Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27]([CH2:29][C:30]#[CH:31])[CH2:26][C@H:25]3[C:32](OC(C)(C)C)=[O:33])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[NH2:46][OH:47]>>[OH:47][NH:46][C:32]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH2:28][N:27]([CH2:29][C:30]#[CH:31])[CH2:26]1)=[O:33]
Reactant: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Reactant: NO
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)NO)C1
Yield: 54 %

Procedure:
According to the procedure of Example 17, Steps 4 and 5, 117 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine-3-carboxylate, was treated with trifluoroacetic acid, followed by the reaction with hydroxylamine to give 56 mg of cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine-3-carboxamide in 54% yield. MS: 495 2(M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH2:37](O)[CH2:38][OH:39].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]3[O:39][CH2:38][CH2:37][O:18]3)=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C3OCCO3)=CS[C@H]12

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate (21.5 g., 41.5 mmol.) was combined with 11.6 ml. of ethylene glycol (0.2 mole) and toluenesulfonic acid monohydrate (0.197 g., 1.04 mmol.) in 500 ml. benzene. The mixture was refluxed for 10 hours using a Dean-Stark trap (1.5 ml. water collected), cooled, and evaporated in vacuo to dryness. The product was taken up in ethyl acetate and washed successively with sodium bicarbonate solution (2X), water (2X) and sodium chloride solution and subsequently dried over Na2SO4. Evaporation in vacuo to dryness gave a product which was chromatographed on 40 g. of silica gel using a benzene-ethyl acetate gradient. Crystallization of the purified product from methylene chloride-hexane gave benzhydryl 7-(2-thienylacetamido)-3-(1,3-dioxolan-2yl)-2-cephem-4-carboxylate as colorless needles (15.07 g., 64.2%: mp 142°-143° ; ir (CHCl3) 1780 cm-1 (β-lactam C = O); nmr (CDCl3) δ3.3-3.9 (m, 4, --CH2 --CH2), 3.83 (s, 2, side chain CH2), 5.10 (d, 1, J = 4.0 Hz, C6 --H), 5.17 (s, 1, acetal CH), 5.21 (s, 1, C4 --H) and 5.45 (q, 1, J = 4.0 and 8.0 Hz, C7 --H).
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[C:11]=2[N:13]=O)[CH:6]=[N:5]1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=O>O1CCCC1.CN(C)C1C=CN=CC=1.[Pd]>[CH3:23][O:24][CH2:25][C:26]1[O:15][C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[N:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:12]=3[C:11]=2[N:13]=1
Reactant: COCC(=O)Cl
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
A solution of the product from Step A (1.05 g, 4.75 mol) in tetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) was stirred under an atmosphere of hydrogen at room temperature for 18 hours. The reaction mixture was filtered, pyridine (1.0 mL, 12.3 mol) and methoxy acetyl chloride (0.43 mL, 4.75 mol) were added, and this mixture was stirred at room temperature. More pyridine (5.0 mL) was added and the reaction mixture was stirred at room temperature for 20 minutes followed by the addition of 4-dimethylaminopyridine (0.1 g); this mixture was heated at 60° C. for 3 hours followed by removal of solvents by heating at 220° C. for 30 minutes. The resulting dark liquid was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a yellow oil (200 mg, 16%): LC/MS m/z 262.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1-c1ncco1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1-c1ncco1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (15 mg) in 2 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 2 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified via flash column (35% ethyl acetate in hexane) to afford 8.0 mg of title compound as an off white solid. MS: (M+H)/z=542.3.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:27][C:26]1[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=[CH:10][N:9]=3)=[CH:15][CH:16]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Fc1cccnc1Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2C2CCOCC2)cc1

