Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]#[N:10])=[CH:4][N:3]=1
Reactant: Cc1ncc(CC#N)cn1
Reactant: Clc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(C#N)c2ccncc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1.0 g, 7.51 mmol) and 4-chloropyridine hydrochloride (1.13 g, 7.51) in dioxane (20 mL) in a dried flask was degassed and filled with nitrogen. t-BuOK (18.8 mL, 1M in THF) was added. The mixture was stiffed at 100° C. for 4 h and cooled to room temperature, quenched by cooled sat. aq. NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (MeOH: EtOAc=1:10) to give 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile (700 mg, crude).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].[CH3:17]I>C(O)C.O>[CH3:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: CI
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cc3ccccc3cc2[nH]1
Yield: 122.3 %

Procedure:
20.0 g of 1H-naphth[2,3-d]imidazole-2-thiol and 4.0 g of sodium hydroxide were heated for 1 hour under reflux and in 150 ml of ethanol with 6.5 g of methyl iodide. The reaction solution was diluted with 500 ml of water and the precipitated product was suction filtered. Crystallisation from dioxane provided 12.0 g of 2-methylthio-1H-naphth[2,3-d]imidazole haing a m.p. of 242°-244°.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(O)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) 75.0 mg (0.143 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.01 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.4 Hz), 7.45 (2H, s), 7.20-7.17 (3H, m), 6.92-6.89 (2H, m), 5.97 (1H, t, J=4.7 Hz), 2.35 (2H, d, J=4.7 Hz), 1.34 (6H, s).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NS(C)(=O)=O)cc3F)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 34-1 (49 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in 2 mL of DCM, was added mesyl chloride (10 μL, 0.13 mmol). After 2 h, a second equivalent of triethylamine (17 μL, 0.12 mmol) and mesyl chloride (10 μL, 0.13 mmol) was added. After 1 h, the mixture was washed with brine, concentrated and purified on preparative HPLC to give 44-1: LC-MS 489.1 (MH), tR=7.31 (Method 2). EC50: 170 nM.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27]Cl)[CH3:24]>>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: CCN(CC)CCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-diethylaminoethylchloride.
Reaction SMILES: C([N:4]1[CH2:12][CH:11]2[C:6]([C:22]3[S:23][C:24]([F:27])=[CH:25][CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)C=C>C(Cl)(Cl)Cl.ClCCl.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>[F:27][C:24]1[S:23][C:22]([C:6]23[CH2:5][NH:4][CH2:12][CH:11]2[CH2:10][S:9][C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]3)=[CH:26][CH:25]=1
Reactant: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccc(F)s2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(NC1=NC2(c3ccc(F)s3)CNCC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Through a stirred solution of racemic N-[6-allyl-7a-(5-fluoro-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (163 mg, 0.406 mmol) in chloroform (4.1 mL) is passed a stream of nitrogen for 20 minutes. N,N-Dimethylbarbituric acid (380 mg, 2.44 mmol) is added and degassing is continued for a further 5 minutes. Tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) is added and the mixture is stirred under nitrogen at room temperature for 45 minutes. The mixture is diluted with dichloromethane (approximately 15 mL) and extracted twice with 1 M hydrochloric acid (10 mL). The pH of the combined aqueous acid extracts is adjusted with 5 M sodium hydroxide (5 mL). The aqueous solution is extracted three times with dichloromethane (20 mL) and the combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated to give the title compound (135 mg, 92%). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3Cl)[N:12]=2)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[N:38][CH:37]=1)CCC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)[N:12]=2)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2cccc(-c3ccnnc3)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (S)-2-amino-4-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile 59 (50 mg, 0.12 mmol), 4-(tributylstannyl)pyridazine (89 mg, 0.24 mmol) and PdCl2(dppf) (9.7 mg, 0.012 mmol) in 1,4-dioxane (5 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT, poured into water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 3% MeOH-DCM to afford the product, (S)-2-amino-4-((1-(4-oxo-3-phenyl-5-(pyridazin-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 66. ESI-MS m/z: 462.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][CH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:21][C:20]2[C:15]([CH2:14][OH:13])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCc1ccccc1
Reactant: OCc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCc1ncccc1OCCCCCc1ccccc1

