Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.[BrH:11].Br.[NH+]1C=CC=CC=1>C(O)(=O)C>[BrH:11].[NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH2:9][Br:11])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)c1sc(N)nc1C
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1nc(N)sc1C(=O)CBr
Reaction time: 5 h

Procedure:
To a suspension of 2-amino-4-methyl-5-acetylthiazole (15.6 g) in 30% solution of hydrogen bromide in acetic acid (120 ml) was added pyridinium hydrobromide perbromide (36 g) at ambient temperature and the mixture was stirred at the same temperature for 5 hours. The precipitate was collected by filtration, washed with diisopropyl ether, and dried over calcium chloride to give 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (26.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>CN(C=O)C>[O:13]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:18])[N:12]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7]
Reactant: N#CCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a solution of 5-bromovaleronitrile (5.12 g, 30.0 mmol) in DMF (40 mL) was added potassium phthalimide (6.00 g, 32.4 mmol). The above suspension was heated at 60° C. for 16 h, concentrated, and partitioned between H2O and DCM. The DCM layer was separated, washed with H2O (3×) and brine, dried over Na2SO4, and concentrated to give the title compound (6.84 g, quantitative yield) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>ClCCCl>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 92.5 %

Procedure:
4.9 g (0.12 mole) of sodium borohydride was suspended at room temperature in a solution of 24.9 g (0.10 mole) of isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate dissolved in 100 ml of 1,2-dichloroethane. Thereto was dropwise added slowly 24.0 ml (0.60 mole) of methanol with stirring so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature with the disappearance of the raw material being monitored by GC, to give rise to a reaction. 20 hours were necessary. Then, 50 ml of water was added, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 16.3 g (yield: 92.6%) of an oily title compound (diastereomixture).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CS(C)=O>[CH2:23]([N:15]1[N:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10](/[CH:9]=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:11]=2)[C:16]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: O=c1[nH]ncc2cc(/C=C/c3ccc(O)cc3)ccc12
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Reaction time: 2 h

