Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH:27]2[CH2:31][CH2:30][C:29](=O)[CH2:28]2)[CH3:26])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[F:33][C:34]([F:42])([F:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[OH-].[Na+]>ClCCCl>[CH3:15][C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH3:26])[C@H:27]2[CH2:31][CH2:30][C@@H:29]([N:38]3[CH2:39][CH2:40][CH:35]([C:34]([F:42])([F:41])[F:33])[CH2:36][CH2:37]3)[CH2:28]2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Cc1cccc(S(=O)(=O)N(C)C2CCC(=O)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cccc(S(=O)(=O)N(C)[C@H]2CC[C@@H](N3CCC(C(F)(F)F)CC3)C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.9 %

Procedure:
Sodium triacetoxyborohydride (340.4 mg, 1.61 mmol) was added to a solution of 3-((3,N-dimethyl)benzenesulfonamido)cyclopentan-1-one (280.7 mg, 1.05 mmol), and 4-trifluoromethylpiperidine (194.8 mg, 1.27 mmol) in 1,2-dichloroethane (10 ml). The resulting mixture was stirred at room temperature overnight (20 hours). 1M Aqueous sodium hydroxide (25 ml) was added and the mixture extracted with dichloromethane (2×10 ml). The combined extracts were dried (K2CO3) and evaporated. The residue was purified by medium pressure silica chromatography, eluting with 2.5% methanol in dichloromethane, to afford cis-3,N-dimethyl-N-(3-(4-trifluoromethylpiperidin-1-yl)cyclopentyl) -benzenesulfonamide (93.1 mg, 22%). A portion of this material was dissolved in ethyl acetate, warmed and treated with hydrogen chloride in diethyl ether to afford the title compound as a white crystalline solid; δH (400 MHz, CD3OD) 1.68 (2H, m), 1.83 (4H, m), 2.06-2.18 (4H, m), 2.44 (3H, s), 2.60 (1H, m), 2.79 (3H, s), 2.99 (2H, m), 3.51 (1H, m), 3.63 (1H, m), 3.69 (1H, m), 4.43 (1H, m), 7.47 (2H, m), 7.63 (2H, m); m/z (ES+) 405 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[Br-].[CH:28]1([Zn+])[CH2:30][CH2:29]1>C1COCC1>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([CH:28]2[CH2:30][CH2:29]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: [Zn+]C1CC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(C3CC3)c(-c3cccc(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (0.100 g, 229 μmol), and tetrakis-(triphenyl-phosphine)palladium (13.2 mg, 11.4 μmol) were dissolved in THF (2.5 mL). Cyclopropylzinc(II)bromide (0.5M in THF, 1800 μl, 900 μmol) was added drop by drop at 0° C. and the reaction mixture was stirred at room temperature for 1.5 hours and at reflux temperature overnight. The mixture was partitioned between water and ethyl acetate and the organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 5% to 40% ethyl acetate in n-heptane) to give the desired product (24 mg, 26%) as white solid; MS (EI): 398.2 (M+H). As side product 11 mg of 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl)-amide (Example 2) was isolated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:19]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([N:27]1[CH2:32][CH2:31][N:30]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[O:16][CH3:17])[NH:9][CH:8]=2)=[O:15])[CH2:29][CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12

