Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].COCCO.[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1/[C:19](/[CH3:32])=[CH:20]/[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=1>CCOCC>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1/[C:19](/[CH3:32])=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc(C(C)(C)C)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide, 2-methoxyethanol and ether was added to 70 mg (0.21 mmol) of ethyl 4-[(E)-2-(2-methyl-4-tert-butylphenyl)propen-1-yl]benzoate (Compound 28) and the resulting mixture stirred at room temperature for 5 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18]N(C)C)=[N:4][C:5]([O:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.Cl.[O:23]1CCOCC1>>[F:1][C:2]1[C:3]([NH:17][CH:18]=[O:23])=[N:4][C:5]([O:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CN(C)C=Nc1nc(ON=Cc2ccccc2)ncc1F
Agent: Cl
Product: O=CNc1nc(ON=Cc2ccccc2)ncc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a suspension of N′-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.035 g, 0.12 mmol) in dioxane (1.2 mL) was added dilute hydrochloric acid (HCl, 1 N, 0.006 g, 0.16 mmol) and the mixture was stirred at 23° C. for 16 h. The reaction mixture was purified by flash chromatography (4 g SiO2; 0→60% EtOAc/hexanes) to give N-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}formamide (0.007 g, 22%) as a white solid: mp 210-232° C. dec; 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.36 (s, 1H), 8.79 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 7.80 (dd, J=7.7, 1.6 Hz, 2H), 7.52 (m, 3H); ESIMS m/z 261 ([M+H]+), 259 ([M−H]−).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Br[CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCO>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCC(Br)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCCC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OCC
Temperature: 140 °C
Yield: 98.8 %

Procedure:
206 g (1 mol) of 2,4-di-tert-butylphenol were melted and heated to 140° C. under nitrogen. 185 g (1.03 mol) of a 30% strength NaOMe solution in MeOH and 245 g (1.1 mol) of ethyl 2-bromocaproate were metered in simultaneously in the course of 1 hour. During the addition, a mixture of MeOH and EtOH was distilled off. After the addition, the reaction to give the ester mixture was complete. The mixture was cooled to 80° C., 20 g of NaOMe solution were added and 750 ml of ethanol were then added in the course of 4 hours. A methanol/ethanol mixture distilled off at an overhead temperature of initially 74° to 76° C. At the end, the temperature was increased to 90° C. and pure ethanol distilled over at 78° to 79° C. For isolation, 250 ml of water were added. After separation of the phases and renewed washing with 200 ml of water, 351 g of a viscous yellow oil of the following composition (0.3% of ethyl bromocaproate, 0.7 g of residual phenol, 98% of ethyl 2-(2,4-di-tert-butylphenoxy)caproate and 0.3% of methyl 2-(2,4-ditert-butylphenoxy)caproate, remained. This corresponds to a yield of 98.8% of theory, based on the phenol employed.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:31])=[CH:28][C:29]=1[OH:30])=[O:23]>CC(C)=O>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:28][C:29]=1[OH:30])(=[O:23])[CH3:21]
Reactant: COC(=O)C(C)(C)CCCCBr
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)CCCCOc1ccc(C(C)=O)c(O)c1

Procedure:
Following the procedure of Example 44, 2.5 g. of methyl 6-bromo-2,2-dimethylhexanoate, 1.46 g. of potassium carbonate, a catalytic amount of potassium iodide, and 1.67 g. of 2,4-dihydroxyacetophenone were reacted in 125 ml. of acetone giving 2.3 g. of the title product as an oil. M+ =308; NMR.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-])=O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:2][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2csc(-c3cccnc3)n2)c1
Agent: Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(-c2csc(-c3cccnc3)n2)c1
Temperature: 50 °C
Yield: 84.9 %

Procedure:
A suspension of 4(3-nitrophenyl)-2-(3-pyridyl)-thiazole hydrobromide (3.6 g, 10 mmol) in ethanol (150 ml) was treated with a solution of tin (II) chloride (3.7 g, 30 mmol) in concentrated hydrochloric acid (12 ml). The mixture was heated at 50° C. for 16 h. A further portion of tin (II) chloride (2.9 g, 15 mmol) was added and the mixture heated at 50° C. for a further 4 hours before being evaporated to dryness. The residue was partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The ethyl acetate extract was dried (Na2SO4) and filtered through a plug of silica. Evaporation afforded the title compound as a yellow solid (2.15 g, 85%).
Reaction SMILES: COC1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][C:4]=1C.Br.[C:19]([OH:22])(=O)[CH3:20]>>[CH3:16][N:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:9]([C:6]2[C:7]([CH3:8])=[C:19]([OH:22])[CH:20]=[CH:4][CH:5]=2)=[N:10]1
Reactant: COc1ccc(-c2nn(C)c(C)c2C)cc1C
Reactant: CC(=O)O
Agent: Br
Product: Cc1c(O)cccc1-c1nn(C)c(C)c1C

