Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)s1)NC(=O)OC(C)(C)C

Procedure:
Suzuki Coupling. To a solution of (S)-3-(5-bromo-thiophen-2-yl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in toluene (10 mL) was added 4-cyanobenzeneboronic acid, Pd(PPh3)4, and 1N Na2CO3 solution (4 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic was washed with 10% Na2CO3 and 1 N HCl. The organic was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was then purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[5-(4-cyano-phenyl)-thiophen-2-yl]-propionic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[NH2:16][CH2:17][C@@:18]([CH3:23])([CH:20]1[CH2:22][CH2:21]1)[OH:19]>>[CH:20]1([C@:18]([OH:19])([CH3:23])[CH2:17][NH:16][C:12]([C:8]2[CH:7]=[CH:6][C:5]3[CH2:4][CH2:3][C:2]([CH3:1])([CH3:15])[CH2:11][C:10]=3[N:9]=2)=[O:14])[CH2:22][CH2:21]1
Reactant: CC1(C)CCc2ccc(C(=O)O)nc2C1
Reactant: C[C@](O)(CN)C1CC1
Product: CC1(C)CCc2ccc(C(=O)NC[C@](C)(O)C3CC3)nc2C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid and (αR)-α-(aminomethyl)-α-methyl-cyclo-propanemethanol (CAN 912454-48-9) as starting materials, LC-MS (UV peak area/EIC) 99.3%, 303.2078 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1)=O.N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(B(O)O)o1
Yield: 20.4 %

Procedure:
A solution of 5-chlorooxindole (999 mg, 5.98 mmol), 5-formylfuran-2-boronic acid (832 mg, 5.98 mmol) and piperidine (0.59 mL, 5.98 mmol) in EtOH (5.0 mL) was stirred at rt 90 min. The resulting precipitate was collected by filtration to yield the desired compound (354 mg). LCMS (ES): m/z 290 [M+1]+.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[CH3:9][C:10]1([CH3:31])[O:14][C:13](=[O:15])[C:12]([O:16][CH2:17][C:18]([CH3:20])=[CH2:19])=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)CCl>[CH3:9][C:10]1([CH3:31])[O:14][C:13](=[O:15])[C:12]([O:16][CH2:17][C:18]2([CH3:2])[CH2:20][CH2:19]2)=[C:11]1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: C=C(C)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCCl
Product: CC1(COC2=C(c3ccc(S(C)(=O)=O)cc3)C(C)(C)OC2=O)CC1
Reaction time: 0.08 h

Procedure:
To a solution of Et2Zn (0.82 mL) in 50 mL of ClCH2CH2Cl cooled at 0∞C. was added 1.3 mL of CH2I2 slowly. The mixture was stirred for 5 min. and treated with 0.63 g of the olefin of example 18 at 0∞C. The mixture was stirred for 20 min. at 0∞C. and 3 h at room temperature. The reaction was quenched by addition of 50 mL of saturated NH4Cl solution and the product was extracted with EtOAc (200 mL) The extract was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromotography eluted with 3:2 hexane/EtOAc to give 400 mg of the title product as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH:15]([N:19](C)C)[N:16](C)C)C.C(=O)(O)O.NC(N)=N>C1(C)C=CC=CC=1>[N:16]1[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:12]=[N:13][C:15]=1[NH2:19]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: O=C1CCCc2ncccc21
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Product: Nc1ncc2c(n1)-c1cccnc1CC2
Yield: 11.2 %

Procedure:
To a refluxing solution, under nitrogen, of 45.0 g (0.306 mol) of 7,8-dihydro-5(6H)-quinolinone, (Example 1), in 750 ml of toluene is added dropwise a solution of 49.8 g (0.343 mol) of tris(dimethylamino)-methane in 250 ml of toluene. The solution is refluxed for 2 hours, cooled and concentrated. The residue is dissolved in 1 l of methanol and treated with 66.2 g (0.367 mol) of guanidine carbonate. The reaction mixture is refluxed, under nitrogen, for 2 hours. The mixture is concentrated to a green solid, the solid is washed with 500 ml of water, filtered and vacuum dried to give 69.1 g of crude product. Recrystallization from acetonitrile affords 6.8 g (77%) of the title compound as a light brown solid; mp 220°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C1COCC1>[C:25]([N:14]1[CH2:15][CH2:16][C:17]2[N:18]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[NH:8])[S:11][C:12]=2[CH2:13]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(C(C)=O)CC2

Procedure:
Acetylation of 110 mg N-(2,6-dimethoxybenzyl)-N′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)guanidine (0.26 mmol, Example 221.3) under standard conditions with acetylchloride and triethylamine in 15 ml THF followed by purification, yielded 16 mg of the desired product as a white solid; ESI-MS [M+H+]=390.15.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([C:12]2[C:13]([Cl:27])=[CH:14][C:15]([Cl:26])=[C:16]([S:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])[CH:17]=2)=[N:6][N:7]([CH3:11])[C:8]=1[S:9][CH3:10]>C(O)C.O>[Cl:3][C:4]1[C:5]([C:12]2[C:13]([Cl:27])=[CH:14][C:15]([Cl:26])=[C:16]([S:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])[CH:17]=2)=[N:6][N:7]([CH3:11])[C:8]=1[S:9][CH3:10]
Reactant: CCOC(=O)C(C)Sc1cc(-c2nn(C)c(SC)c2Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1c(Cl)c(-c2cc(SC(C)C(=O)O)c(Cl)cc2Cl)nn1C
Yield: 81.6 %

