Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(N(C)C)=O.C1OC1C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[O:28][S:42]([CH3:41])(=[O:44])=[O:43])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCCC(=S)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: CC1CO1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Reaction time: 4 h

Procedure:
To a solution of 2.5 g. of 7-cyanomethylthioacetamido-3-cephem-3ol-4-carboxylic acid p-nitrobenzyl ester in 25 ml. of dry dimethylacetamide is added 1 ml. of propylene oxide and one equivalent of methanesulfonyl chloride. After stirring for 4 hours, the mixture is taken up in ethyl acetate and washed with saturated sodium chloride solution. Solvent is removed from the ethyl acetate solution under reduced pressure and the residue is purified by thin layer chromatography yielding the product 7-cyanomethylthioacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (brown solid, 1.73 g, 94.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.84 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 6.78 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)[C:10]2[C:9]([O:26][CH3:27])=[C:8]3[O:28][CH2:29][O:30][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.[BrH:31].O.[Br]>>[CH3:1][N:2]1[C@@H:11]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)[C:10]2[C:9]([O:26][CH3:27])=[C:8]3[O:28][CH2:29][O:30][C:7]3=[C:6]([Br:31])[C:5]=2[CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(cc3c(c2OC)OCO3)CCN1C
Reactant: Br
Agent: [Br]
Solvent: O
Product: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(c(Br)c3c(c2OC)OCO3)CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Synthesis of 9-aminonoscapine was shown in Scheme 1. Briefly, noscapine (1) was dissolved minimum amount of 48% hydrobromic acid and then cautiously added freshly prepared bromine water. The reaction mixture stirred for 1 h at 25° C. and the resultant mixture was basified to pH 10 to afford 9-bromonoscapine in 82% yield. Refluxing compound 2 in DMF with sodium azide and sodium iodide for 15 hours gave its azido derivative (3) in quantitative yield. Reduction of azido derivative with tin chloride in the presence of thiophenol and triethylamine in THF for 2 h at 25° C. afforded the title compound, 9-aminonoscapine (4) in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10]([C:25]3[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: N#Cc1cccc(F)c1-n1cc(Br)c2[nH]nc(N)c2c1=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: CN(C)C=O
Product: Cn1ccc(-c2cn(-c3c(F)cccc3C#N)c(=O)c3c(N)n[nH]c23)n1
Temperature: 130 °C
Yield: 27.4 %

Procedure:
A mixture of 2-(3-amino-7-bromo-4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-3-fluorobenzonitrile obtained in Step G (160 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (191 mg), tetrakis(triphenylphosphine)palladium(0) (53 mg), aqueous sodium carbonate solution (2 M, 0.460 mL) and N,N-dimethylformamide (10 mL) was heated with microwave irradiation at 130° C. for 90 min under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give a crude product. The crude product was crystallized from ethyl acetate/diethyl ether to give the title compound (44 mg).
Reaction SMILES: Br[CH2:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][C:4]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:14])[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccccc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)C(=O)Cn1cncn1
Yield: 48.3 %

Procedure:
74 g (0.29 mol) of 1-bromo-3,3-dimethyl-4-phenylbutan-2-one, 40 g (0.58 mol) of 1,2,4-triazole and 80 g of potassium carbonate are dissolved in 700 ml of acetone, and the solution is heated under reflux for 3 hours. Thereafter, it is allowed to cool and is filtered off under suction from the inorganic residue, and the filtrate is concentrated. The residue is recrystallized from ether. 34.1 g (48.4% of theory) of 3,3-dimethyl-4-phenyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 79° C. are obtained. ##STR25##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC(C)(CO)n1cc(N)cn1
Reactant: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 37.9 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 105, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (120 mg) obtained in Step H of Example 103 and acetic acid (48 μL) in ethanol (20 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (110 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>CC#N>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc2c(Br)cccn2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-pyrazolo[1,5-a]pyridin-2-ylamine (Intermediate 3) (259 mg, 1.22 mmol) was dissolved in dry CH3CN (10 mL) at 5° C. and Et3N (425 μL, 3.05 mmol) was added followed by the cyclopropane carbonyl chloride (278 μL, 3.05 mmol). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash column chromatography (2:1 petroleum ether 40-60:EtOAc) yielded cyclopropanecarboxylic acid (4-bromo-pyrazolo[1,5-a]pyridin-2-yl)-amide (Intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)c(Cl)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.16 (d, J 8.4, 1H), 7.31 (s, 1H), 7.52 (d, J 8.4, 1H), 7.77 (t, J 7.8, 11H), 7.89 (d, J 6.5, 11H), 8.16 (d, J 8.1, 1H), 8.22 (d, J 6.4, 11H), 8.59 (d, J 6.2, 11H), 8.64 (t, J 5.8, 11H), 9.49 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:28][C:29]([C:32]([F:35])([F:33])[F:34])=[N:30][N:31]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.69(1H, bs), 9.53(1H, s), 8.91 (1H, s), 8.65(1H, dd), 8.11 (1H, d), 7.64(2H, d), 7.45(5H, m), 7.15(2H, d), 5.19(2H, s); m/z (M+1+) 464.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8].Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)/[C:20](=[N:26]/[OH:27])/[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8]
Reactant: CO[C@]1(c2csc(Sc3ccc4c(c3)CCC4=O)c2)CCO[C@@H]1C
Reactant: NO
Agent: Cl
Product: CO[C@]1(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCO[C@@H]1C
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one oxime in 87% yield, m.p. 140°-142° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:19]=[C:20]4[C:24]=3[NH:23][N:22]=[CH:21]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:29][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:25]([F:27])([F:26])[F:28])[CH:19]=[C:20]3[C:24]=2[NH:23][N:22]=[CH:21]3)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (62 mg, 0.159 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The product was purified by preparative HPLC. The trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 37 mg (58%). 1H-NMR (CDCl3, 500 MHz) δ 9.60 (bs, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.49 (m, 2H), 7.41 (m, 3H), 7.25 (s, 1H), 4.71 (s, 2H), 3.61 (s, 2H), 2.57 (m, 2H), 2.10-2.40 (m, 4H), 2.22 (s, 3H), 1.96 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.9, 139.5, 135.2, 129.0, 127.1, 126.9, 124.7 (q, J=272 Hz), 123.2 (q, J=32 Hz), 121.9, 120.1, 118.3, 80.8, 72.0, 52.0, 46.3, 40.7, 32.9. Mass spec.: 404.01 (MH)+. Accurate mass spec.: m/z [MH]+, Δ=4.4 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]=[C:39](B(O)O)[CH3:40]>CN(C=O)C.O>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[CH:3][C:2]([C:39]([CH3:40])=[CH2:38])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: C=C(C)B(O)O
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
A mixture of 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (103 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol, EMD) and prop-1-en-2-ylboronic acid (52.4 mg, 0.610 mmol) in DMF (1.8 mL) and Water (0.2 mL) was degassed by vacuum and purged with Argon. To the resulting mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16.72 mg, 0.020 mmol, Aldrich) and then heated under microwave conditions at 120° C. for 20 min. The reaction mixture was concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in hexanes) to yield 25 mg of desired product as a light yellow solid. MS (ESI) 467 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 94.8 %