Procedure:
To a round-bottomed flask was added N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine (0.1433 g, 0.393 mmol) in ethyl acetate. Palladium hydroxide (0.028 g, 0.039 mmol) was added. The rxn was placed under 40 psi pressure. The reaction mixture was filtered through celite. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 3-fluoro-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 367.1 (M+1). IC50 (uM) 0.01772.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27].ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)CCl.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Cl)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc2c1cnn2C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
6-chloro-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.10 g, 0.419 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.109 g, 0.503 mmol), 1-hydroxy-7-azabenzotriazole (0.080 g, 0.587 mmol), and then EDC (0.112 g, 0.587 mmol) were added to DMSO (4.0 mL). N-methylmorpholine (0.184 mL, 1.676 mmol) was quickly added via syringe. The contents were stirred at RT overnight Additional HOAT and EDC were added, and the contents were stirred for another 6 h. The contents were slowly poured onto 45 mL of ice-water wherein solid precipitation occurred. The contents were stirred for 10 min., and then allowed to stand for another 10 min. The contents were filtered, the collected solid washed with ca. 5 mL of water. The solid was air dried for 15 min. then dried in vacuum oven at 45° C. for 24 h. The title compound was collected as a white solid (0.160 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3H) 1.42-1.58 (m, 8H) 2.14 (s, 3H) 2.52-2.58 (m, 1H) 4.36 (d, J=5.05 Hz, 2H) 5.04 (quin, J=6.57 Hz, 1H) 5.91 (s, 1H) 7.59 (d, J=1.52 Hz, 1H) 8.06 (s, 1H) 8.38 (s, 1H) 8.61 (t, J=4.80 Hz, 1H) 11.54 (s, 1H); MS (ES) [M+H]+ 400.9.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[NH:34][CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[N:34]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=3)[C:7]([CH3:16])([CH3:15])[CH2:6]2)=[O:4])[CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)CN(C(=O)CCl)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 75.5 %

Procedure:
To 2-chloro-1-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (397 mg, 1.31 mmol) in anhydrous THF (1.23 mL) was added triethylamine (366 μL, 2.60 mmol) and a solution of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (380 mg, 1.6 mmol) in anhydrous THF (730 μL). The reaction was heated to 65° C. for 3 h, cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0-80%, EtOAc/petrol), to give the title compound (447 mg, 75%) as a colourless solid. 1H NMR (Me-d3-OD): 8.15 (1H, d), 7.20 (1H, d), 7.09 (1H, dd), 5.51 (2H, s), 4.23-4.13 (1H, m), 4.09-3.96 (3H, m), 3.81-3.65 (2H, m), 3.64-3.47 (2H, m), 2.97-2.82 (2H, m), 2.67 (1H, dd), 1.48 (9H, s), 1.37 (6H, s), 1.26-1.22 (3H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]2[C:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].Cl[C:26]1[C:27]2[N:34]=[CH:33][S:32][C:28]=2[N:29]=[CH:30][N:31]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[CH:22]1([N:5]2[C:6]3[C:12]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=3[N:8]=[C:4]2[C@@H:2]([NH:1][C:26]2[C:27]3[N:34]=[CH:33][S:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH3:3])[CH2:23][CH2:24]1
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Reactant: Clc1ncnc2scnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Nc1ncnc2scnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
A mixture of [2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone (108 mg, 0.33 mmol), 7-chloro-thiazolo[5,4-d]pyrimidine (61 mg, 0.36 mmol) and DIPEA (170 μL, 0.98 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 400 as a pale yellow solid (110 mg, 39%). LCMS (Method K): RT 3.16 min [M+H]+ 468.02. 1H NMR (CDCl3, 400 MHz): δ 8.82 (0.7H, s), 8.77 (0.3H, s), 8.54 (0.3H, s), 8.52 (0.7H, s), 7.73-7.65 (1H, m), 7.17 (0.7H, d, J=8.02 Hz), 7.05-6.95 (1H, m), 6.67 (0.3H, d, J=8.45 Hz), 6.31-6.23 (0.3H, m), 6.14-6.04 (0.7H, m), 4.23-4.14 (1H, m), 3.93-3.72 (4H, m), 3.68-3.51 (2H, m), 3.47-3.33 (2H, m), 1.84 (1H, d, J=6.77 Hz), 1.75 (2H, d, J=6.76 Hz), 1.54-1.46 (0.7H, m), 1.41-1.29 (1H, m), 1.20-1.10 (0.3H, m), 1.03-0.93 (1H, m), 0.86-0.71 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH3:15])[CH3:14])=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C(O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH3:15])[CH3:14])=[C:4]([CH:3]=1)[NH2:16]
Reactant: CC(C)c1nccn1-c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nccn1-c1ccc(Cl)cc1N