Procedure:
A solution of 27.5 gm of trans-6-[2-(4-hydroxyphenyl)ethenyl]-1-(2H)-phthalazinone (as prepared in Example 2) in 1300 ml DMSO was treated with 135 ml 2.5N sodium hydroxide solution, followed by 12.5 ml n-butyl iodide. The reaction mixture was stirred for 21/2 hours, then added to 8000 ml ethyl acetate. After stirring for a few minutes the insoluble material was filtered off and washed with a little ethyl acetate. The ethyl acetate was removed on a rotary evaporator and the residue added to 8000 ml water, stirred for an hour and allowed to settle overnight. The clear supernatant liquid was syphoned off and the residual slurry was filtered and the crude product washed thoroughly with water. After air drying it weighed 24.8 gm. The crude product was recrystallized from 125 ml 2-methoxyethanol, filtered and washed with isopropanol and ether. After drying at 60° for 24 hours, it weighed 17.4 gm and melted at 225°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([NH2:21])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:23]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: NC(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96 but replacing Compound 22c for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 1:0 to 93:7) giving the title compound as a white solid. Yield: 76.9%.
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13]CC)=[O:12])[C:6](OCC)=O)(=O)C.[O-]CC.[Na+].[Na].BrC[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:4][CH:5]([CH2:6][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: NC(CCCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Diethyl acetamidomalonate (220 g) in 1 L of absolute ethanol was added to a stirred solution of sodium ethoxide in ethanol, prepared by dissolving sodium (24 g) in absolute ethanol (500 mL), under nitrogen. The reaction mixture was refluxed under nitrogen for 30 minutes, then 1-bromo-3-phenylpropane (200g) was added. The reaction mixture was refluxed overnight, cooled to ambient temperature, filtered, and the solvent was removed under vacuum. Concentrated HCl (800 mL) was added to the residue, and the reaction mixture was refluxed for 14 hours. The cooled aqueous solution was washed with ether, and the residual ether in the aqueous phase was removed by bubbling nitrogen through the solution. The pH of the aqueous phase was adjusted to pH 7-8 by the addition of ammonium hydroxide. The title compound was collected by filtration, air dried and recrystallized from ethanol-water (150 g) m.p. 255-257° C. MS m/z: 194 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:4]=[CH:3]1.Cl.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[OH-].[Na+].C(O)(=O)C>[CH:38]1([CH2:41][N:26]2[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]3[CH:17]=[N:16][C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[CH2:8][N:7]4[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:29]5[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=5)[C:32]#[N:33])=[N:6]4)=[N:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:40][CH2:39]1
Reactant: O=CC1CC1
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCNCC5)cn4)c3)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCN(CC6CC6)CC5)cn4)c3)n2)c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
130 mg (0.185 mmol) of 3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile (liberated from the hydro-chloride by suspension in THF and extraction with 1N NaOH)), 28 μl (0.37 mmol) of cyclopropanecarboxaldehyde and 78 mg (0.37 mmo) of sodium triacetoxyborohydride are dissolved in 10 ml of THF, and 200 μl of acetic acid are added. The reaction mixture is stirred at 40° C. for 15 h. The reaction mixture is filtered and washed with THF. The filtrate is evaporated and purified by means of preparative HPLC.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16](O[Si](C(C)(C)C)(C)C)[O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:53]CC1>>[C:1]([N:11]1[CH2:15][C@H:14]([OH:53])[CH2:13][C@H:12]1[CH2:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OC(Oc1cccnc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1COc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 700 mg (1.6 mmol) sample of 3-(1-CBZ-(t-butyldimethylsilyloxy)-2-(S)-pyrrolidinylmethoxy)pyridine, prepared as in Example 72d above, was dissolved in 10 mL of THF and 5.0 mL (4.8 mmol) of 1 M tetra-n-butylammonium fluoride was added. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed. The residue was purified on a column of silica gel, eluting with 3:1 ethyl acetate:hexane to give 466 mg of the title compound. MS (DCI/NH3) m/e: 328 (M+H)+. 1H NMR (CDCl3,300 MHz) δ: 8.28 (s, 1H), 8.21 (m, 1H), 7.33 (s, 5H), 7.27 (m, 1H), 7.20 (m, 1H), 5.13 (s, 2H), 4.59 (m, 1H), 4.37 (m, 1H), 3.62 (m, 2H), 3.59 (m, 1H), 3.20 (m, 1H), 2.18 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cccc(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a solution of 2.6-dibromopyridine (5.0 g, 21.1 mmol) in dry THF (50 ml) at 0° C. was added iso-propyl magnesium chloride (11.6 ml, 23.21 mmol) dropwise for 20 min. The reaction was stirred at RT for 2 h, then cooled to 0° C. Tri-butyl tin chloride (7.55 g, 23.21 mmol) was added dropwise in 15 min. The mixture was stirred at RT for 12 h. The reaction was quenched with 10% NH4Cl solution and was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified with silica gel chromatography to give 2-bromo-6-(tributylstannyl)pyridine (3.7 g, 40.3%). MS (ESI, pos. ion) m/z: 448 (M+1); 1H-NMR (CDCl3, 300 MHz) δ 7.3-7.5 (3H, m), 1.5-1.7 (6H, m), 1.3-1.4 (6H, m), 1.1-1.25 (6H, q), 0.7-0.9 (9H, q).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][C:15]=2[F:26])=[N:11][C:10]=1[C:27]([OH:29])=O)=O)(C)(C)C.[NH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][CH2:40][C@H:39]([NH:43]C(=O)OC(C)(C)C)[CH2:38]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:16][C:15]=2[F:26])=[N:11][C:10]=1[C:27]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][CH2:40][C@@H:39]([NH2:43])[CH2:38]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Product: CC(C)NC(=O)c1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@@H](N)C3)c(N)s2)c1
Yield: 8 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2-fluoro-5-(isopropylcarbamoyl)phenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (5 mg, 8%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.61 (dd, J=7.4, 2.2 Hz, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 7.98-7.86 (m, 1H), 7.69 (s, 2H), 7.48 (dd, J=11.3, 8.7 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 4.13 (td, J=13.5, 6.8 Hz, 1H), 3.20 (d, J=8.8 Hz, 9H), 3.01 (d, J=12.1 Hz, 2H), 2.70 (d, J=18.9 Hz, 1H), 1.89 (d, J=9.6 Hz, 1H), 1.78 (d, J=22.6 Hz, 2H), 1.40-1.23 (m, 1H), 1.19 (d, J=6.6 Hz, 6H). ESIMS m/z=498.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([OH:16])=O)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl.[CH3:18][NH:19][CH3:20].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([N:19]([CH3:20])[CH3:18])=[O:16])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)NC(=O)C(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxy-2-oxo-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), 1-hydroxybenzotriazole (2.85 g), and triethylamine (8.5 g) in acetonitrile (400 ml) was added WSC (6.5 g). The reaction mixture was stirred at room temperature for 24 hr and concentrated. The residue was diluted with ethyl acetate and the organic layer was washed with 1 N aqueous hydrochloric acid, 10% aqueous potassium carbonate, and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (1.63 g).
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH3:10][NH2:11]>C1(C)C=CC=CC=1>[OH:3][C@H:2]1[CH2:4][C:5](=[O:6])[N:11]([CH3:10])[C:1]1=[O:9]
Reactant: CN
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: Cc1ccccc1
Product: CN1C(=O)C[C@H](O)C1=O

