Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: Brc1cccs1
Product: O=C(O)CCC(=O)c1ccc(Br)s1
Yield: 51 %

Procedure:
As described for Example 1, 0.3 mole of 2-bromothiophene is reacted with succinic anhydride to give 4-(5-bromo-2-thienyl)-4-ketobutyric acid (51%), m.p. 141°-143° C. The preceding compound is coupled to L-proline to give 1-[3-(5-bromo-2-thenoyl)propionyl]-L-proline (56%) as crystals, m.p. 166°-168° C. The preceding compound (0.008 mole) is reacted with bromine in acetic acid to yield 1-[3-bromo-3-(5-bromo-2-thenoyl)propionyl]-L-proline as a glass (97%). As for Example 1, reaction of the preceding compound with sodium thioacetate gives the product of the Example (88%) as a yellow glass.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:28]2[CH2:29][CH2:30][CH:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCOC(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2CCN(CCOC(c3ccccc3)c3ccccc3)C2)c1
Temperature: 80 °C
Yield: 43 %

Procedure:
A solution of 17.5 g (60 mmole) of 1-(diphenylmethoxy)-2-bromoethane in 50 cm3 of dimethylformamide was added to a mixture of 10.6 g (60 mmole) of 3-(3-methoxyphenyl)pyrrolidine [prepared according to A. Ebnother and K. Hasspacher, Swiss Patent No. 526 536], 16.6 g (120 mmole) of potassium carbonate, 300 cm3 of dimethylformamide and a few potassium iodide crystals. The mixture was heated at 80° C. for 13 hours, and concentrated to dryness under reduced pressure after it returned to room temperature. The residue was taken up with 500 cm3 of 1N hydrochloric acid and extracted with ether. The aqueous acid phase was separated, basified with 10N sodium hydroxide solution, and extracted with methylene chloride. The organic solution was dried on sodium sulfate. The evaporation of the solvent provided an oily residue. Purification by silica gel filtration (eluent, hexane-ethyl acetate, 1/1) yielded 10 g of 1-[2-(diphenylmethoxy) ethyl]-3-(3-methoxyphenyl)pyrrolidine, which was dissolved in 100 cm3 of ether. To this solution was added a solution of 2.55 g (28.3 mmole) of oxalic acid in 30 cm3 of acetone. The oxalate precipitate was filtered and recrystallized from acetone.
Reaction SMILES: C(=O)CCCCC.[CH2:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20]C(CO)CO)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(C1C=CC(CCCCBr)=CC=1)CC>>[CH2:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(CCCCC(CO)CO)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCCCC=O
Agent: CCCc1ccc(CCCCBr)cc1
Product: CCCc1ccc(CCCCC(C(=O)OCC)C(=O)OCC)cc1

Procedure:
A mixture of 1 g of hexanal, 2.5 g of 2-(4-p-propylphenylbutyl)-propane-1,3-diol (obtainable by reacting diethyl malonate with 4-p-propylphenylbutyl bromide to give diethyl 2-(4-p-propylphenylbutyl)-malonate and reducing the latter with LiAlH4), 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours under a water separator and is cooled, washed with water and evaporated. This gives 2-pentyl-5-(4-p-propylphenylbutyl-1,3-dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 47 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 47%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH:25]=[CH:26][CH:27]=2>>[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:25]=[CH:26][CH:27]=2
Reactant: NCCCCCCN1C(=O)c2cccc3cccc(c23)C1=O
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
Batch size: 5.3 g (35.5 mmol) 3-(3-pyridyl)-acrylic acid, 12.4 g (97.9 mmol) oxalyl chloride and 8.6 g (32.6 mmol) 6-(1,3-dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-hexylamine.
Reaction SMILES: C(OC(=O)C[C:8]1[C:9]([Cl:17])=[N:10][C:11]([NH2:16])=[N:12][C:13]=1[C:14]#N)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C.[C:26](#[N:28])C>>[NH2:16][C:11]1[N:10]=[C:9]([Cl:17])[CH:8]=[C:13]([CH2:14][C:26]#[N:28])[N:12]=1
Reactant: CC(C)(C)OC(=O)Cc1c(Cl)nc(N)nc1C#N
Reactant: CC#N
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Product: N#CCc1cc(Cl)nc(N)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
2-amino-4-chloro-6-cyano-pyrimidylacetate-t-butyl ester (100 g, 372.5 mmol) was suspended in dry acetonitrile (1.2 l) containing sodium iodide (55.84 g, 372.5 mmol) and warmed to 40° C. until the mixture became homogeneous. Then chlorotrimethylsilane (200 ml) was added and the orange suspension was heated at reflux. After 1 hour, TLC analysis (elute with 1:1 ethyl acetate/hexanes) indicated a complete reaction and the reaction was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate and washed with water and sodium bicarbonate solution and dried with magnesium sulfate. The crude product was slurried in activated carbon, filtered and concentrated to give 38.46 g of a green solid. This was again dissolved in ethyl acetate and passed through a 4-inch pad of silica gel and then concentrated to give the desired subject as a green solid, m.p. 110°-115° C. NMR (200 mHz) D6-acetone δ 6.8 (s, 1 H), 6.8-6.6 (bs, 1 H), 3.95 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([OH:18])=[O:17].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:23](=[O:25])[CH3:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of N-(3,4-Dichlorobenzyl)-5-hydroxyindole-2-carboxylic acid (10 g) in warm ethyl acetate (250 ml) was added 4-dimethylaminopyridine (100 mg) and acetic anhydride (5.0 ml) and the resulting mixture was stirred for 2 hours. The organics were washed with 1N HCl and dried. Hexane was added to cause crystallision of the product. The solid was filtered and washed with hexane to give the desired product. (5 g, 44%). 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 5.85 (s, 2H), 6.9 (dd, 1H), 7.05 (dd, 1H), 7.3-7.6 (m, 5H); m/z 378, 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11](C)[C:10](=O)[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:30].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:30][C:10]1[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:13]=[C:12]([S:14][CH3:15])[N:11]=1
Reactant: CSc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(-c2cccc(C(F)(F)F)c2)c(-c2ccnc(Cl)c2)n1
Temperature: 25 °C

