Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]([CH3:25])=[N:19]4)=[CH:9][C:10]=2[C:11](O)=[O:12])[CH2:5][CH2:4]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:27]([NH:26][C:17]1[C:18]([CH3:25])=[N:19][C:20]2[C:15]([N:16]=1)=[C:14]([C:8]1[NH:7][C:6]3[C:3]4([CH2:5][CH2:4]4)[NH:2][C:11](=[O:12])[C:10]=3[CH:9]=1)[C:23]([F:24])=[CH:22][CH:21]=2)([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a suspension of 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (295c) (140 mg, 0.32 mmol) in 8 mL of DMF and 8 mL of DCM at RT was sequentially added 1-hydroxybenzotriazole (AK Scientific, Inc., Union City, Calif.) (65 mg, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma-Aldrich) (93 mg, 0.48 mmol) and DIPEA (Sigma-Aldrich) (0.34 mL, 1.94 mmol). The reaction mixture was stirred at RT for 16 h and was then concentrated. The yellow oil was dissolved in CH2Cl2 and washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 2′-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (295) (50 mg, 0.13 mmol, 41% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 7.70 (dd, J=9.00, 5.87 Hz, 1H), 7.63 (s, 1H), 7.30 (dd, J=10.47, 8.90 Hz, 1H), 6.49-6.55 (m, 1H), 6.07 (s, 1H), 2.54 (s, 3H), 1.43 (s, 9H), 1.37-1.41 (m, 2H), 1.29-1.35 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ ppm −111.61 (s, 1F). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.CC(O)(C)C.[Br-:16].[Br-:17].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH2:37]>CCOC(C)=O>[Br:16][C:10]1([Br:17])[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:8][C:9]1=[O:37]
Reactant: O
Reactant: [Br-]
Reactant: Clc1ccnc2[nH]ccc12
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: O=C1Nc2nccc(Cl)c2C1(Br)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure described in WO2001046196A1. To a stirred suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) in t-BuOH (131 ml, 13.1 mmol) was added pyridinium tribromide (14.1 g, 44.2 mmol) by small portions. The solution was stirred at rt for 2 h. After 3 h, LCMS showed product and mono brominated product. 5.00 g of pyridinium tribromide was added. After 1.5 h, LCMS showed mainly product and excess pyridinium tribromide. After another 0.5 h, water was added and the whole was diluted with EtOAc until all solids were dissolved. The product was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Trituration of the crude product with hexanes gave an orange solid. 1H NMR confirmed the product, 3,3-dibromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (4.07 g, 95% yield). The product was insoluble in DCM and CHCl3. MS Calcd for C7H3Br2ClN2O: [M]+=324. Found: [M+H]+=325, [M+3H]+=327.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCCCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CS(C)=O.C(O)(=O)C>[Cl:8][C:7]1[C:6]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[NH2:13]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 911 gm (4 mole) of 2,3,4-trichloronitrobenzene was dissolved in 4 liters of dimethyl sulfoxide and mixed in a 10-liter autoclave with 400 ml of liquid ammonia. The autoclave was closed and kept at 50° C. for 24 hours, a pressure of 5.3 bars being set. After cooling of the mixture and ventilation of the pressure vessel, the mixture was removed and stirred in a 15 liter vessel with 400 gm of 40% (% by weight) sodium hydroxide solution. In so doing, ammonia escaped and was drawn off. Four hundred sixteen grams of phenol (4.4 mol) were then added to the solution which was heated to 50° C., and 440 gm of 40% by weight solution of sodium hydroxide solution were dropped therein. The mixture was stirred for 7 hours at 50°-60° C. To complete the reaction, 41 gm of phenol and 44 gm of 40% by weight solution of sodium hydroxide were added again, and the mixture was kept at 60° C. for a further 3 hours. The mixture was allowed to cool and was acidified with 100 ml of glacial acetic acid, and the product was precipitated with ice water by trituration. The yellowy brown solid crude product was extracted, washed with water, and dried. The crude product (980 gm m.p. 70°-78° C.) was recrystallized from 2.5 liters of isopropanol. The yield was 800 gm (75.5% of theory) of a yellowy brown solid, m.p. 81.5°-83.