Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([N:19]3[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]3)=[CH:14][C:13]=2[CH3:27])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:37]OS(OC)(=O)=O.C(OCC)(=O)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([N:19]3[C:24](=[O:25])[N:23]([CH3:37])[C:22](=[O:26])[CH:21]=[N:20]3)=[CH:14][C:13]=2[CH3:27])=[O:7])=[CH:33][CH:34]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2C)cc1C(=O)c1ccc(F)cc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)n(C)c3=O)cc2C)cc1C(=O)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-{4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-3,5-dimethyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (50 mg) and potassium hydroxide (12 mg) in methanol (2 mL) was added dimethylsulfate (41 mg) to produce a thick slurry. After 3 h, the reaction mixture was diluted into ethyl acetate, washed with 1N aqueous sodium hydroxide, the organic layer dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was flash chromatographed on silica gel (20%-35% ethyl acetate/hexanes) to afford the title compound of this EXAMPLE as a colorless solid, 24 mg. MS Calc.:475.5 Found:476.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH:36][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:20])([F:21])[F:22])[C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2cccc(C(F)(F)F)c2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cccc(C(F)(F)F)c2F)n1
Yield: 28.7 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.085 g; 0.254 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.065 g; 0.281 mmol), HATU (0.107 g; 0.281 mmol), N,N diisopropylethylamine (0.094 mL; 0.703 mmol), in DMF (3 mL). The crude mixture was purified by flash column chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.034 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH2:22]([S:29]CCN)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:29][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: NCCSCc1ccccc1
Product: O=C(NCCSCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 2-(benzylsulfanyl)ethanamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.33-10.38 (1H, m) 8.22 (1H, t, J=5.66 Hz) 8.00 (1H, d, J=5.47 Hz) 7.76 (1H, d, J=5.47 Hz) 7.45-7.51 (1H, m) 7.15-7.36 (5H, m) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.42, 1.85 Hz) 3.75 (2H, s) 3.35-3.47 (2H, m) 2.51-2.58 (2H, m)
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH3:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Li+]>O1CCOCC1.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>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3](=[O:14])[N:4]([CH3:13])[C:5]([NH:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)=[N:6][CH:7]=2)=[CH:25][C:24]=1[F:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1c(NCC2CC2)ncc(Br)c1=O
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
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: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(NCC2CC2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A suspension of 5-bromo-2-(cyclopropylmethylamino)-3-methylpyrimidin-4(3H)-one (0.112 g, 0.434 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.128 g, 0.521 mmol), Pd(PPh3)4 (0.025 g, 0.022 mmol) and lithium chloride (0.092 g, 2.17 mmol) in dioxane (1.5 mL) and 2M aqueous Na2CO3 (1.5 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude black solid. The crude product was purified by flash column chromatography, eluting with 10:1 dichloromethane/EtOAc. The desired product (0.128 g, 78%) was obtained as a foamy off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.57 (dd, J=2.0, 13.7 Hz, 1H), 7.49-7.31 (m, 7H), 7.19 (t, J=9.0 Hz, 1H), 5.19 (s, 2H), 3.35 (s, 3H), 3.24 (t, J=6.1 Hz, 2H), 1.16 (m, 1H), 0.44 (m, 2H), 0.25 (m, 1H). LRMS (APCI pos) m/e 380 (M+1).
