Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]=[N:21][N:22]([CH2:24][CH2:25][CH2:26]Br)[N:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[CH3:32][S:33]C.[Na].O.C(OCC)(=O)C>CS(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]=[N:21][N:22]([CH2:24][CH2:25][CH2:26][S:33][CH3:32])[N:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CSC
Reactant: CCCc1c(COc2ccc(Cc3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(COc2ccc(Cc3nnn(CCCSC)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-bromopropyl)-2H-tetrazole (3.1 g, 0.006 mol) was dissolved in DMSO (20 ml). A large excess of sodium methyl sulfide was added and the reaction mixture was stirred at room temperature for three hours. Water (100 ml) was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 2.1 g, 77.8% yield of the title product as a yellow oil which crystallized upon standing: n.m.r. (300 MHz, CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 2.1 (s, 3H); 2.3 (m, 2H); 2.5 (m, 2H); 2.6 (s, 3H); 2.7 (t, 2H); 4.2 (s, 2 H); 4.7 (t, 2H); 5.1 (s, 1H); 6.9 (d, 2H); 7.0 (d, 1H); 7.3 (d, 2H); 7.6 (d, 1H); 12.7 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1>O=[Mn]=O>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH:20]=[O:21])[N:8]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Agent: O=[Mn]=O
Product: O=Cc1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Reaction time: 48 h

Procedure:
A suspension of {3-[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-phenyl}-methanol (566 mg, 1.57 mmol) was treated with MnO2 (1.4 g, 15.7 mmol) for 15 h. Another aliquot of 500 mg MnO2 was added and the reaction was allowed to stir for 48 h. The mixture was filtered over celite and dried in vacuo to afford 375 mg (88% pure by LCMS and 1H NMR) which was used crude in the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@H:12]1[CH2:15][C@H:14]([OH:16])[CH2:13]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1.C(OCC)(=O)C>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([C:23]2[C:18]([O:16][C@H:14]3[CH2:13][C@H:12]([C:4]4[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[N:3]=4)[CH2:15]3)=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1
Reactant: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Reactant: Fc1ncccc1C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(O[C@H]2C[C@H](c3nc4ccccc4[nH]3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.049 g, 1.2 mmol) was added to a solution of trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol) in DMF (1.5 mL) under argon and the mixture was stirred for 45 min at RT. 2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.58 mmol) was added and the mixture was stirred for 16 h at 110° C. Ethyl acetate was added and the mixture was washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 2-(trans-3-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)-1H-benzo[d]imidazole (37 mg, 0.11 mmol, 18% yield) as a white solid. [M+1]: 350.3. IC50 (uM) 0.01041.
Reaction SMILES: Br[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Yield: 51.2 %

Procedure:
The product was prepared in the same manner as described in example 66 using N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide (200 mg, 461 μmol) and 2-methoxyphenylboronic acid (140 mg, 921 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 10% as eluent affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (109 mg, 51.3%) as a light brown foam. MS: m/z=462.5 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH2:31]([NH2:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:17][C:16]([S:18]([NH:43][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)s1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonyl chloride (2.00 g, 5.85 mmol), DIEA (1.134 g, 8.78 mmol) in DCM (20 mL) was added dodecyl amine (1.41 g, 7.61 mmol) at rt and the reaction mixture was stirred for 2 h at rt. A 1 M aqueous solution of HCl (10 mL) was added and the aqueous layers were extracted with DCM (2×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a yellowish oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 4/1 in about 0.5 h) to give the title compound as a white solid (2.10 g, 73%). 1H NMR (CD3OD, 300 MHz) δ 7.91 (m, 2H), 7.85 (m, 2H), 7.43 (d, 1H, J=3.7 Hz), 7.17 (d, 1H, J=3.7 Hz), 5.05 (s, 2H), 2.90 (t, 2H, J=6.9 Hz), 1.50-1.38 (m, 2H), 1.35-1.16 (m, 18H), 0.86 (t, J=7.9 Hz, 3H) M−(LC/MS): 489.3; M+(LC/MS): 491.2. HPLC (Condition A), Rt: 6.64 min (HPLC purity: 95.9%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2ncccc12
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: c1ccc(COc2ccc(Nc3ncnc4ncccc34)cc2)cc1
Yield: 6.1 %

