to those in Example 3, in THF (10 mL) was added dropwise over 30 minutes. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was quenched with 10% citric acid and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give crude product as yellow oil. Further purification by flash chromatography (30% ethyl acetate in hexanes) afforded 1,1-dimethylethyl 3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate as a pale yellow oil (0.2 g, 7% yield). 1H NMR (400 MHz, CDCl3): 7.17-7.40 (m, 5H), 4.42 (d, 1H), 4.04-4.18 (m, 1H), 3.83-4.00 (m, 1H), 3.70-3.75 (m, 2H), 1.70-1.87 (m, 4H), 1.45 (s, 3H), 1.41 (s, 9H), 1.22-1.26 (m, 1H), 1.13-1.18 (m, 2H); MS (EI) for C22H31N3O3: 386 (MH+).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1.N(OCCC(C)C)=O.[ClH:27]>C(#N)C.[Cu](Cl)Cl>[Cl:27][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cl
Reactant: Cc1nc(N)c(C#N)c(C2CCCCO2)c1C#N
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1nc(Cl)c(C#N)c(C2CCCCO2)c1C#N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
610 mg (2.52 mmol) of the compound from Example 39A are initially charged in 44 ml of acetonitrile, and 590 mg (5.04 mmol) of isopentyl nitrite and 677 mg (5.04 mmol) of copper(II) chloride are added. The reaction mixture is stirred at 60° C. for 30 min. 40 ml of 1 N hydrochloric acid are then added to the mixture and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product is used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol), 2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxide monohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heat the resulting mixture to 55° C. for 40 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Chromatograph the solid using flash chromatography and elute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5% dichloromethane. Obtained 2.267 g of the title compound (8.36 mmol, 45% yield) as an orange amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1470 mg, 4.62 mmol) in acetonitrile (10 mL) was added tert-butyl (3-hydroxyphenyl)carbamate (966 mg, 4.62 mmol) and K2CO3 (1280 mg, 9.24 mmol) and the mixture heated at 80° C. with stirring overnight. The reaction was then cooled to rt, EtOAc (20 mL) added, washed with water (50 mL), the aqueous layer extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a light oil. Upon standing, the light oil solidified to give the title compound (2052 mg, 90% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38-9.83 (m, 1H) 7.73 (d, J=3.78 Hz, 1H) 7.41-7.46 (m, 2H) 7.51 (s, 1H) 6.97 (dt, J=5.98, 2.68 Hz, 1H) 6.58 (d, J=3.78 Hz, 1H) 5.64 (s, 2H) 3.54-3.67 (m, 2H) 1.54 (s, 9H) 0.91-0.96 (m, 2H) 0.00 (s, 9H). LCMS (ESI, pos): m/z (ESI+) for C23H31ClN4O4Si 491.20 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)ccn1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.2017 g, 0.566 mmol), 2-methoxypyridin-4-ylboronic acid, trans-dichlorobis(triphenylphosphine) palladium (II) (0.032 g, 0.045 mmol), and sodium carbonate (0.300 g, 2.83 mmol) in DME (0.906 mL) and water (0.226 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 30 min. The crude product was purified by chromatography to give the title compound. MS (ESI, pos. ion) m/z: 356 (M+1). IC50 (uM) 0.003548.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:30]=[C:31]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=[C:33]([F:36])[C:34]=1[F:35]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:31]1[CH:30]=[C:29]([F:28])[C:34]([F:35])=[C:33]([F:36])[CH:32]=1)(=[O:39])=[O:38]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (2.8 g, 13 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.6 mL, 15.6 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then cooled to −78° C. and 3,4,5-trifluorobenzene-1-sulfonyl chloride (3.0 g, 13.0 mmol) was added. The mixture was stirred at −78° C. for 0.5 h, warmed to 0° C. and 4,5-trifluorobenzene-1-sulfonyl chloride (0.6 g, 2.6 mmol) was added. The mixture was allowed to warm to ambient temperature, stirred for 20 h, diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (200 mL) and brine (200 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane to afford N-(2,4-dimethoxybenzyl)-3,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 53% yield (3.1 g): 1H NMR (300 MHz, CDCl3) δ8.24-8.18 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.22 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.39-6.32 (m, 1H), 6.29-6.24 (m, 1H), 5.27 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H).