Procedure:
6-(2-chloro-4-pyridyl)-3-methyl-2-methylthio-5-(3-(trifluoromethyl)-phenyl)-(3H)-pyrimidin-4-one (2.05 g, 5 mmol), POCl3 (3.05 g, 20 mmol), and diisopropylethylamine (2.58 g, 20 mmol) in a 50-ml r.b.flask with a stir bar was stirred at 120° C. for 16 h. The reaction was cooled to RT, 20 ml of EtOAc and 5 g of SiO2 gel were added into the cooled solution, then solvents were evaporated in vacuo at 40° C. The brown solid was placed on a cake of SiO2 gel (˜20 g) and washed by 200 ml of 30% EtOAc in hexane. The brown filtrate was evaporated in vacuo to give an oil product; MS m/z (M+H)+ 416.2. The crude intermediate was used in the next step directly.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12]C)=[C:10]([F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[C:11]([OH:12])=[C:10]([F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(F)c(OC)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(O)c1F
Yield: 72.5 %

Procedure:
In 20 ml of methylene chloride was dissolved 2.00 g of methyl 2,4-difluoro-3-methoxy-benzoate, and to the solution was added 12.8 ml of a 1 M solution of boron tribromide in methylene chloride at -30° C., after which the resulting mixture was stirred under ice-cooling for 2 hours. The reaction mixture was added to a mixed solvent of 150 ml of ethyl acetate and 150 ml of water and the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-exane:ethyl acetate=3:1) to obtain 1.35 g of methyl 2,4-difluoro-3-hydroxybenzoate as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:11]([O:14][C:15]1[CH:27]=[CH:26][C:18]([CH:19]=[CH:20][C:21](OCC)=[O:22])=[CH:17][C:16]=1[O:28][CH3:29])([CH3:13])[CH3:12].S(=O)(=O)(O)O>C(OCC)C.C(OCC)C.O1CCCC1.O>[CH:11]([O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:17][C:16]=1[O:28][CH3:29])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C=Cc1ccc(OC(C)C)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc(/C=C/CO)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
A solution of aluminium chloride (AlCl3) (6.1 g) in diethyl ether (70 ml) was added dropwise to a suspension of lithium aluminum hydride (LiAlH4) (6.4 g) in diethyl ether (270 ml) at 0° C., and the mixture was stirred at room temperature for 10 minutes. Then, a solution of ethyl 4-isopropoxy-3-methoxycinnamate (35.4 g) in diethyl ether-tetrahydrofuran (3:1, 220 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. Then water (170 ml) and 6N sulfuric acid (270 ml) were added dropwise under ice-cooling, and the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:2, v/v) gave (E)-3-(4-isopropoxy-3-methoxyphenyl)-2-propenol (27.0 g, 91%) as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:22]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(NC(=NC3CCCCC3)NC3CCCCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
3.8 g of 4-amino-1-benzylpiperidine (20 mmol) was combined with 4.7 g of dicyclohexylcarbodiimide (23 mmol) in 80 ml of DMF and stirred for 12 hours at 80° C. The solvent was evaporated in vacuo and the residue was flash chromatographed using ethyl acetate/methanol (1:1) whereby 54. g of 1-benzyl-4(N′, N″-dicyclohexyl-guanidino)-piperidine was obtained (71%). 5 g of the product (12.6 mmol) was dissolved in 60 ml of methanol and hydrogenated using 0.6 g of Pd(C) at 2 bar hydrogen pressure. Thus obtained was 4 g of 4(N′, N″-dicyclohexyl-guanidino)-piperidine (63%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][OH:9])[CH3:2].C(N(CC)CC)C.CS(C)=O.Cl>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC[C@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Under atmosphere of argon, to a solution of (4R)-5-hydroxy-4-t-butoxycarbonylaminopentanoic acid ethyl ester (15.0 g), triethylamine (32.0 mL) and dimethylsulfoxide (39 mL) in ethyl acetate (120 mL), a solution of sulfur trioxide pyridine complex (18.3 g) in mixed solvent ethyl acetate (30 mL) and dimethylsulfoxide (75 mL) was added at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was added by water (5 mL) at 0° C. and was added by 1N hydrochloric acid (240 mL). Separated aqueous layer was extracted by ethyl acetate. The combined organic layer was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (14.7 g) having the following physical data.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[K+]>C(OCC)C>[CH:1]([C:4]1[C:12]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:20])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)c1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc(C(=O)c2c(C(C)C)nn3ccccc23)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.6 %