Procedure:
4-Chloropyrido[2,3-d]pyrimidine (prepared as described in: R. K. Robins and G. W. Hitchings, J. Am. Chem. Soc, 77, 2256 (1955)) (0.165 g, 1.0 mmol) and 4-benzyloxyaniline (0.199 g, 1.0 mmol) were reacted in ethanol (10 ml) for ca. 2 hours, according to Procedure A. After cooling, the mixture was filtered, treated with triethylamine and concentrated in vacuo. Purification by column chromatography on silica, eluting with methanol/chloroform (1:10), gave the product as a yellow solid (0.020 g, 6%) with m.p. 235-237° C.; (Found: C, 72.34; H, 4.85; N, 16.57. C20H16N4O0.25H2O requires: C, 72.16; H, 4.99; N, 16.83%); δH [2H6]-DMSO 9.10 (1H, d, J 9) and 9.08 (1H, d, J 5) (6H, 8-H), 8.78 (1H, s, 2-H), 7.76 (1H, dd, J 9, 5, 7-H), 7.62 (2H, d, J 9, 2′-H, 6′-H), 7.43 (2H, d, J 7, 2″-H, 6″-H), 7.38 (2H, t, J 7, 3″-H, 5″-H), 7.30 (1H, t, J 8, 4″-H), 7.08 (2H, d, J 9, 3′-H, 5′-H), 5.11 (2H, s, CH2); m/z (%) 328 (68, M+), 237 (100), 91 (64).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (11.2 g, 30.0 mmol), morpholine (26.0 mL, 294.0 mmol), copper(I) iodide (3.4 g, 18.0 mmol), N,N-dimethylglycine hydrochloride (3.4 g, 24.0 mmol), and potassium carbonate (12.4 g, 90.0 mmol) in dimethyl sulfoxide (65 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (9.1 g, 80%) as a white solid: MS (ESI) M+1=381.0.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7].B(F)(F)F.CCOCC.C(Cl)Cl>C1COCC1.CO>[Cl:3][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][OH:7]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A 500-mL 3-necked round-bottom flask was charged with a solution of NaBH4 (4 g, 105.26 mmol, 2.10 equiv) in THF (100 mL). To this was added a solution of 2-chloro-3-nitrobenzoic acid (10 g, 49.75 mmol) in THF (100 mL) at 0° C. After 10 minutes, BF3.Et2O (15 mL) in THF (50 mL) was added dropwise over 10 minutes. The resulting solution was stirred at room temperature overnight. The reaction progress was monitored by TLC (DCM: MeOH=5:1). Upon completion, the reaction was quenched with water (500 mL) and extracted with ethyl acetate (3×300 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording (2-chloro-3-nitrophenyl)methanol as light yellow solid (9 g, 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 184 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=155-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.2 and 8 Hz, 1H), 7.77 (dd, J=1.2 and 8 Hz, 1H), 7.67 (dt, J=1.2 and 8 Hz, 1H), 7.49 (dt, J=1.2 and 8 Hz, 1H), 7.31 (d, J=9.2 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.10-4.17 (m, 1H), 4.00 (dd, J=1.2 and 4.8 Hz, 2H), 2.99-2.95 (s, 3H), 2.74-2.86 (m, 2H), 2.64-2.7 (m, 2H), 2.51-2.6 (m, 1H), 2.13-2.2 (m, 2H), 1.84-1.98 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=50.98 min.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][C:3]1=[O:13].[F:14][C:15]([F:35])([F:34])[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32]Cl)[C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][N:10]([CH2:32][CH2:31][CH2:30][N:19]3[C:18]4[CH:17]=[C:16]([C:15]([F:35])([F:14])[F:34])[CH:29]=[CH:28][C:27]=4[S:26][C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:9][CH2:8]2)[O:4][C:3]1=[O:13]
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=C1N(C)C(=O)OC12CCN(CCCN1c3ccccc3Sc3ccc(C(F)(F)F)cc31)CC2
Reaction time: 6 h
Yield: 75.3 %

Procedure:
A mixture containing 11.0 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 41.3 g of 3-(2-trifluoromethyl-10H-phenothiazin-10-yl)propyl chloride, 16.6 g of anhydrous potassium carbonate and 0.6 g of potassium iodide in 110 ml of methyl isobutyl ketone is refluxed under nitrogen while stirring for 6 hours. After evaporating the solvent under reduced pressure benzene and water are added to the evaporation residue, the organic phase is separated, washed with water to neutral, dried over anhydrous sodium sulfate, then the solution is evaporated under reduced pressure. The solid residue is boiled with hexane, after cooling down the precipitate is filtered off and recrystallized from ethanol to give the title compound in a yield of 75.3%; m.p.: 116°-117.5° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11]C(C)(C)[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[OH-].[Na+].O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:16])=[O:9])[C:12]([OH:13])=[O:11])=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(Cc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-(4-fluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.118 g, 135.26 mmol, Intermediate 7: step a) and 6 M aqueous NaOH (136 mL) was heated to 120° C. under a reflux condenser and positive pressure of nitrogen for two days. The mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the layers were separated. The aqueous layer was acidified to pH 0 with 6 M aqueous HCl and the mixture was stirred at room temperature for 30 minutes. Dichloromethane was added to the mixture, the organic layer was separated, and the aqueous layer was extracted with excess ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]([C:28](F)(F)F)=O.[CH2:32]([O:39][N:40]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:41]1[CH2:42][CH2:43][C@H:44]2[C:49]([NH:51][NH2:52])=[O:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([NH:52][NH:51][C:49]([C@@H:44]1[CH2:43][CH2:42][C@@H:41]2[CH2:48][N:45]1[C:46](=[O:47])[N:40]2[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:50])(=[O:25])[CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
HATU (0.90 g, 2.48 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (1.0 g, 2.48 mmol), acetic acid (0.12 g, 2.07 mmol) and DIPEA (1.1 g, 8.3 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The mixture was then quenched with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 1:10 petroleum ether/EtOAc) to afford (2S,5R)—N′-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.6 g, 73%). ESI-MS (EI+, m/z): 333 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.11) (0.197 g, 0.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.21 g, 0.6 mmol) according to the general procedure III. Obtained as an off-white solid (0.1 g), which was subsequently deprotected.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:29]([O:28][CH3:27])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1OC
Temperature: 5 °C
Yield: 56.8 %