Procedure:
1.9 g (6.01 mmol) of phenylpentyl bromide, 1.00 g (8.00 mmol) of 2-hydroxymethyl-3-pyridinol and 1.2 g (8.8 mmol) of potassium carbonate are heated at reflux overnight. The mixture is taken up in ethyl acetate, washed with water, 2N aqueous sodium hydroxide solution and water, dried and concentrated under reduced pressure.
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([OH:40])=O)[CH:35]([CH3:37])[CH3:36])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O.Cl>C1COCC1>[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([N:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1)=[O:40])[CH:35]([CH3:36])[CH3:37])([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of the crude N-Me-Tyr(3-t-Bu)-NHSO2Me (0.51 g, 1.43 mmol), Z-N-Me-Val-OH 0.49 g, 1.86 mmol) and CMPI (0.51 g, 2.00 mmol) in THF (10 ml), TEA (0.60 ml, 4.29 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water, rendered acidic by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:3 containing 0.5% acetic acid) to give the titled compound (0.70 g, in 2 steps, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[O:16]1[CH:20]=[CH:19][NH:18][C:17]1=[S:21]>>[O:16]1[CH2:20][CH2:19][N:18]=[C:17]1[S:21][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]1[OH:14]
Reactant: S=c1[nH]cco1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(SC2=NCCO2)C1O

Procedure:
Following the procedure described in the Example 1, using (±) 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 3H-oxazole-2-thione as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[N:17]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(Nc2nc3cc([N+](=O)[O-])ccc3o2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cc(N)ccc3o2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of 4-(5-nitro-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (2.0 g, 5.98 mmol, 1.0 equiv; intermediate L/step 3 (4-(5-nitro-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester)) in ethanol (90 mL) was added palladium on activated charcoal 10% (0.2 g, 0.19 mmol, 0.03 equiv) and the reaction vessel filled with hydrogen (3.5 bar). After stirring at 40° C. for 18 h, the reaction mixture was filtered over celite, concentrated under reduced pressure and the residue purified with column chromatography on silica eluting with ethyl acetate/hexane (2:1) containing 5% methanol to yield 1.8 g (99%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.1 Hz, 3H), 1.44-1.54 (m, 2H), 2.07-2.10 (m, 2H), 2.92-3.01 (m, 2H), 3.72 (br s, 1H), 3.88 (br s, 1H), 4.10 (br s, 1H), 4.14 (q, J=7.1 Hz, 2H), 6.33 (dd, J=8.4 Hz, J=2.2 Hz, 1H), 6.61 (br d, J=4.6 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.61, 32.13, 42.29, 50.18, 61.37, 102.92, 107.98, 108.53, 142.04, 143.49, 143.80, 155.46, 162.14. MS (ISP): 305.4 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:15][CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-(trifluoromethyl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+]>Cl.O>[ClH:9].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: Nc1cc(Br)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)ccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 248.8 %