Procedure:
After addition of NaOH (0.31 g, in pellet form, 95% content) to a solution of ethyl 2-[5-(4-chloro-1-methyl-5-methylthio-1H-pyrazol-3-yl)-2,4-dichlorophenylthio]propionate (2.28 g, 5.18 mmoles) in 50 ml ethanol, several drops of water added, thereby conducting the reaction for 3 hours at room temperature. Then the solvent was removed by evaporation of the resulting solution under reduced pressure. Water and ethyl acetate were added to the residue and the formed aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid. The objective product was extracted from the aqueous layer with ethyl acetate. The extract solution was washed with water, dehydrated, and evaporated to dryness, giving crystals (1.74 g) of the title compound, m.p. 180.0° C., yield 81.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)c(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(-c2ccccc2C#N)cc1Br)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a solution of 670 mg (2.35 mmol) of 3'-bromo-4'-hydroxymethyl-1,1'-biphenyl-2-nitrile (Step F) in 5 mL of dry dimethylformamide under a nitrogen atmosphere was added 237 mg (3.49 mmol) of imidazole. The reaction mixture was cooled to 0° C. and 0.73 mL (2.8 mmol) of t-butylchlorodiphenylsilane was added dropwise by syringe over 5 minutes. The resulting solution was stirred at 0° C. for 15 minutes then at room temperature for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with ether (3×75 mL). The combined ether extracts were washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to afford 1.24 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): δ 1.13 (s, 3H), 4.80 (s, 2H), 7.30-7.50 (m, 9H), 7.55-7.80 (m, 7H), 7.86 (d, 8 Hz, 1H). FAB-MS: calculated for C30H28BrNOSi 526; found 527, 528, 271 (60%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].[Se](=O)=[O:24]>O1CCOCC1.O>[CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18]([OH:24])=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22]
Reactant: O=[Se]=O
Reactant: CN1C(=O)NC(=O)C12Cc1cc3ccc(C=O)nc3cc1C2
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)O)nc3cc1C2

Procedure:
A mixture of (±)-2,3′-dimethyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione (500 mg, 1.78 mmol, described in Intermediate 19) and selenium dioxide (592 mg, 5.33 mmol) in dioxane (30 mL) and H2O (3 mL) are heated at reflux for 18 h. The reaction mixture is allowed to cool, filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give the title compound. MS: m/z=312 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH3:28])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH3:28])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(methylthio)propanoate (1.01 g), 10% aqueous sodium hydroxide solution (10 mL) and methanol (20 mL) was heated at reflux for 1 hour. The mixture was diluted with water (300 mL) and washed with dichloromethane (3×200 mL). The aqueous layer was acidified to pH2 with concentrated hydrochloric acid, extracted with ethyl acetate (3×200 mL) and the extracts washed with brine (2×200 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 2% methanol in dichloromethane as eluent to afford the title compound, mp 140°-1° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1.[CH3:21][N:22]([CH3:39])[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[CH3:21][N:22]([CH3:39])[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[C:29]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:30])(=[O:24])=[O:25]
Reactant: COC(=O)CNc1cnccc1-c1cccnc1OC
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). The product-containing fractions were pooled and evaporated and the residue poured on 30 mL 1M aqueous HCl and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed twice with 30 mL 1M aqueous HCl followed by 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (30%). MS (ESI): m/z=553.135 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([C:21](O)=[O:22])=[C:8]2[N:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:21]([C:7]2[C:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=3[CH3:27])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[O:22])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2ccccn2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of the crude compound obtained in step 4 (125 mg, 0.35 mmol), 1-tert-butoxycarbonyl-piperazine (67.9 mg, 0.37 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.4 mg, 0.38 mmol) and 1-hydroxybenzotriazole (61.3 mg, 0.40 mmol) in DMF (2 ml) was added N-methyl-morpholine (0.115 ml, 1.04 mmol). The mixture was stirred at room temperature overnight, then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 158 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[C:18](N)=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12].[I:20]CI>>[CH3:9][O:10][C:11]([C:13]1[C:18]([I:20])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COC(=O)c1nccnc1N
Reactant: ICI
Agent: CC(C)CCON=O
Product: COC(=O)c1nccnc1I
Temperature: 100 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
Isoamyl nitrite (5.2 mL, 39 mmol) was added to a suspension of 3-aminopyrazine-2-carboxylic acid methyl ester (1.9 g, 12 mmol) in diiodomethane (20 mL) at 85° C., then the mixture was stirred at 100° C. for 15 hours. The reaction mixture was allowed to stand and purified by silica gel column chromatography to give 1.4 g of the title reference compound as a pale yellow solid. (Yield 44%)
Reaction SMILES: [O:1]1[CH2:3][C:2]21[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=1.[NH2:18][NH2:19]>>[NH:18]([CH2:3][C:2]1([OH:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[NH2:19]
Reactant: NN
Reactant: c1ccc2c(c1)CCc1ccccc1C21CO1
Product: NNCC1(O)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 10.0 g. of 10,11-dihydro-spiro[dibenzo[a,d] cycloheptene-5,2'-oxirane] and 100 ml. of anhydrous hydrazine is refluxed for 3 hours, the resulting mixture evaporated in vacuo to dryness, the residue dissolved in methanol and again evaporated in vacuo to dryness. The residue is crystallized from diethyl ether to obtain 5-hydrazinomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5-ol, m.p. 95°-105° C. (decomp.). It was observed that this product decomposed slowly at room temperature to form dibenzo[a,d]cyclohepten-5-one and thus must be stored at reduced temperatures if to be preserved in relatively pure form for any substantial period of time.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[C:11](=[O:12])([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: OC1CCCCCCC1
Product: CCOC(=O)OC1CCCCCCC1