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[NH:18][CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C1NCCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A solution of 7-bromochroman-4-one (340 mg, 1.5 mmol) and methanesulfonic acid (3 mL, 23.0 mmol) in DCM was cooled to 0° C. and treated with NaN3 (146 mg, 2.25 mmol) portionwise, while maintaining the internal temperature below 5° C. The reaction was then stirred at 0° C. for 4 h. At completion, the reaction was slowly neutralized with 8 N aq. NaOH, then diluted with DCM (20 mL) and water (20 mL). The layers were separated and the organics were dried over MgSO4, filtered and evaporated to afford 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (370 mg, 100% yield). MS (EI) m/z=242.1 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N:14]([CH3:16])[CH3:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(OP(OCC)OCC)C.C[O-].[Na+].[CH3:30][O:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[CH3:43]>CCOC(C)=O.CCO.CN(C=O)C>[CH3:15][N:14]([CH3:16])[C:12]1[CH:11]=[C:5]([CH:4]=[C:3](/[CH:2]=[CH:38]/[C:37]2[CH:40]=[C:41]([CH3:42])[C:34]([O:33][CH2:32][O:31][CH3:30])=[C:35]([CH3:43])[CH:36]=2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(CCl)cc(N(C)C)c1
Reactant: COCOc1c(C)cc(C=O)cc1C
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(/C=C/c2cc(C)c(OCOC)c(C)c2)cc(N(C)C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
Compound 3 (1.224 g, 4.277 mmol) and triethylphosphite (1.512 mL, 8.555 mmol) were heated to 150° C. for 3 hours. The reaction mixture was cooled to 0° C. and then 6 mL of DMF and 6 mL of EtOH were added. NaOMe (486 mg, 8.554 mmol) and 4-(methoxymethoxy)-3,5-dimethylbenzaldehyde (0.831 g, 4.277 mmol) were added to the solution. After 18 hours, the mixture was diluted with EtOAc and the solution was washed with brine. After drying on Na2SO4, the organic layer was filtered and concentrated under reduced pressure. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=9/1) to give Compound 4 (1.10 g, 67%). 1H-NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.30 (m, 1H), 7.20 (s, 2H), 7.06 (d, J=16.3 Hz, 1H), 6.99 (d, J=16.3 Hz, 1H), 6.97 (s, 1H), 4.96 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.62 (s, 3H), 3.03 (s, 6H), 2.32 (s, 6H), 1.42 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 167.23, 154.65, 150.72, 138.36, 133.12, 131.48, 131.24, 128.70, 127.78, 127.07, 115.70, 114.53, 112.47, 99.11, 60.92, 57.39, 40.65, 16.99, 14.40; ESI-MS: m/z (MH+): 384.2169 (calc'd), 384.2173 (found).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:19][CH3:20])=[N:13][C:14]([CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[CH2:20]([NH:19][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:21])[NH:5][N:6]=3)=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:18])[N:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Product: Cc1nc(NCc2ccccc2)c2ccc(C3=NNC(=O)CC3C)cc2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 0.76 g of Compound 64 obtained in Example 66, 15 ml of benzylamine and 15 ml of dimethylsulfoxide was stirred at 150° C. for 3 hours, and then concentrated. The residue was subjected to partition between water and chloroform, and the organic layer was dried and concentrated. The residue was purified by column chromatography using 100 g of silica gel to give 0.31 g (32%) of 6-(4-benzylamino-2-methylquinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Compound 65).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.O[CH:13]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:14].C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:35]([CH:13]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:14])=[N+:36]=[N-:37]
Reactant: Cc1ccc(C(C)O)s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)N=[N+]=[N-])s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
Add DBU (1.228 g, 1.2 mL, 8.07 mmol) to a solution of (−)-2-(1-hydroxyethyl)-5-methylthiophene (0.955 g, 6.72 mmol) and diphenylphosphoryl azide (2.22 g, 1.74 mL, 8.07 mmol) in anhydrous toluene. Stir at room temperature for 18 h. Dilute the mixture with EtOAc and wash with water and 0.5N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as an oil (0.875 g, 78%). GC-MS m/z 167 (M+).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20]([Cl:22])=O>>[ClH:22].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:20]([C:19]3[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:30])[F:29])=[CH:26][C:18]=3[F:17])[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(C(F)(F)F)cc3F)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 2-fluoro-4-trifluoromethylbenzoyl chloride.