Procedure:
A suspension of 5-bromo-2-chloroaniline (23 g, 0.11 mol) in concentrated hydrochloric acid (150 mL) and water (90 mL) was cooled in an ice/salt bath. A solution of sodium nitrite (8 g, 0.11 mol) in water (50 mL) was added dropwise to the reaction mixture while maintaining the temperature below 4° C. After stirring for 30 minutes the suspension was transferred via cannula to a solution of SnCl2 dihydrate in concentrated hydrochloric acid (170 mL) and cooled to 5° C. The resulting thick suspension was stirred for 2 h at 5° C. and the solid was isolated via filtration. The solid was air dried and then further dried by adding chlorobutane (500 mL) and refluxing using a Dean-Stark condenser. After cooling, the solid was isolated by filtration to afford the title compound as an off-white solid (35.3 g).
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39])C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2Cl)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a stirred solution of 1 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-{1(R)-hydroxyethyl}-azetidin-2-on-1-yl]-3-(4-methylthiophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -40° was added a solution of 1.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the reaction was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound as a pale yellow foam (0.66 g, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.O[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>CO.CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)sc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (0.300 g, 1.304 mmol), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.365 g, 1.695 mmol), triphenylphosphine (0.455 g, 1.695 mmol), diisopropyl (E)-diazene-1,2-dicarboxylate (DIAD) (0.330 mL, 1.695 mmol), and NMP (5 mL). The reaction mixture was then permitted to stir at room temperature for two hours. The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) tert-butyl 4-[(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)methyl]piperidine-1-carboxylate (11-1) as a tan solid. HRMS (M+H)+: observed=427.0691, calculated=427.0686.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=[C:3]1[CH:23]=O.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(O)(=O)C.CO>[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29]/[N:30]=[CH:23]/[C:3]1[N:2]([CH3:1])[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=1
Reactant: Cn1c(C=O)nc2c(-c3ccccc3)ccc(-c3ccccc3)c21
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C/N=C/c2nc3c(-c4ccccc4)ccc(-c4ccccc4)c3n2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.1 g (0.32 mmol) 1-methyl-4,7-diphenyl-1H-benzimidazole-2-carbaldehyde, 55 mg (0.32 mmol) 2,4-dimethoxybenzylamine and 1 drop glacial acetic acid in 8 ml methanol were stirred for 12 hour at room temperature. The reaction mixture was cooled to −20° C. and filtered while cold. The solid was washed with cold (−20° C.) methanol (2×1 ml) and dried at reduced pressure. Yield—0.12g (81.1%). %). 1H NMR (250 MHz, CDCl3), δ, ppm: 3.76 (s, 3H), 3.80 (s, 6H), 4.81 (s, 2H), 6.46 (m, 2H), 7.14 (d, JHH=8.8 Hz, 1H), 7.25 (d, JHH=7.6 Hz, 1H), 7.46 (m, 9H), 8.02 (d, JHH=7.0 Hz, 2H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:9]=[C:10]1[NH:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH2:12][O:11]1>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][C@H:13]4[CH2:12][O:11][C:10](=[O:9])[NH:14]4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:4][CH2:3]1
Reactant: O=C1N[C@@H](Cc2ccc3[nH]ccc3c2)CO1
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Yield: 25.5 %

Procedure:
1-Methyl-4-piperidone (0.47 g, Aldrich) was added to a stirred solution of the product from step (b) (0.30 g) in glac. acetic acid (2.0 ml) and the mixture stirred at 100° C. for 2 hours. The cooled mixture was poured onto ice/NH4OH (20 ml) and the resulting solid filtered off. The latter was eluted through a silica column using DCM/EtOH/NH4OH (60:8:1) as eluant and crystallised from ethyl acetate to give the desired product as a colourless solid (0.11 g), mp 225°-227° C., [α]D20 -45.4° (c=0.5. 1N aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:25])=O>ClCCl.CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([Cl:25])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cn1cccc1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (4 mmol) of 1-methyl-2-pyrrolecarboxylic acid in 5 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream. There are added, dropwise, 790 μl (4 mmol) of dicyclohexylamine and, 30 minutes later, 290 μl (4 mmol) of thionyl chloride. The medium is stirred for 1 hour at room temperature and then heated for 2 hours at 50° C. The mixture is then diluted with ether and the precipitate is filtered off. The filtrate is evaporated off and a brown oil is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cn1
Reaction time: 24 h
Yield: 80 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min benzylbromide (1.1 eq.) is added and the reaction solution is stirred 24 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 5-Benzyloxy-2-bromo-pyridine is obtained after column chromatography as brown oil in a yield of 80%. HPLC (method C): 2.01 min; LC-MS (method A): 1.97 min, 264.00 (MH+).