Reaction SMILES: [C:1]([NH2:6])(=[S:5])[CH2:2][CH2:3][CH3:4].[CH:7]([CH:9](Cl)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH2:2]([C:1]1[S:5][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCCC(N)=S
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CCCc1ncc(C(=O)OCC)s1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
A mixture of 38 g of thiobutyramide, 54.2 g of ethyl 2-formyl-2-chloro-acetate, 185 ml of dioxane and 22 g of magnesium carbonate was heated for 4 hours at 60°C and the precipitate formed was removed by filtration. The dioxane was distilled from the filtrate and the residue was taken up in 665 ml of a 1-1 ethyl ether-water mixture. The ether phase was recovered by decantation and was washed with aqueous 10% hydrochloric acid solution and then with water until the wash waters were neutral, dried over magnesium sulfate and distilled to dryness. The residue was distilled to obtain 57 g of ethyl 2-n-propylthiazol-5-carboxylate boiling at 95°-106°C under 0.5 mm Hg.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:28]=[N:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[OH:40]>N1C=CC=CC=1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:28]=[N:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[OH:40])=[O:24])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
To a mixture of 1.15 g of WSC and 8 ml of pyridine, 1.43 g of 3-tert-butoxycarbonylamino isonicotinic acid was added and stirred at room temperature for 15 minutes. To the reaction mixture, 1.06 g of 2-amino-4-(trifluoromethyl)phenol was added and stirred while heating at 60° C. for two hours. Thereafter, the mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.79 g of 3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C1COCC1.O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:22]2[N:21]=[N:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Potassium tert-butoxide (0.87 g, 7.75 mmol) was added in portions to a solution of 4-hydroxybenzoic acid methyl ester 1 (1.15 g, 7.56 mmol) in anhydrous THF (25 ml). The mixture was stirred at room temperature for 30 minutes, then 3,6-dichloro-pyridazine (1.12 g, 7.56 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and heated at reflux for 14 h. The mixture was cooled to room temperature and diluted with water (100 ml). The formed precipitate was collected by filtration, washed with water and dried to obtain 1.315 g (66%) of 4-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH3:41])[C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (45.8 mg, 0.079 mmol) and sodium triacetoxyborohydride (83.7 mg, 0.395 mmol) in DMF (1 mL) was added acetic acid (23.7 mg, 22.6 μL, 0.395 mmol). The reaction mixture was heated to 60° C., then 37% w/w aq. formaldehyde (9.48 mg, 23.5 μL, 0.316 mmol) was added dropwise over 1 min. The reaction mixture was heated at 60° C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+): 594.2; Found: 593.7 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:29]=1)[C:7]([N:9]=[S@@:10]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:30]([C:32]1[CH:33]=[C:34]([NH:38][C:39]([C:41]2[N:45]([CH3:46])[N:44]=[C:43]([CH3:47])[CH:42]=2)=[O:40])[CH:35]=[CH:36][CH:37]=1)#[CH:31]>>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][S@:10](=[O:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:9][C:7](=[O:8])[C:6]1[CH:29]=[C:2]([C:31]#[C:30][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39]([C:41]3[N:45]([CH3:46])[N:44]=[C:43]([CH3:47])[CH:42]=3)=[O:40])[CH:33]=2)[CH:3]=[N:4][CH:5]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCO[Si](C)(C)C(C)(C)C)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 506 (step 3), (S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]nicotinamide and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide are converted to the title compound.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][O:27][C:28]2[C:33]([NH2:34])=[C:32]([NH:35][CH2:36][CH:37]3[CH2:45][CH2:44][C:40]4([CH2:43][CH2:42][CH2:41]4)[CH2:39][CH2:38]3)[N:31]=[C:30]([C:46]#[N:47])[N:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][O:27][C:28]2[C:33]([NH:34][S:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[C:32]([NH:35][CH2:36][CH:37]3[CH2:45][CH2:44][C:40]4([CH2:43][CH2:42][CH2:41]4)[CH2:39][CH2:38]3)[N:31]=[C:30]([C:46]#[N:47])[N:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2N)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2NS(=O)(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzylsulfonylchloride (0.50 mmol) is added to a solution of 4-(2-{5-amino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid t-butyl ester (167 mg) and pyridine (0.66 mmol) in CH2Cl2 (3 mL) are added at 0° C. After stirring at room temperature for 1 h, benzylsulfonylchloride (0.50 mmol), pyridine (0.66 mmol) and DMAP (catalytic amount) are added to the reaction mixture again. The reaction mixture is stirred at room temperature for 1 h and diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2-{2-cyano-5-phenylmethanesulfonylamino-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[N:15][N:16]([CH2:26][CH3:27])[C:17]=2[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.BrC1C=CC(C=O)=CC=1.C(N1C(N)=CC(C2C=CC=CN=2)=N1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[N:15][N:16]([CH2:26][CH3:27])[C:17]=2[NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CC(=O)O)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: CCn1nc(-c2ccccn2)cc1N