Procedure:
To a stirred solution of 134 g (1 mole) of (S)-malic acid in 700 ml of toluene was added 97 ml of 40% aqueous methylamine. The temperature slowly rose to 50° C. After 0.5 hr the stirred mixture was heated to reflux and the water was collected in a Dean-Stark trap for 48 hours. A total of 93 ml of water was collected. The toluene residue was treated with 300 ml of ethanol and concentrated on the rotary evaportor. The residue was distilled. The yield of product obtained was 101 g (78%), b.p. 140°/2 mm; 145°/0.5 mm.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[C:6]2[C:15]=1[S:14](=[O:17])(=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[N:7]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:22][C:3]1[C:2]([OH:1])=[C:15]2[C:6]([NH:7][C:8]3[C:13]([S:14]2(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=12
Reactant: O=C1C(O)=C2C(=Nc3ccccc3S2(=O)=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)c2ccccc2Nc2c1c(O)c(O)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a suspension of 6-hydroxy-5H-benzo[a]phenothiazine-5-one-7,7-dioxide (430 mg) in water (10 cc) and ethyl acetate (10 ml) there was added sodium dithionite (1 g). The suspension was stirred vigorously at room temperature for 2 hours, then the insolubles were filtered and washed with water and ethyl acetate. There was obtained 346 mg of the title compound, m.p. 330° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([SH:9])[N:6]2[N:10]=[C:11]([CH3:13])[N:12]=[C:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:9][C:7]3[N:6]4[N:10]=[C:11]([CH3:13])[N:12]=[C:5]4[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=3)[CH2:28][S:27][C@H:22]12
Reactant: Cc1nc2nc(CO)cc(S)n2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: O
Product: Cc1nc2nc(CO)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 120 ml of acetonitrile were suspended 9.8 g of 5-hydroxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine and 13.6 g of 7-aminocephalosporanic acid, and 22 ml of boron trifluoride-ethyl ether complex was added to the suspension and the mixture was stirred at 50° C. for 3 hours. After cooling the reaction mixture, 250 ml of water was added thereto and the mixture was adjusted to pH 2 with conc. aqueous ammonia precipitated crystal was collected by filtration, washed with water, washed with acetone and then dried to obtain 11.6 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:14][S:15]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:17])=[O:16]
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1