Procedure:
A mixture of 1-(4-chloro-2-nitrophenyl)-2-isopropyl-1H-imidazole as synthesized in above Production Example 7, 0.98 g, tin (II) chloride dihydrate 4.16 g and ethanol 8.8 mL was heated under reflux for 2.7 hours. Neutralizing the reaction liquid with 2N aqueous sodium hydroxide solution under cooling with ice, chloroform was added to the reaction liquid and filtered through Celite. The Celite was washed with chloroform, transferred into a separating funnel and extracted twice with chloroform. The organic layer was washed with water, dried over magnesium sulfate and removed of the solvent by distillation, to provide 0.72 g of the title compound.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:68][O:69][C:70](=[O:83])[CH:71]([O:73][C:74]1[CH:79]=[CH:78][C:77](Br)=[C:76]([O:81][CH3:82])[CH:75]=1)[CH3:72]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43]([C:77]3[CH:78]=[CH:79][C:74]([O:73][CH:71]([C:70]([O:69][CH3:68])=[O:83])[CH3:72])=[CH:75][C:76]=3[O:81][CH3:82])[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Reactant: COC(=O)C(C)Oc1ccc(Br)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)Oc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c(OC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture under N2 of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (95 mg, 0.20 mmol, 1.00 eq.) and potassium phosphate (85 mg, 0.40 mmol, 2.00 eq.) in toluene (0.6 mL) and water (0.035 mL) was stirred at r.t. for 2 min. A solution of (±)-2-(4-Bromo-3-methoxy-phenoxy)-propionic acid methyl ester (58 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 2 days. The mixture was allowed to cool to r.t., filtered through celite and concentrated in vacuo. The crude residue, redissolved in MeCN (1.5 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a colorless oil.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([CH3:19])=[CH:14][CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=2)[CH:9]=1)=[O:7])C.O.Cl>CO>[Br:27][C:23]1[N:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=3)[C:17](=[O:18])[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(=O)c(C(=O)O)cn(Cc3cccc(Br)n3)c2n1
Yield: 69.4 %

Procedure:
0.110 g (4.62 mmol) of lithium hydroxide was added to 0.620 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester dissolved in 50 mL methanol and 100 mL of water and was heated at 60° C. for 3 hours. After the reaction was cooled to room temperature 1M HCl was added until the product precipitated from solution. The white solid was collected by vacuum filtration to yield 0.400 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21]([NH:25][CH2:26][CH2:27][NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][C:35]([S:39]([NH:42][C:43]6[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH:51]=6)[C:48]([OH:50])=[O:49])(=[O:41])=[O:40])=[CH:36]5)=[CH:31][CH:30]=4)=[CH:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].Cl[C:54](Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl.Cl>C(=O)([O-])[O-].[Na+].[Na+].O.C1COCC1.CS(C)=O.O.C(#N)C>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21]([N:25]4[CH2:26][CH2:27][N:28]([C:29]5[CH:38]=[C:37]6[C:32]([CH:33]=[CH:34][C:35]([S:39]([NH:42][C:43]7[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH:51]=7)[C:48]([OH:50])=[O:49])(=[O:41])=[O:40])=[CH:36]6)=[CH:31][CH:30]=5)[C:54]4=[O:56])=[CH:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(NS(=O)(=O)c2ccc3ccc(NCCNc4ccc5ccc(S(=O)(=O)Nc6ccc(O)c(C(=O)O)c6)cc5c4)cc3c2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc3ccc(N4CCN(c5ccc6ccc(S(=O)(=O)Nc7ccc(O)c(C(=O)O)c7)cc6c5)C4=O)cc3c2)ccc1O
Reaction time: 0.25 h