Agent: O=Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CCn1nc(-c2ccccn2)c(C(CCO)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
3-(4-Bromophenyl)-3-(5-((tert-butoxycarbonyl)amino)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)propanoic acid (0.786 g, 1.525 mmol, prepared using W from 4-bromobenzaldehyde, X from 1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine then Y) was added in one portion to a mixture of LAH (0.232 g, 6.10 mmol) and Et2O (15.0 mL) under N2 at about 0° C. After about 1 h, the ice bath was removed. After stirring at rt for about 3 h, LAH (0.116 g, 3.05 mmol) was added in one portion. After about 2 h, the mixture was cooled to about 0° C. Sodium sulfate decahydrate was slowly added over about 15 min. After about 15 min, the ice bath was removed, the mixture was diluted with Et2O (20 mL), and then the mixture was left to vigorously stir for about 63 h. The mixture was filtered rinsing with Et2O (100 mL). The organic volatiles were removed under reduced pressure. The residue was purified on silica gel using a gradient of 50-75% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford tert-butyl (4-(1-(4-bromophenyl)-3-hydroxypropyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.359 g, 0.715 mmol, 47%) as a very pale yellow film. LC-MS (Table 1, Method g) Rt=2.45 min; m/z 501 and 503 (M+H)+; 1H NMR (400 MHz, DMSO) 8.82 (s, 1H), 8.59-8.52 (m, 1H), 7.89-7.72 (m, 2H), 7.39-7.18 (m, 5H), 5.02-4.87 (m, 1H), 4.61-4.45 (m, 1H), 3.97-3.86 (m, 2H), 3.36-3.22 (m, 1H), 2.36-2.04 (m, 2H), 1.43 (s, 9H), 1.43-1.21 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1[O:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Oc1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-Hydroxyquinoline (I) (prepared according to the procedure of Naumann et. al., Synthesis 4:279–281 (1990)) (3 g) and 1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) and heated with cesium carbonate (7.4 g) for 2 h at 60° C. The reaction was poured into ice/water (500 mL). The resulting off-white precipitate was collected by filtration and rinsed with hexane to afford compound II as a solid (6.9 g) suitable for use in the next reaction.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH:7]=1)=O>[NH4+].CO>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:8]([CH2:26][C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH:7]=1
Reactant: Cc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Agent: [NH4+]
Solvent: CO
Product: Cc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Yield: 37.5 %

Procedure:
A solution of 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetamide (300 mg, 0.60 mmol) in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 16 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (90 mg, yield 37%). MS calcd for (C14H17BN4O5S): 400.2. MS found (ESI negative): (M−H)−=399.1. 1H NMR (DMSO-d6) δ (ppm): 10.0 (s, 1H), 9.20 (bs, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 4.85 (s, 2H), 4.41 (s, 2H), 2.39 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.ClCCl.CN(C)C=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)(=[O:23])=[O:8])=[CH:5][N:6]=1
Reactant: Nc1ncc(S(=O)c2cccnc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(S(=O)(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
A mixture of 2-amino-5-(3-pyridylsulfinyl)thiazole (1.6 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (150 ml), dichloromethane (50 ml) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 3 hours. The reaction mixture was extracted with diluted hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 8.5 using sodium bicarbonate and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was triturated with ethanol to give 2-amino-5-(3-pyridylsulfonyl)thiazole (0.30 g, yield: 17.5%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>C1COCC1>[CH:3]1([C:8](=[O:10])[CH2:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C1CCCC1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CC(=O)C1CCCC1)c1ccc(Oc2ccccc2)cc1
Yield: 63.2 %

Procedure:
Sodium hydride (1.508 g, 37.7 mmol, 60% suspension in mineral oil) was added in small portions to a solution of methyl cyclopentanecarboxylate (1.449 g, 11.31 mmol) and 1-(4-phenoxyphenyl)ethanone (2.00 g, 9.42 mmol) in THF (100 mL). Ethanol (0.5 mL) was then added. The mixture was heated to reflux for 5.5 h, quenched with saturated NaCl (50 mL) and acidified to pH 2 with 1 N HCl. THF was evaporated in vacuo. The residue was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with 5% ethyl acetate in hexanes and eluting with 5-20% ethyl acetate in hexanes, gave 1-cycloperityl-3-(4-phenoxyphenyl)propane-1,3-dione as white solid (1.837 g, 63% yield). MS (ES+) m/z: 309 (M+H); LC retention time: 5.015 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[N:13]O)[CH3:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([NH2:13])[CH3:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: CC(=NO)c1cc(F)cc2[nH]cnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cc(F)cc2[nH]cnc12
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanone oxime (351 mg, 1.82 mmol), Zn powder (1.18 g, 18.2 mmol), and NH4Cl (973 mg, 18.2 mmol) in MeOH (50 mL) and HOAc (10 mL) was heated at 80° C. for 4 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. To the residue was added NH4OH (50 mL), and the mixture was extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.2) to afford 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanamine (121) as a yellow solid (318 mg, 97.7%). MS (ESI): m/z=180.1 [M+1]+.