Procedure:
Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200° C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 μl, 0.295 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): δ7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:6](N)[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CCOC(C)=O>[CH3:12][C:11]([O:10][C:8]([N:4]1[CH2:5][CH:6]([C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:2]([OH:1])[CH2:3]1)=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)C1CN(C(=O)OC(C)(C)C)CC1O
Yield: 65.6 %

Procedure:
To a solution of 3-hydroxy-4-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (202 mg, 1.14 mmol) in CH2CI2 (5 mL) was added CBZ-leucine (302.9 mg, 1.14 mmol), HOBT (154 mg, 1.14 mmol) and EDC (262.2 mg, 1.37 mmol). The reaction was allowed to stir until complete by TLC analysis whereupon it was diluted with EtOAc and washed sequentially with pH 4 buffer, sat. K2CO3, water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3:1 EtOAc:hexanes) gave 325 mg of the title compound: MS (ES+) 450.3 (MH+), 472.2 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+].Cl>C1(C)C=CC=CC=1>[NH:18]1[C:6]([C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:7][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nnn[nH]2)cc1
Yield: 44.1 %

Procedure:
A mixture of p-amino benzonitrile (2 g, 16.9 mmol), triethylamine hydrochloride (3.49 g, 25.38 mmol) and sodium azide (1.65 g, 25.38 mmol) were taken in anhydrous toluene (20 ml) and heated to reflux for 24 hr. The reaction mixture was cooled to room temperature and neutralized with dilute hydrochloric acid. The resultant precipitate was filtered, washed with water then dried to give 4-(1H-tetrazol-5-yl)-phenylamine (1.2 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[C:10]=2[Cl:35])=[C:4]([F:27])[CH:3]=1
Reactant: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1c(=O)c(Cl)c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20C (60 mg, 0.136 mmol) was dissolved in 2 mL DCM. NCS (22 mg, 0.165 mmol) was added. The mixture was stirred at room temperature overnight. Example 29 (35.3 mg, 54%) was isolated by preparative HPLC separation. 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1 H) 7.45 (d, J=8.0 Hz, 1 H) 7.38 (d, J=8.0 Hz, 1 H) 7.10 (t, J=8.0 Hz, 1 H) 4.51 (m, 1 H) 4.03 (m, 1 H) 3.88 (m, 1 H), 3.82 (s, 3 H) 3.68 (d, J=4 Hz, 2 H). [M+H] calc'd for C17H15BrClFN4O4, 475; found, 475.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][CH:26]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C#N)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 55 °C
Yield: 88.6 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.0317 mol), tert-butyl 4-[(E)-2-cyanovinyl]piperidine-1-carboxylate (10.7 g, 0.0430 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (470 uL, 0.0032 mol) in acetonitrile (100 mL, 2 mol) was heated at 55° C. overnight. The solvent was removed by rotary evaporation to give an orange foam. The resultant material was chromatographed with 0-100 ethyl acetate/hexane to give 15.5 g white solid/foam (100% yield). 1H NMR (400 MHz, CDCl3): δ 8.93 (1H, s); 8.41 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 4.32 (2H, m); 4.15 (1H, br); 3.6 (2H, t); 3.22-3.05 (2H, m); 2.95-2.6 (2H, m); 2.15 (1H, m); 1.95 (1H, m); 1.45 (9H, s); 1.35 (3H, m); 0.97 (3H, t); 0 (9H, s). LCMS (M+1): 552.