Procedure:
Precursor 5b, 1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 4d, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C21H20ClN4O4: 427.12; found 427.12. HPLC retention time: 1.28 minutes (column A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 59.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (211 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 169 mg (59.4%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: N#CC1CN(CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidine-3-carbonitrile (44.8 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol, 73.2%) as a white solid. MS (M+H)+=653.1; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.56 (t, J=73.7 Hz, 1H), 5.75 (s, 2H), 4.57 (t, J=6.6 Hz, 2H), 3.24-3.40 (m, 3H), 2.50 (t, J=6.6 Hz, 2H), 2.08 (quin, J=6.5 Hz, 2H), 1.65 (s, 9H), 0.91-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][N:8]3[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[C:6]([CH3:19])=[N:7]3)=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NS(=O)(=O)c3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfonamide formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 54 mg, 0.20 mmol) in dichloromethane (1 mL) was added triethylamine (72 μL, 0.51 mmol) and phenylsulfonyl chloride (36 μL, 0.25 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (0.5 mL) and treated with aqueous LiOH solution (1 M, 0.4 mL). After 1.5 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% trifluoroacetic acid).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH2:21][CH3:22].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:10]=2[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into a 25 ml sealed tube containing a solution of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (100 mg, 0.26 mmol, 1.00 equiv) in dioxane (5 mL) was added 2-(tributylstannyl)pyridine (96 mg, 0.26 mmol, 1.00 equiv) and Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.16 equiv) at room temperature under nitrogen. The sealed tube was heated with stirring overnight at 100° C. The reaction mixture was cooled to room temperature and diluted with 20 mL of H2O, extracted with 3×50 mL of ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 49.0% in 27 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-N-[6-ethyl-5-(pyridin-2-yl) thieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (12 mg) as a light yellow oil. MS (ES, m/z): 382 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.75-8.41 (d, 1H), 7.90 (s, 1H), 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 6.73-6.71 (d, 1H), 3.95-3.89 (m, 1H), 2.89-2.81 (dd, 2, H), 2.29 (s, 6H), 2.25-2.04 (m, 3H), 1.90-1.86 (m, 2H), 1.47-1.38 (m, 2H), 1.32-1.27 (m, 3H), 1.05-1.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].Cl.N[C@@H:20]([C:24]1(C)CCCCC1)[C:21](O)=O>>[CH3:1][C:2]1([C@H:3]([NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6])[C:13]([OH:15])=[O:14])[CH2:17][CH2:24][CH2:20][CH2:21][CH2:16]1
Reactant: CC1([C@H](N)C(=O)O)CCCCC1
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Product: C=CCCCOC(=O)N[C@H](C(=O)O)C1(C)CCCCC1

Procedure:
(2S)-(1-methylcyclohexyl) {[(pent-4-en-1-yloxy)carbonyl]amino}acetic acid was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using (2S)-amino(1-methylcyclohexyl)acetic acid-HCl instead of t-butylglycine. LRMS (ESI) m/z 347.3 [(M+Na+CH3CN)+; calcd for C17H28N2NaO4: 347.2].
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[F:46][C:47]1[CH:57]=[C:56](F)[CH:55]=[CH:54][C:48]=1[C:49]([N:51]([CH3:53])[CH3:52])=[O:50]>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:56]2[CH:55]=[CH:54][C:48]([C:49](=[O:50])[N:51]([CH3:53])[CH3:52])=[C:47]([F:46])[CH:57]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Reactant: CN(C)C(=O)c1ccc(F)cc1F
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 2,4-difluoro-N,N-dimethyl-benzamide. 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J=8.08 Hz, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 6.67 (dd, J=10.61, 2.27 Hz, 1 H) 3.67-3.73 (m, 1 H) 3.56-3.62 (m, 1 H) 3.08-3.18 (m, 4 H) 2.97 (d, J=1.52 Hz, 3 H) 2.77 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.43 (s, 3 H); LCMS for C24H28FNO6 m/z 446.00 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.COCCOC.O>[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Reactant: Nc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Nc1ccncc1-c1ccnc2c1cnn2-c1cccc(S(N)(=O)=O)c1
Temperature: 105 °C
Yield: 33.1 %