Procedure:
Thus, for example, when 1-benzyl-3-pyrrolidinol is reacted with methanesulfonyl chloride in the presence of sodium hydroxide using a mixed solvent composed of toluene and water as the reaction solvent and the reaction mixture is obtained in the form of a two-phase system composed of a toluene phase and an aqueous phase, it is possible to obtain 1-benzyl-3-pyrrolidinol methanesulfonate as a concentrate by removing the solvent by concentrating, under reduced pressure, from the toluene solution obtained by phase separation of the reaction mixture, after or without washing the toluene phase with water.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+].[F:42][C:43]([F:50])([F:49])[C:44]1[CH:48]=[CH:47][NH:46][N:45]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([C@:13]23[CH2:14][C@H:15]2[CH2:16][N:11]([CH2:10][CH2:9][CH2:8][N:6]2[CH:7]=[C:2]([N:46]4[CH:47]=[CH:48][C:44]([C:43]([F:50])([F:49])[F:42])=[N:45]4)[C:3](=[O:28])[NH:4][C:5]2=[O:27])[CH2:12]3)=[CH:18][CH:19]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-n1ccc(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 60 mg, 0.119 mmol), copper(1+) iodide (24.88 mg, 0.131 mmol), N,N-dimethylglycine (13.47 mg, 0.131 mmol) and K2CO3 (36.1 mg, 0.261 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (1 ml) to give a light blue suspension with a white solid. 3-(trifluoromethyl)-1H-pyrazole (commercially available from Apollo, 53.3 mg, 0.392 mmol) was added. After shaking at 150° C. for 18 h, the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, filtered ant the solvent evaporated. The obtained crude was purified by preparative LC-MS. Obtained 12.5 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:19])([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl>O1CCOCC1.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:19])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C(=O)O)CCN(c2ncc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
Ethyl 1-(5-bromopyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (400 mg, 1.22 mmol) was stirred in dioxan (4 ml) and concentrated hydrochloric acid was added (2.8 ml). The reaction was stirred in a sealed tube at 100° C. for 5 h. LCMS indicated 90% conversion to the acid. The reaction was allowed to cool, diluted with a saturated aqueous solution of sodium hydrogen carbonate to adjust the pH to ˜5 at which point a solid precipitated. The solid was collected by filtration and dried to afford the desired product as a yellow solid (270 mg, 90% purity by LCMS) (77%).
Reaction SMILES: [C:1]([C:5]1[C:9]([C:10]#[N:11])=[C:8](Cl)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([OH:21])[C:18]([CH3:22])=[CH:17][C:15]=1[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:16][C:15]1[C:14]([CH3:13])=[CH:20][C:19]([O:21][C:8]2[S:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=2[C:10]#[N:11])=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: CC(C)(C)c1nsc(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2snc(C(C)(C)C)c2C#N)c(C)cc1N

Procedure:
A suspension of 5.0 g (24.9 mmol) of 3-tert-butyl-5-chloroisothiazole-4-carbonitrile, 3.41 g (24.9 mmol) of 2,5-dimethyl-4-hydroxyaniline and 5.51 g (39.86 mmol) of potassium carbonate in 100 ml of DMF is heated under reflux for 6 h. After cooling, the reaction mixture is poured onto ice-water. After extraction with dichloromethane, the combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([NH:12][OH:13])=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH:14]2[C:18]([CH3:20])([OH:19])[CH:17]([OH:21])[CH:16]([CH2:22][OH:23])[O:15]2)[CH:4]=1)#[CH:2].[H][H]>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:13][NH:12][C:10]1[C:11]2[C:3]([CH:1]=[CH2:2])=[CH:4][N:5]([CH:14]3[C:18]([CH3:20])([OH:19])[CH:17]([OH:21])[CH:16]([CH2:22][OH:23])[O:15]3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: [H][H]
Reactant: C#Cc1cn(C2OC(CO)C(O)C2(C)O)c2ncnc(NO)c12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Product: C=Cc1cn(C2OC(CO)C(O)C2(C)O)c2ncnc(NO)c12

Procedure:
The title compound from Example 29 is dissolved in THF and placed under hydrogen (1 atm) in the presence of Lindlar's catalyst until one mole of hydrogen is consumed.
Reaction SMILES: C1(N=C=N)CCCCC1.[C:10]([OH:18])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.Cl.[N:33]1([CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:55]=[CH:54][C:46]([CH2:47][N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:45][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:11]1([C:10]([N:51]2[CH2:52][CH2:53][N:48]([CH2:47][C:46]3[CH:45]=[CH:44][C:43]([O:42][CH2:41][CH2:40][CH2:39][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:55][CH:54]=3)[CH2:49][CH2:50]2)=[O:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1cc(OCCCN2CCCCC2)ccc1CN1CCNCC1
Agent: Cl
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
N-Cyclohexylcarbodiimide, N-methyl polystyrene HL (200-400 mesh) 1.8 mMol/g (650 mg, 1.172 mmol) was suspended in a (1:1) mixture of dichloromethane and dimethylformamide and treated sequentially with benzoic acid (72 mg, 0.58 mmol), 1-hydroxybenzotriazole hydrate (80 mg, 0.58 mmol) and stirred for 10 minutes at room temperature. A solution of 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine trihydrochloride (D2) (125 mg, 0.29 mmol) in dichloromethane (1 ml) and triethylamine (0.13 ml, 0.87 mmol) was then added to the reaction and stirred at room temperature for 16 hours. After filtration, the filtrate was applied to a Mega Bond elute SCX ion exchange column washing sequentially with water and methanol, followed by 0.880 ammonia/methanol (1:10) to elute the crude reaction mixture. Purification by silica gel chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title product (95 mg, 77%); MS (ES+), m/e 422 [M+H]+.