Procedure:
The product was obtained similarly as in Example 1 by reacting cyclooctanol with ethyl chloroformate and a colorless liquid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C:7](=O)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([SH:35])[CH2:33][SH:34].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][C:7]2([S:35][CH2:32][CH2:33][S:34]2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:20]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2

Procedure:
Dissolve 7.0 g of 1-benzyloxycarbonyl-4-keto-(S)-proline methyl ester in 75 ml of glacial acetic acid. Add 0.7 g of p-toluenesulfonic acid and 2.8 g of 1,2-ethanedithiol and heat under reflux with stirring for eighteen hours. Add the reaction mixture to saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (300 g, 60-200 mesh) and elute with hexane:ethyl acetate (1:1) to give 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid methylester, a yellow oil having [α]D26 -12.6° (dioxane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([I:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:17])(=[O:13])=[O:12])=[C:7]([I:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)O)c(I)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Cl)c(I)c1
Temperature: 77.5 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a suspension of 100 (12.0 g; 35.0 mmol) in dichloroethane (300 mL) at 50° C. was added phosphorus pentachloride (11.01 g; 52.9 mmol). After addition was complete, the reaction mixture was heated at 75-80° C. overnight, cooled to 50° C., and additional phosphorus pentachloride (6.0 g; 28.8 mmol) was added. After heating at 85° C. for an additional 12 hours, the reaction mixture was again cooled to 50° C. and additional phosphorus pentachloride (2.0 g; 9.60 mmol) was added. Heating was continued at 90° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting crude oil was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 20% v/v over 400 mL gradient elution) to give the title compound as a yellow oil (9.98 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1)[C:3](N(C(C)C(O)C1C=CC=CC=1)C)=[O:4].[OH2:25]>>[NH2:1][C@@H:2]([CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1)[C:3]([OH:4])=[O:25]
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)C(N)CCCC1OCCO1
Reactant: O
Product: N[C@@H](CCCC1OCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml flask equipped with an argon inlet, magnetic stir bar and reflux condenser was charged with 5.9 g of the product from Example 1 and water (80 ml). The reaction was refluxed for seven hours and then allowed to stir overnight at room temperature. The reaction mixture was diluted with water (120 ml) and washed with methylene chloride (2×50 ml). The combined methylene chloride layers were extracted once with water (50 ml), and the combined aqueous layers were concentrated in vacuo. The residue was concentrated in vacuo from 100% ethanol (2×100 ml) to a solid. The solid was dissolved in water (15 ml) and the solution was stirred with a magnetic stir bar as 100% ethanol (150 ml) was added in a slow stream. Stirring was stopped, and the mixture was allowed to stand for one hour and then filtered. The solids were washed with 100% ethanol (2×25 ml), air-dried for 15 minutes, and then volatiles were removed under high vacuum overnight to give 2.0 g of the desired product as a white powder; m.p. 224-226°(decomp.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[N].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: O=C(Cl)c1ccccc1
Agent: [N]
Solvent: c1ccncc1
Product: O=C(OCCCCCCCCCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
In a 100 mL two-neck flask under a static head of nitrogen 12-bromo-dodecanol (5.0 g, 18.9 mmol) is weighed, pyridine (25 mL) is added and the whole is brought to 0° C. with an external bath of ice and salt. Benzoyl chloride is dripped slowly and, when adding is finished, the ice bath is removed and the whole is left stirring at room temperature. After 18 hours ethyl acetate (100 mL) and distilled water (100 mL) are added. The organic phase is washed 3 times with distilled water (3×50 mL) and anhydrified on anhydrous sodium sulphate. It is filtered under a vacuum and the solvent is eliminated in the Rotovapor and in the high vacuum pump. The product is purified with column chromatography on silica gel with an eluant mixture of petroleum ether/ethylic ether 5/1. 4.5 g of 12-bromododecyl benzoate are isolated as a colourless oil with a yield of 65%.