Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[OH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44].OS(C(F)(F)F)(=O)=O.[C:58]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[N:71]=[C:72]([NH:79][CH:80]4[CH2:84][CH2:83][CH2:82][CH:81]4[NH2:85])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:66][CH2:65]2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[OH:45][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:44])=[O:42].[C:58]1([N:64]2[CH2:65][CH2:66][N:67]([C:70]3[N:71]=[C:72]([NH:79][C@H:80]4[CH2:84][CH2:83][CH2:82][C@@H:81]4[NH:85][C:6]([C:5]4[O:1][N:2]=[CH:3][CH:4]=4)=[O:8])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:68][CH2:69]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NC1CCCC1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2)c1ccno1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
0.004 g (0.03 mmol) of isoxazole-5-carboxylic acid (IX), 0.012 g (0.03 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.017 mL (0.10 mmol) of diisopropylethylamine are placed in 1 mL of dimethylformamide, stirred for 0.1 hours at ambient temperature. Then 0.020 g (0.03 mmol) of N-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamine ditriflate (VIII) (chiral) in 1 mL of dimethylformamide are added. The mixture is shaken for 1 hour at ambient temperature. Then the reaction mixture is purified directly by HPLC through an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroacetic acid (B)).
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.C([O-])(=O)C.[Na+:48]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:48]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate (13 g) was added and charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium (19.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)OB([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]2[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccccc2)c2c(Cl)ncnc21
Temperature: 70 °C
Yield: 47.9 %

Procedure:
A stirred suspension of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (3.31 g, 11.3 mmol), tetramethyl-2-phenyl-1,3,2-dioxaborolane (2.76 g, 13.53 mmol) and sodium carbonate (3.59 g, 33.8 mmol) in 1,4-dioxane (90 ml) and water (18.0 ml) was degassed by bubbling N2 through it for 10 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.921 g, 1.13 mmol) was then added and the reaction mixture degassed with N2 again for 10 min before heating at 70° C. for 2 h. The solvent was removed in vacuo and the residue partitioned between saturated sodium hydrogen carbonate (90 ml) and dichloromethane (90 ml). The layers were separated and the aqueous phase extracted with dichloromethane (3×45 ml). The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (1.32 g, 48%). LCMS RT=1.26 min, [M(35Cl)+H]+=244.1, [M(37Cl)+H]+=246.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2/[C:7](=[N:10]\O)/[CH2:8][CH2:9][C:2]=12.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([NH2:10])[CH2:8][CH2:9][C:2]=12
Reactant: O/N=C1/CCc2ncccc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1CCc2ncccc21
Temperature: -40 °C
Yield: 68 %

Procedure:
To a solution of (5Z)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one oxime (320 mg) in methanol (20 ml) under N2 was added nickel chloride hexahydrate. The reaction mixture was cooled to −40° C. and sodium borohydride (817 mg) was slowly added over 30 min. The reaction mixture was warmed to ambient temperature for 1 h and silica gel was added. The reaction mixture was concentrated. MPLC chromatography was run using a biotage 25S column with 5–8% methanol/methylene chloride with 0.5% ammonium hydroxide to provide the title compound as an oil (197 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 8.43, 7.66, 7.28, 7.15, 4.42, 3.13–3.00, 2.97–2.91, 2.63–2.55, 1.81–1.72.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)[CH3:2].C([O-])(=O)C.[NH4+:33]>C(O)C>[NH2:33]/[C:6](/[CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:5]\[C:4]([O:3][CH2:1][CH3:2])=[O:28]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-[3-(ethyloxy)-3-oxopropanoyl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 3; 7.2 g) in ethanol (250 mL) was added ammonium acetate (6.93 g). The reaction mixture was heated to reflux for 7 hours and then left to stand at room temperature overnight. The reaction mixture was evaporated and then partitioned between 2× EtOAc and water. The combined organic phases were washed with water, dried through a hydrophobic frit and evaporated to give the title compound as a yellow oil (7.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:43])[F:44])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate (200 mg, 0.32 mmol), KOH (100 mg, 1.78 mmol) in methanol (5 mL) was stirred at 25° C. for 12 h. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 85% B in 10 min; 254 nm. This resulted in 28.5 mg (15%) of 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidin-4-yl]amino]acetic acid as a white solid. LCMS (Method 25) [M+H]+=603.1, RT=1.39 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 8.98 (dd, 1H, J=1.2, 6.8 Hz), 8.54-8.53 (m, 2H), 8.24 (s, 1H), 7.57 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=2.8, 8.8 Hz), 7.30 (d, 1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.70 (t, 1H, J=73.4 Hz), 5.23-5.10 (m, 2H), 4.54 (d, 1H, J=13.2 Hz), 4.05 (d, 1H, J=13.6 Hz), 3.45 (s, 2H), 3.30-3.11 (m, 4H), 2.71-2.65 (m, 1H), 2.11-2.05 (m, 1H), 1.58-1.43 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1>C(O)C.[Ni].O>[NH2:11][C:5]1[C:6]([CH2:8][C:9]#[N:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: N#CCc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(Cl)ncc1N
Reaction time: 2.5 h