Procedure:
19.56 g of N-bromosuccinimide and 4.84 g of benzoyl peroxide were added to a solution of 19.40 g of ethyl 2-methoxy-6-methylbenzoate in 150 ml of carbon tetrachloride. The reaction medium was refluxed for 6 hours (no further change). The reaction medium was cooled to 5° C. and the succinimide was filtered. The organic phase was washed with a saturated sodium hydrogen carbonate solution (2×150 ml), dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (column puriFlash, IR-50SI/800G, Spot II) eluted with heptane/ethyl acetate (gradient). 15.5 g of ethyl 2-bromomethyl-6-methoxybenzoate were obtained in the form of a yellow oil which later crystallizes. Yield=56%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([F:19])[CH:18]=2)[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12]3)[N:5]=[C:4]([NH:21][C:22]2[NH:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:19][C:17]1[CH:18]=[C:9]([S:8][C:6]2[N:5]=[C:4]([NH:21][C:22]3[NH:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[CH:3]=[C:2]([N:38]3[CH2:37][CH2:36][N:35]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:40][CH2:39]3)[N:7]=2)[CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12]2
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCN(C4CCN(C)CC4)CC3)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Temperature: 90 °C
Yield: 30.3 %

Procedure:
To a stirred mixture of 6-chloro-2-(8-fluoro-2-methylquinolin-6-ylthio)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.5 mmol), 1-(1-methylpiperidin-4-yl)piperazine (367 mg, 2 mmol) and diisopropylethylamine (194 mg, 1.5 mmol) in nBuOH (5 ml) was heated to 90° C. for 18 hours. The crude mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was further extracted with water. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was triturated with cold acetonitrile, filtered and dried to afford the title compound as an off-white solid (83 mg, 30% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(OC([N:31]1[CH2:35][C@H:34]([C:36]#[N:37])[CH2:33][C@H:32]1[C:38](=[O:40])[NH2:39])=O)(C)(C)C.CO>C(Cl)Cl>[C:36]([C@H:34]1[CH2:35][N:31]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:32]([C:38]([NH2:39])=[O:40])[CH2:33]1)#[N:37]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(N)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@H](C#N)C[C@H]3C(N)=O)cc1OCC2
Yield: 72 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and (2S,4R)-2-carbamoyl-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester were reacted. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 430 as an off-white solid (41 mg, 72%). LCMS: RT=2.85 min, [M+H]+=435. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (1H, s), 7.88 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.56 (1H, br, s), 7.11 (1H, br, s), 6.04 (1H, s), 5.94-5.93 (1H, m), 4.51 (4H, d, J=15.42 Hz), 4.44 (1H, d, J=5.97 Hz), 3.92 (1H, dd, J=10.05, 7.55 Hz), 3.72 (1H, t, J=8.49 Hz), 3.61-3.53 (1H, m), 2.55-2.54 (1H, m), 2.35 (1H, ddd, J=12.61, 6.87, 3.63 Hz), 1.47 (6H, dd, J=6.59, 3.21 Hz)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc2c(c1)CCN2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ccccc43)n2)c1

Procedure:
B52 was prepared following the general procedure reported for B10 using A1 and indoline; yield: 76.2 mg (20%), pale yellow solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.11-3.18 (m, 2H), 4.14-4.26 (m, 2H), 4.23 (s, 2H), 6.84 (s, 2H), 6.97 (t, J=7.1 Hz, 1H), 7.01-7.09 (bm, 1H), 7.13-7.21 (bm, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.64-7.90 (bm, 2H), 8.29-8.41 (bm, 1H), 8.43 (s, 1H), 9.90 (s, 1H). MS (ES) C18H18N6O2S requires: 382. found: 383 (M+H)+.