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-1,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 65) 0.6 g, 47% hydrobromic acid 5 ml and acetic acid 5 ml was stirred with heating under reflux for thirteen hours. The solvent was distilled off and to the resulting residues was added ethyl acetate 30 ml, and the resulting mixture was stirred at room temperature for one hour. The precipitates were filtered and were washed with hexane, and were concentrated under reduced pressure to give (1,4,5-trimethyl-1H-pyrazol-3-yl)-2-methyl-phenol 0.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:10][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(COC(C)=O)nc1

Procedure:
The crude N-oxide product obtained above (13.5 g.) was then placed in acetic anhydride (100 ml.) and heated on a steam bath for a period of three hours. The excess anhydride was thereafter removed by means of distillation and the liquid residue so obtained was fractionally distilled to give pure 2-acetoxymethyl-5-methoxypyridine (yield, 6.6 g.), b.p. 148°-150° C./12 mm. Hg. This particular product was then hydrolyzed by heating same on a steam bath while in concentrated hydrochloric acid for a period of four hours. Evaporation of the resulting reaction solution then gave crude 2-hydroxymethyl-5-methoxypyridine as the residue.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(C2CC2)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1ccnc(C2CC2)n1
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbonitrile (600 mg, 4.13 mmol) in ethanol (10 mL) was added sodium ethoxide (561.9 mg, 8.27 mmol). After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 2-cyclopropylpyrimidine-4-carbimidate (400 mg) as a pale yellow liquid. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[O:22]1[CH2:25][CH:24]([CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29])[CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([CH2:27][CH2:26][CH:24]2[CH2:25][O:22][CH2:23]2)(=[O:30])=[O:29])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)CCC1COC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)CCC2COC2)c2n(c1=O)CCO2
Yield: 5.4 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Example 7A, 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.2 g, 0.673 mmol) was reacted with 2-(oxetan-3-yl)ethanesulfonyl chloride (0.18 g, 1.009 mmol) in dry pyridine (3 mL) to afford the crude product. Purification by preparative HPLC, followed by flash column chromatography (3% methanol in chloroform) afforded 20 mg of the compound (17A) (9% yield) and 3 mg of the hydrolyzed by-product (compound (17B).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].C(O)(=O)C>CN(C=O)C>[CH2:25]([N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])[CH2:26][CH2:27][CH3:28]
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Yield: 44.9 %

Procedure:
7-benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8 mmol) [Synthetic Communications, 20(16), 2459-2467, 1990] and potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400 mL) at 40° C. After stirring for thirty minutes, butyl iodide (8.76 mL, 77.0 mmol) was added, and the mixture was stirred at 40° C. overnight. 50% Aqueous acetic acid (60 mL) was added, and the solution was concentrated under reduced pressure. The residue was suspended in water (500 mL), and the products were extracted into chloroform. The organics were collected, concentrated, and product was isolated using flash chromatography eluting with 1% methanol in dichloromethane to provide the product (9.49 g, 45%); 1H NMR (400 MHz; CDCl3) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s); m/z 299 [MH+].
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Cu])#[N:11].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([C:10]#[N:11])=[CH:7][N:6]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(N)ncc1Br
Solvent: NCCN
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)ncc1C#N
Temperature: 170 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-4-methyl-pyridin-2-ylamine (500 mg, 2.67 mmol), CuCN (478 mg, 5.34 mmol) and DMA (2 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 851A (309 mg, 87%) as a white solid.
Reaction SMILES: [OH:1][CH2:2]C(CO)OCN1C=C(C=C)C(=O)NC1=O.ClN1C(=O)CCC1=O.[OH:26][CH2:27][CH2:28][O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]>ClCCl.CO>[OH:26][CH2:27][CH:28]([CH2:2][OH:1])[O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]
Reactant: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=NC(CCl)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 57 %