Procedure:
A solution of (2-chloro-5-nitro-4-pyridyl) acetonitrile in ethanol (100 mL) was added to a suspension of 50% Raney nickel in water (3.2 g) diluted with ethanol (150 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure for 2.5 hours and then filtered through Celite® (diatomaceous earth) to remove the catalyst. The solvent was removed in vacuo to leave a dark oil which was subjected to flash chromatography on silica gel using 3:1 ethyl acetate/hexanes as eluant. Fractions containing only the title compound were combined and concentrated to afford an oil (850 mg, 32%). Less pure fractions were also combined and concentrated to give an oil (600 mg) of which the title compound was the major component (about 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)=[O:13].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][C:27](O)=[O:28].CCN(CC)CC>C(Cl)Cl.N#N>[Br:20][C:16]1[CH:15]=[C:14]([C:12]([C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COc1cc(N)c(C(=O)c2cccc(Br)c2)cc1OC
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccs2)c(C(=O)c2cccc(Br)c2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5-dimethoxyphenyl)(3-bromophenyl)methanone (5 g, 14.9 mmol) in dry DCM (125 mL) was added thiophen-2-ylacetic acid (2.54 g, 17.9 mmol) and Et3N (6.77, 66.9 mmol) at 0° C. in N2. 10 minutes later, POCK (3.4 g, 22.31 mmol) was added dropwise at 0° C. in N2. The reaction mixture was stirred for 1 hour at 0° C. and then quenched with saturated NaHCO3, and neutralized to pH=8. The mixture was exacted with ACM (30 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2-(thiophen-2-yl)acetamide. MS (M+H)=460 and 462.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)C.[CH3:30][NH2:31]>C(O)C.O>[CH3:30][NH:31][C:4](=[O:3])[CH2:5][C:6]1[N:7]=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1
Reactant: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reaction time: 0.5 h

Procedure:
In a 10 ml glass tube were placed (5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester (35 mg, 0.088 mmol) and a saturated solution of methylamine in ethanol (2.0 ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 100° C. Once 100° C. was reached, the reaction mixture was held at this temperature for 30 minutes. The temperature was then ramped up to 150° C. and the reaction mixture was held at this temperature for a further 30 minutes. The resultant mixture was diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 5% methanol in dichloromethane to give N-methyl-2-{5-phenyl-4-[{pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetamide (2 mg).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.C(N(CC)CC)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[C:12]([NH:13][C:14](=[O:15])[CH:5]3[CH2:4]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:18][CH:17]=1
Reactant: ClCCCc1ccncc1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2N2CCN(CCCc3ccncc3)CC12

Procedure:
A solution of 6.1 g. (0.03 mole) of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 6.3 g. (0.04 mole) of 3-(4-pyridyl)-1-chloropropane, 10 g. of potassium carbonate, 5 g. of potassium iodide and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone for 48 hours, then cooled and filtered. The solvent was removed, and the residue was dissolved in ethanol-ether and treated with dry hydrogen chloride saturated ether. The product hyrochloride was filtered and recrystallized two times from methanol. Dried at 100° C./0.1 mm. Yield: 6.2 g. (44%) as the dihydrochloride salt, m.p. 188°-190° C.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([Br:15])=[CH:10][C:9]=3[N:8]=[C:7](Cl)[C:6]=2[N:17]=1.[NH3:23]>CO>[NH2:2][C:3]1[N:4]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([Br:15])=[CH:10][C:9]=3[N:8]=[C:7]([NH2:23])[C:6]=2[N:17]=1
Reactant: CC(C)(O)Cn1c(N)nc2c(Cl)nc3cc(Br)ccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: CC(C)(O)Cn1c(N)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
1-(2-Amino-7-bromo-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide (1.18 g, 3.19 mmol) and ammonia (50 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 140° C. for five days. Additional ammonia in methanol was added after two days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was stirred with aqueous sodium hydroxide (100 mL of 2 N) for 15 minutes. A solid was present and was isolated by filtration, washed with water and diethyl ether, and dried under vacuum to provide 681 mg of 1-(2,4-diamino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a gray solid.
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@H:12]1[N:15]([Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:1]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@H]1C=O
Reaction time: 16 h