Procedure:
Example 79 was prepared according to the general procedure in Example 2, except heating at 105° C. for 2.25 h, and using the following materials: Intermediate 1A (50 mg, 0.084 mmol), 4-aminopyridin-3-ylboronic acid (81 mg, 0.59 mmol), sodium carbonate (31 mg, 0.292 mmol), EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (9.65 mg, 8.35 μmol). Example 79 was isolated as a yellow solid (10.2 mg, 32.3%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 5% Solvent B to 85% Solvent B over 12 min, ret. T=5.7 min. 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.93-9.00 (1 H, m), 8.71-8.79 (1 H, m), 8.60-8.67 (1 H, m), 8.22-8.27 (1 H, m), 8.18 (1 H, s), 8.09-8.14 (1 H, m), 7.84-7.93 (1 H, m), 7.69-7.80 (1 H, m), 7.37-7.47 (1 H, m), 6.79-6.92 (1 H, m) LC/MS (Condition B): ret. T=1.75 min, (M+H)+ 366.98. Analytical HPLC: (Condition A): >97%, ret. T=13.51 min, (Condition B): >97%, ret. T=15.81 min, (Condition C): >99%, ret. T=4.54 min, (Condition D): >97%, ret. T=4.87 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: O=C(Cc1ccccc1F)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2F)cc([N+](=O)[O-])c1O
Yield: 23.9 %

Procedure:
To a solution of 2-(2-fluorophenyl)-1-phenylethanone (200 mg, 0.93 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (196 mg, 0.93 mmol) and urea (846 mg, 1.4 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 13 (100 mg, yield 23.8%). 1H NMR (DMSO-d6 400 MHz): δ 10.26 (s, 1H), 8.81 (s, 1H), 7.53 (s, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.22-6.87 (m, 7H), 5.22 (s, 1H), 4.00 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); MS (ESI): m/z 450.2 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@H](N)COc2ccc(F)cc21
Yield: 90.3 %

Procedure:
A solution of 0.85 g (2.74 mmol) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml dichloromethane was treated with 21 ml trifluoroacetic acid for 3 hours. Extraction with aqueous sodium bicarbonate solution and dichloromethane and removal of the solvent gave 0.52 g (90%) (S)-7-amino-2-fluoro-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one as white solid, MS m/e (%): 211.3 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf2O (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][CH:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) is dissolved in a minimum amount of water and 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) are added. The reaction is then heated at 80° C. for 3 days. After cooling to room temperature, the mixture is concentrated under reduced pressure, is taken up in ethyl acetate (15 mL) and washed with saturated aqueous ammonium chloride (2×10 mL) followed by water (10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated as a colourless solid (80% yield).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CNCC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 206.4 %

Procedure:
To a stirred solution of 247A (310 mg, 1.21 mmol) in 2 mL of CH2Cl2 at room temperature was added TFA (2.00 mL, 26.0 mmoL). This mixture was stirred at room temperature for 15 min and concentrated in vacuo to give 390 mg of (3R,4R)-rel-4-azido-3-methoxypiperidine as the TFA salt. Compound 247B was prepared from this TFA salt (52.0 mg, 0.19 mmoL) in a similar process as described for 146E. It had an analytical HPLC retention time=1.97 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=409.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:7][CH:6]=1.[NH2:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]([CH2:4][C:5]2[CH:14]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16](=[O:22])[CH2:17][CH2:18][C:19]([NH:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:7][CH:6]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)c2ccccc12
Reactant: C=CC(N)CC(=O)OCC
Agent: Cl
Product: C=CC(CC(=O)OCC)NC(=O)CCC(=O)N(Cc1ccccc1)c1ccc(C=NN)c2ccccc12

Procedure:
The title compound was prepared in the manner of Example 1 substituting 4-[[4-(aminoiminomethyl)naphthyl]amino]-4-oxobutanoic acid hydrochloride for 4-[[4-(aminoiminomethyl)-3-phenyl]amino]-4-oxobutanoic acid hydrochloride and using ethyl 3-amino-4-pentenoate. The product was purified by reverse phase HPLC using the conditions of Example 1 to afford the title compound. The product was verified by 13C NMR (CD3OD) δ 13.2, 30.5, 31.3, 39.0, 48.5, 60.4, 114.6, 120.3, 123.1, 123.9, 124.8, 126.6, 127.0, 128.0, 128.1, 130.3, 136.8, 137.4, 167.6, 171.0, 172.6, 173.0; Chemical Ionization Mass Spectrometry (MH+)=411