Procedure:
Reaction of 9a with N-chlorosuccinimide, using the procedure outlined for the preparation of 2b, and purification of the product by silica gel column chromatography using dichloromethane-methanol (90:10, v/v) as eluent yielded 10b as a syrup (75 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].[OH-:16].[K+].OO.Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:4]=1[C:5]([OH:16])=[O:6]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirred solution of 2-methoxy-5-trifluoromethoxybenzaldehyde (2.0 g, 9.09 mmol) and 50% KOH (4.1 ml) in MeOH (15 ml) at 65° C. was added dropwise hydrogen peroxide (30%, 7.4 ml) over 20 min. The reaction mixture was then stirred at 65° C. for 10 min., cooled to room temperature, acidified with 1 M HCl, and extracted with Et2O (3×40 ml). The combined organic extracts were washed with brine (35 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a pale yellow viscous oil which solidified at room temperature overnight to give the title compound (1.95 g, 91%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CN1CCNCC1=O
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)C(=O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-methyl-piperazin-2-one. ES-MS m/e (%): 505 (M+Na+, 31), 483 (M+H+, 100).
Reaction SMILES: C[C:2]1[CH:6]=C(C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.NN1CC[O:30][CH2:29][CH2:28]1>>[NH2:20][C:8]([NH:4][N:3]1[CH2:2][CH2:6][O:30][CH2:29][CH2:28]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: NN1CCOCC1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CS(=O)(=O)O
Product: NC(=NS(=O)(=O)c1ccc(Cl)cc1)NN1CCOCC1

Procedure:
The compound of Example 28 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 318.78; found mol. wt. (M+H) 319.3; 637.0 (Dimer)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:28][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][N:22]2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CN1CCCCC1CO
Product: CN1CCCCC1COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-Methyl-2-piperidinemethanol.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[N:25]([CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CN=[N+]=[N-])c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (2.00 g, 4.76 mmol) in N,N-dimethylformamide is treated with sodium azide (0.325 g, 5.00 mmol), stirred overnight at room temperature, treated with 18-crown-6, stirred at room temperature for two hours, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31](O)=[O:32])[CH2:29][CH2:28]1.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:32])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(O)(c1ccccn1)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccn1)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (120 mg, 0.316 mmol), the sodium salt of 2-cyclopropyl-2-(2-pyridyl)hydroxyacetic acid from the previous step (63 mg, 0.326 mmol), and NMM (36 μL, 0.326 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (173 mg, 0.391 mmol). The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN containing 0.1% TFA) over 60 min with a flow rate of 60 mL/min. After concentration of desired fractions in vacuo, the two diastereomers of 1-(2-cyclopropyl-2-(2-pyridyl)hydroxyacetyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide were obtained as amorphous solids (isomer 1 (less polar) 50 mg; HPLC RT=3.06 min, method A; LC-MS m/z=543.2; 1H NMR, 400 MHz, CDCl3, 7.81 ppm (d, 1H), 7.74 ppm (t, 2H), 7.28 ppm (d, 2H), 7.22 ppm (d, 1H), 7.14 ppm (t, 1H), 5.45 ppm (br s, 1H), 5.0 ppm (br s, 1H), 4.8 ppm (d, 1H), 4.6 ppm (dd, 1H), 4.42 ppm (d, 1H), 4.35 ppm (m, 1H), 4.2 ppm (m, 1H), 3.43 ppm (m, 1H), 3.1 ppm (br t, 1H), 2.25 ppm (m, 1H), 2.1 ppm (m, 1H), 1.8 ppm (m, 2H), 1.48 ppm (m, 1H), 1.45 ppm (s, 9H), 1.0 ppm (m, 1H), 0.85 ppm (m, 1H), 0.65 ppm (m, 1H), 0.5 ppm (m, 1H); isomer 2 (more polar)38 mg; HPLC RT=2.99 min, method A; LC-MS m/z=543.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>CC(O)=O>[Br:19][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 46.8 %

Procedure:
A mixture of 5-chloro-2-nitrobenzenamine (6.0 g, 34.9 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was heated at 110° C. for 1 h. The solution was cooled to RT and the reaction mixture was poured into an ice-water (800 mL). The resulting solid was filtered, washed with water (50 mL×3), and dry under vacuum to afford 4.0 g (44%) of 4-bromo-5-chloro-2-nitrobenzenamine (246) as yellow solid: MS (ESI) m/z=250.9 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][CH:14]3[O:18][C:17]([NH2:19])=[N:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.C([O:23][C:24](=O)[CH:25]([CH:28]=O)[CH2:26][CH3:27])C>C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C@H:14]3[O:18][C:17]4=[N:19][C:24](=[O:23])[C:25]([CH2:26][CH3:27])=[CH:28][N:16]4[CH2:15]3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(C=O)CC
Reactant: CC1(C)CCCc2cc(OCC3CN=C(N)O3)ccc21
Solvent: CCO
Product: CCc1cn2c(nc1=O)O[C@H](COc1ccc3c(c1)CCCC3(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 5-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol) in ethanol (16 mL) was added 2-formyl-butyric acid ethyl ester (0.39 g, 2.7 mmol). The reaction mixture was stirred at room temperature for one hour, and then heated at reflux for 24 hours. It was then concentrated and loaded on a silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.15 g the title product. [α]D25=−26.8 (c=0.74, CHCl3).