Procedure:
To 8 mg (0.011 mmol) of compound 121 in 2 mL of saturated sodium carbonate and 2 mL of water was added 3 mg (0.010 mmol) of triphosgene dissolved in 0.5 mL of THF, dropwise. The addition was made over a period of 15 min. The reaction was judged incomplete by HPLC, so another 4.5 mg (0.015 mmol) of triphosgene in 0.5 mL of THF was added as before. After 2 hours, the reaction was acidified with 6N HCl and a precipitate formed. The suspension was frozen and lyophilized. The resulting solid was dissolved in dimethyl sulfoxide/water/acetonitrile and purified by reverse-phase HPLC (C18, 250×20 mm column) using trifluoroacetic acid (TFA) buffer system (Buffer A: 5% acetonitrile, 95% water, 0.05% TFA; Buffer B: 95% acetonitrile, 5% water, 0.05% TFA; 19 mL/min; 0–100% B in 20 min). This provided 1 mg of the desired compound 122.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH2:18][N:19]([CH:21]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:22](=[O:41])[N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:25][CH2:24]2)[CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:50]>O1CCOCC1>[ClH:49].[ClH:50].[ClH:49].[ClH:49].[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][CH:21]([N:19]([CH3:20])[CH2:18][CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)[C:22]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:25][CH2:24]2)=[O:41])=[CH:48][CH:47]=1
Reactant: CN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CC1Cc2ccccc2CN1)C(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The material from Step B was taken up in a 4M solution of HCl in dioxane (30 mL). The reaction was stirred at r.t. overnight under nitrogen. The mixture was concentrated to remove dioxane, and the resulting film was triturated with diethyl ether and then concentrated (2×). Trituration with diethyl ether, isolation by suction filtration, and drying at r.t. under vacuum gave about 0.103 g of the final compound as yellow solids (97%). MS (m/z, ES+): 586.3.
Reaction SMILES: [CH:1]([C:4]1[N:20]=[C:7]2[CH:8]=[C:9]([NH:12]C(=O)OC(C)(C)C)[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl>O1CCCC1>[CH:1]([C:4]1[N:20]=[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(N)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a solution of tert-butyl 2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (400 mg, 1.45 mmol) in tetrahydrofurane (10 ml) is added hydrochloric acid (5 N in diethyl ether, 20 ml, 100 mmol). The resulting suspension is stirred for 18 hours at 25° C. The solvent is evaporated and the residue diluted with ethyl acetate, made basic with sodium hydroxide 2N and washed with water and brine. The organic layer is dried with magnesium sulfate and the solvent is evaporated under reduced pressure. The residue (416 mg) is purified by chromatography on a 20 g silicagel column using heptane/ethyl acetate 50-100% as eluent affording 2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (159 mg, 62.3%) as a white solid. Mp.: 174-6° C. MS: m/z=177.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH3:21])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].OO.C(=O)([O-])[O-:25].[K+].[K+].O>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:25])[CH:8]=3)=[CH:10][C:11]([CH3:21])=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-c2ccnc(C(N)=O)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 628.7 %

Procedure:
To a solution of 2-cyano-4-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 32; 1.0 g, 0.0036 mol) in 25 mL of DMSO was added hydrogen peroxide (0.43 mL, 0.0036 mol) and potassium carbonate (0.072 g, 0.00051 mol) at zero degrees C. The reaction mixture was warmed up to room temperature over 1 hour. Water was added and the mixture was stirred for 0.5 hours. The resulting precipitate was collected by filtration to give 0.95 g (89% yield) of product as a pale yellow solid: mp: 168-170° C.; Anal. Calc'd. for C16H13FN4O: C, 64.86; H, 4.42; N, 18.91. Found: C, 64.48; H, 4.27; N, 18.80.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.O=[Pt]=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:16](=[O:17])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Yield: 105.6 %

Procedure:
A solution of 2-benzothiazolyl 2-[1-(phenylmethyl)-4-piperidinyl]vinyl ketone (146 mg, 0.4 mmol) in a mixture of ethyl acetate/ethanol (10 ml/10 ml) was treated with PtO2 (20 mg) and hydrogenated at 50 psi for 3 hours. The mixture was filtered through Celite® and the filtrate was concentrated to dryness to give 0.154 g of a dark oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 37 mg of the title compound as a brown oil.