Procedure:
Ozone was passed through a -78° C. methylene chloride (100 mL) solution of compound 4b (4.73 g, 7.22 mmol) until a blue color was maintained. Excess ozone was purged with nitrogen. Dimethyl sulfide (10 mL) was added. The solution was allowed to stand for 16 h and concentrated to afford the title product which was not further purified but used directly in Step B.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[F:36])=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1.O>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[F:36])=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)c(F)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
A solution of HCl (4 M in 1,4-dioxane, 4.4 mL, 17.5 mmol) was added to a solution of (2R)-4-[5-fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.5 g, 2.9 mmol) in 1,4-dioxane (20 mL), DCM (20 mL), and water (5 mL) and the reaction was stirred for 20 min at rt. The reaction was concentrated under reduced pressure, isopropyl alcohol (10 mL) was added to the residue and the mixture was concentrated. Isopropyl alcohol (30 mL) was added to the residue and the solution was stirred overnight at rt to afford a precipitate. The precipitate was collected via filtration, washed with isopropyl alcohol, and dried under vacuum to afford the title compound as a light brown solid (725 mg, 58%) MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.07-2.25 (m, 1 H) 2.42-2.48 (m, 1 H) 3.11 (s, 3 H) 3.71-3.81 (m, 1 H) 3.83 (s, 3 H) 4.00-4.11 (m, 1 H) 6.44 (d, J=7.02 Hz, 1 H) 6.92 (dd, J=8.59, 2.54 Hz, 1 H) 7.00 (dd, J=12.39, 2.44 Hz, 1 H) 7.42 (t, J=8.49 Hz, 1 H) 8.03 (d, J=5.85 Hz, 1 H) 9.25 (br. s., 1 H) 11.10 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=S)=[CH:4][CH:3]=1.[N:21]#[C:22][NH2:23].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:23][C:22]#[N:21])=[N:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: S=C(NCCOc1ccc(Cl)cc1)Nc1cccnc1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1cccnc1)NCCOc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
N-(2-p-Chlorophenoxyethyl)-N'-3-pyridylthiourea (1.05 g) was suspended in acetonitrile (10 ml), and cyanamide (285 mg), N,N'-dicyclohexylcarbodiimide (1.40 g) and triethylamine (0.04 ml) were added. The mixture was kept with stirring at room temperature for a week, when it was filtered, washed with acetonitrile and with ether. The solid mixture of the crude product and N,N'-dicyclohexylthiourea was extracted with chloroform (15 ml) to leave the pure product, which was collected by filtration and washed with chloroform and ether.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C-:17]#[N:18].[Na+]>C(OCC)C.O.Cl>[C:17]([CH:2]([OH:1])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (60 g) in diethylether (150 mL) were added a solution of sodium cyanide (32.4 g) in water (100 mL) and concentrated hydrochloric acid (55 mL) by small portions at 0° C. The reaction system was stirred for 4 hr, and the organic layer was washed with brine, dried, and concentrated to give the title compound (67.0 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][S:24]4(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 73 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (157 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OC1CNC1
Product: OC1CN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-azetidinol (35.4 mg; 0.48 mmol) to give Example 135 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.7, 1.5 Hz), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.7, 1.6 Hz), 7.57-7.47 (4H, m), 5.35 (1H, d, J=6.4 Hz), 4.27-4.19 (1H, m), 3.67 (2H, s), 3.55 (2H, dd, J=7.4, 5.8 Hz), 2.83 (2H, t, J=6.6 Hz). LC/MS (Method C): 470 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 98.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.O1CCCC1.C(OCC)(=O)C>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A sample of 5-Amino-indan-1-one (100 mg, 0.68 mmol) is treated with a solution pyridine (59 mg, 0.75 mmol) in a mixture of dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL). The reaction is then cooled in an ice bath. A solution of methanesulfonyl chloride (86 mg, 0.75 mmol) in tetrahydrofuran (1.5 mL) is added dropwise and the reaction is allowed to stir for 2 hours at ice bath temperature and overnight at room temperature. The reaction is diluted with ethyl acetate and extracted twice with 1 M HCl. The organics are dried over MgSO4 and the solvent is removed to afford the title material (64 mg, 42% yield) which is not purified but carried on as is: LC/MS calculated for [M+H]+ C10H11NO3S: 226.0, found: 226.0.