Reaction SMILES: C([Li])CCC.CCCCCC.[Br:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=3)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=2[CH:14]=1.Cl[Si:44]([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[Br:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:20][CH:21]=3)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=2[CH:14]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium in hexane (6.0 mL, 1.6 M, 9.6 mmol) was added to a solution of 2,7-dibromo-9,9-di-n-octylfluorene (7) (5.00 g, 9.13 mmol) in dry THF (50 mL) in a schlenk flask at −78° C. and the mixture was stirred for 20 minutes. Then chlorotrimethylsilane (1.5 mL, 1.29 g, 1.3 equiv) was added and the reaction was allowed to slowly warm to room temperature. The mixture was stirred overnight and the reaction was quenched with saturated brine. The product was extracted into diethyl ether, and the extract was washed with brine and dried over MgSO4. The crude product was chromatographed on silica using hexane as eluent to give 2-bromo-7-trimethylsilyl-9,9-di-n-octylfluorene as a colourless oil, (3.50 g, 71%). n-Butyllithium in hexane (4.4 mL, 1.6 M, mmol) was added to a solution of 2-bromo-7-trimethylsilyl-9,9-di-n-octylfluorene (3.47 g, 6.41 mmol) in dry THF (75 mL) in a schlenk flask at −78° C., and the mixture was stirred for 20 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.44 mL, 1.31 g, 7.04 mmol) was added and the reaction was stirred for 24 h after warming to room temperature. The reaction was then quenched with brine, and the product was extracted into diethyl ether. The extract was washed with brine and dried over MgSO4. The crude product was chromatographed on silica using 0–3% ethylacetate in hexane as eluent, to give 8 as a colourless solid (2.67 g, 71%). 1H NMR (CD2Cl2): δ 7.73 (m, 4H) 7.51 (m, 2H) 1.99 (t, 4H, J=8.2 Hz) 1.36–0.54 (m, 42H) 0.31 (s, 9H)ppm. 13C NMR: δ 151.60, 151.34, 149.76, 145.29, 142.69, 141.07, 134.71, 133.01, 130.08, 129.03, 120.50, 120.25, 84.93, 56.22, 41.26, 33.01, 32.84, 31.11, 30.37, 25.98, 24.95, 23.85, 15.08, 0.01. FDMS m/z 588.90.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: OCCc1cc(F)c(F)cc1OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CCI)c(OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of Ph3P (691 mg, 2.63 mmol) and imidazole (179 mg, 2.63 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (668 mg, 2.63 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(2-(Benzyloxy)-4,5-difluorophenyl)ethanol (580 mg, 2.195 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temperature. After 5 h, the mixture was filtered and washed the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-20% EtOAc/hexane) to give 1-(benzyloxy)-4,5-difluoro-2-(2-iodoethyl)benzene (630 mg, 1.684 mmol, 77% yield) as colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.50-7.34 (m, 6H), 7.00 (dd, J=10.3, 9.2 Hz, 1H), 6.77 (dd, J=12.0, 6.6 Hz, 1H), 5.06 (s, 2H), 3.37 (t, J=7.5 Hz, 2H), 3.21-3.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[Br:11]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.CCOC(C)=O.O>[Br:11][C:4]1[N:3]=[C:2]([F:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Oc1cccnc1F
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)nc1F
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