Procedure:
3.2 ml of 2-isopropylpyrazolo[1,5-a]pyridine, 2.2 g of 4-methoxybenzoyl chloride and 200 mg anhydrous AlCl3 were mixed with stirring at room temperature for 4 days. After cooling, 50 ml of ethyl ether was added to the mixture, followed by addition of 4N KOH solution to pH 8-8.5 at 0-5° C. The mixture was extracted with ethyl acetate twice. The combined organic phases were washed with brine and dried over MgSO4. The ethyl acetate was evaporated under reduced pressure to obtain 6.4 g of crude product, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 510 mg (13.6%) of (2-isopropylpyrazolo[1,5-a]pyridin-3-yl)(4-methoxyphenyl)methanone. Compound 1008.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][N:11]([CH3:12])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[N:2]=2)[N:8]=1)=[O:14]
Reactant: CN(C)C(=O)Nc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50 %

Procedure:
N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea (0.72 g, 3.8 mmol) and methyl thiosalicylate (0.89 g, 5.2 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected and recrystallized from diisopropyl ether-methanol to give the titled compound (0.62 g, 50%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.049 min, m/z=391; 1H NMR (CDCl3) 1.06-1.19 (d, 6H), 1.50 (s, 3H), 2.11-2.38 (m, 6H), 2.80 (m, 1H), 5.66 (m, 1H), 6.97 (m, 2H), 7.04 (d, 2H), 7.18 (m, 1H), 7.23 (m, 2H), 7.58 (m, 1H), 7.73 (m, 3H), 8.60 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[OH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH2:4][NH2:5]
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: NCc1cc(CO)ccc1F

Procedure:
2-Fluoro-5-formylbenzonitrile was treated with sodium borohydride and dimethyl sulfate in THF to obtain 5-hydroxymethyl-2-fluorobenzylamine. F: 156.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
A mixture of tert-butyl 2-(6-nitro-1H-indol-1-yl)acetate (1.44 mmol, 1 equiv.), iron powder (5.76 mmol, 4 equiv.), ammonium chloride (4 equiv.) and ethanol (10 ml) was stirred for 4 h at boiling temperature. The reaction mixture was cooled to 25° C. and filtered over celite. The filtrate was concentrated, diluted with water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 10 ml), dried over Na2SO4 and concentrated under reduced pressure. For purification, the product was recrystallized from ethyl acetate/hexane. Yield: 61%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and Cul (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A 500-mL round-bottomed flask was charged with a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (16 g, 79.60 mmol, 1.00 equiv) in DCM (200 mL), 4-nitrobenzene-1-sulfonyl chloride (17.6 g, 79.64 mmol, 1.00 equiv) and pyridine (9 mL). The resulting solution was stirred at 40° C. for 16 hours. The reaction progress was monitored by TLC (EtOAc: PE=1:2). Upon completion, the reaction was then quenched by the addition of aqueous NaHCO3 (200 mL). The resulting mixture was extracted with dichloromethane (4×100 mL). Combined organic layers were washed with brine (1×30 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:2) affording tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate as yellow solid (23 g, 75%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:33])[NH:17][C:18]1([CH:22]([OH:32])[C:23](=[O:31])[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:35]>O1CCOCC1>[NH2:7][CH:8]([CH2:9][C:10]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:16]([NH:17][C:18]1([CH:22]([OH:32])[C:23](=[O:31])[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)[CH2:21][CH2:20][CH2:19]1)=[O:33].[ClH:35]
Reactant: Cn1ccc(NC(=O)C(O)C2(NC(=O)C(CC3(F)CCCC3)NC(=O)OC(C)(C)C)CCC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)C(N)CC3(F)CCCC3)CCC2)n1
Reaction time: 0.33 h

Procedure:
The Boc-protected amine 56-a (332 mg, 0.689 mmol) was added 4M HCl in 1,4-dioxane (5 mL) and the reaction was stirred for 20 min. The product was isolated by degassing the reaction (N2/vacuum cycles) followed by lyophilisation. This gave the title compound as the bis HCl salt (310 mg, >99%). ES+ 382.1 [M+H]+.