2-Fluoropyridin-3-ol (5.96 g, 52.7 mmol) was suspended in acetic acid and cooled in an ice bath. NaOH (10.0 N, 6.0 mL, 60.0 mmol) was added and the mixture stirred for 10 min. Bromine (2.8 mL, 54.4 mmol) was added dropwise and the mixture stirred for 20 min. Sodium sulfite (1.4 g) was added and the mixture stirred for 10 min. Water (400 mL) and EtOAc (400 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 6-bromo-2-fluoropyridin-3-ol (3.67 g, 19.12 mmol, 36.3% yield) MS m/z=192.0, 194.0 [M+H]+. Calculated for C5H3BrFNO: 190.94.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.CCOC(C)=O.C1C(=O)N([Br:22])C(=O)C1.N>C(O)(=O)C>[Br:22][C:3]1[C:4]([OH:8])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccnc(O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-pyridin-2-ol V-a (25 g, 229 mmol) in glacial acetic acid (350 mL) and EtOAc (680 mL) was treated with NBS (37.4 g, 210 mmol) and stirred at room temperature for 30 min. The mixture was then taken to pH 8 with aqueous ammonia and extracted with EtOAc. The separated organics were washed with 1:1 H2O/brine then dried (MgSO4), filtered and evaporated before purification by silica column chromatography (1-4% EtOH/DCM) to afford the desired product V-b as a white solid (8.66 g). 1H NMR (300 MHz, DMSO) δ 11.90 (s, 1H), 7.32 (d, J=6.6 Hz, 1H), 6.19 (d, J=6.6 Hz, 1H), 2.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccccc1F
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.81 (1H, d, J=1.6 Hz), 7.09-7.20 (2H, m), 7.36-7.41 (2H, m), 7.48-7.51 (1H, m), 7.58 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11FN4O, 295; Found, 295.
Reaction SMILES: Cl[C:2]1[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C1COCC1>[N:9]1([C:2]2[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1NCCC=C1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCC=C1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]=1[F:18])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][O:28][CH3:29])[CH2:16][CH2:17]2)[C:7]=1[F:18])(=[O:3])=[O:4]
Reactant: COCCBr
Reactant: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenyl methanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 288 (6), 287 (15), 286 (bp), 207 (47).
Reaction SMILES: [NH:1]([C:8](=[O:44])[CH:9]([C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:26]=[CH:25][C:24]=2[NH:34]C(=O)OC(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[CH2:10][NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:34][C:24]1[CH:25]=[CH:26][C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH:9]([CH2:10][NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:44])=[CH:43][CH:42]=1
Reactant: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-({[(methylamino)-carbonyl]-amino}methyl)-2-oxoethyl]benzoyl}amino)-4-(3-thienyl)phenyl]carbamate (49 mg, 0.08 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 3 h. Concentration yielded a yellow residue that was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and evaporated to give N-[2-amino-5-(3-thienyl)-phenyl]-4-[2-anilino-1-({[(methylamino)carbonyl]amino}methyl)-2-oxoethyl]benzamide as a white solid. 1H NMR (DMSO-d6) δ 10.19 (s, 1H), 9.66 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 7.54-7.52 (m, 2H), 7.49-7.47 (m, 3H), 7.38 (dd, J=4.8, 1.3 Hz, 1H), 7.33 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (t, J=7.9 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.08 (t, J=6.0 Hz, 1H), 5.77 (q, J=4.4 Hz, 1H), 5.00 (s, 2H), 4.01 (dd, J=9.1, 5.6 Hz, 1H), 3.52 (ddd, J=13.5, 8.8, 5.0 Hz, 1H), 3.42 (dt, J=12.8, 6.4 Hz, 1H), 2.51 (d, J=4.7 Hz, 3H). MS (ESI) calcd [M+H]+ 514.1, found 514.1.