Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].Cl.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@:3]([CH3:17])([C:1]2[N:26]=[N:27][NH:28][N:2]=2)[CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nn[nH]n1
Temperature: 103 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a mixture of 6.96 g of tert-butyl (4R)-4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 12.5 g of triethylamine hydrochloride, and 105 ml of toluene was added 5.84 g of sodium azide, followed by stirring at 103° C. for 3 hours. The insoluble materials were separated by filtration and the filtrate was concentrated. The obtained residue was purified twice by silica gel column chromatography to obtain 7.65 g of tert-butyl (4R)-2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:24]([O:1][CH:2]1[CH:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1)(=[O:26])[CH3:25]
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCN2C(=O)N(c3ccc(C#N)c4ccccc34)C(=O)C12
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 6C (123 mg, 0.4 mmol) in pyridine (3 mL) was added acetic anhydride (0.26 mL, 2.8 mmol), followed by 4-dimethylaminopyridine (15 mg). The reaction mixture was stirred at RT for 3 h, then quenched with water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 2% MeOH in EtOAc/hexane (1:1) to give 70 mg of the title compound (racemate) as a white solid. m.p. 105° C.; HPLC: 99% at 4.8 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 350 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.N1C=CC=CC=1.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:21]3[N:22]([CH3:23])[C:34]2=[O:40])[CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(=O)n([C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a round bottomed flask was added N2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-methylpyrazine-2,3-diamine (0.1100 g, 0.337 mmol) and pyridine (0.082 mL, Sigma-Aldrich Chemical Company, Inc.) in DCM (1.1 mL) to stir at −40° C. for 30 mins. Triphosgene (0.120 g, 0.404 mmol, Sigma-Aldrich Chemical Company, Inc.) was added to stir for 30 mins. The temperature was brought to 0° C. and allowed to stir for 5 h. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 40% to 100% EtOAc in hexane, to provide the title compound (0.0352 g, 0.100 mmol, 29.6% yield). LCMS showed product peak at 1.51 min (m+1=353.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.72-2.85 (m, 1 H) 2.94-3.08 (m, 1 H) 3.34 (s, 2 H) 4.14-4.28 (m, 1 H) 4.62-4.76 (m, 1 H) 6.98-7.07 (m, 1 H) 7.19-7.26 (m, 1 H) 7.40 (d, J=7.43 Hz, 1 H) 7.64-7.71 (m, 1 H) 7.98 (s, 1 H) 8.52 (d, J=6.65 Hz, 1 H)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C=O.[CH3:10][CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19].N[CH2:21]C(OC)=O>C(O)(=O)C.O>[CH3:18][C:13]1([CH2:21][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:12]([CH3:19])=[C:11]([CH3:10])[C:15]([CH3:16])=[C:14]1[CH3:17]
Reactant: COC(=O)CN
Reactant: CC1=C(C)C(C)C(C)=C1C
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CNCC1(C)C(C)=C(C)C(C)=C1C
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a stirred mixture of methyl glycinate hydrochloride (6.28 g, 0.05 mole) in 30 mL of glacial acetic acid and 37% aqueous formaldehyde (4.1 g, 1.5 g real, 0.05 mole) is added pentamethylcyclopentadiene (6.81 g, 0.05 mole) after all of the solid methyl glycinate has dissolved. A light brown solution is initially obtained. The temperature is kept at 35° C. for five minutes with ice-bath cooling to control the exotherm. The color of the solution changes to light purple and the temperature is then kept at 33° C. for about 6 hours. This reaction mixture is combined with 100 mL of water and the aqueous phase is extracted with two×20 mL portions of methylene chloride. The clear aqueous phase is then treated with 50% sodium hydroxide, with cooling to maintain a temperature of 35° C., to pH 12. The basic aqueous phase is extracted with two×30 mL portions of methylene chloride. The organic layer is concentrated in vacuo to give approximately 5.0 g of the title compound. Yield is 40%, about 80% purity, of the product which is identified by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and electron impact mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40].CO>C1COCC1>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:38](=[O:41])[CH:39]=[CH2:40])[CH:10]=1)[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2cccnc2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of 1-[6-(2-amino-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-pyridin-3-ylmethyl-urea (53 g, 0.1 mmol) in THF (10 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 0.5 mL, 0.1 mmol) at −10° C., and the mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-TLC to obtain the title compound (9 mg, yield: 15%). 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 6H), 5.01 (s, 2H), 5.69 (d, 1H), 5.75 (s, 1H), 6.10 (dd, 1H), 6.34 (d, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.09-7.24 (m, 2H), 7.28 (t, 1H), 7.32 (s, 1H), 7.47 (d, 1H), 7.69-7.71 (m, 2H), 8.31-8.34 (m, 2H), 8.40-8.42 (m, 1H), 12.60 (s, 1H); MS (ESI): 594 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([CH3:30])=[CH2:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2([CH3:30])[CH2:29][O:9]2)=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=C(C)COc1ccc(OCc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(COc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
3-Chloroperbenzoic acid (1.43 g of 50%, 4.14 mmol) was added to an ice-cooled mixture of 94 (500 mg, 1.97 mmol) and powdered Na2HPO4 (974 mg, 6.86 mmol) in CH2Cl2 (20 mL), and the resulting mixture was stirred at room temperature for 3.5 h. Cold aqueous Na2SO3 (50 mL of 10%) was added, and the mixture was extracted with CH2Cl2 (3×50 mL). The extracts were sequentially washed with cold aqueous Na2SO3 (50 mL of 10%), aqueous NaHCO3 (50 mL) and brine (50 mL). The combined extracts were then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 25% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 25-33% CH2Cl2/petroleum ether gave 2-{[4-(benzyloxy)phenoxy]methyl}-2-methyloxirane (95) (460 mg, 87%) as a white solid: mp (CH2Cl2/pentane) 105-107° C.; 1H NMR (CDCl3) δ 7.44-7.28 (m, 5H), 6.90 (dt, J=9.3, 2.9 Hz, 2H), 6.85 (dt, J=9.3, 2.9 Hz, 2H), 5.01 (s, 2H), 3.97 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.5 Hz, 1H), 2.85 (d, J=4.8 Hz, 1H), 2.71 (d, J=4.8 Hz, 1H), 1.47 (s, 3H). Anal. (C17H18O3) C, H, N.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:14][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2])[CH:22]=[CH2:21]
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1C=O
Temperature: 60 °C
Yield: 89.6 %

Procedure:
To a stirred solution of ethyl 3-formyl-4-hydroxybenzoate [see: Skattebol, Acta. Chemica. Scandinavica 1999, 53, 258] (1.9 g, 10.0 mmol) and anhydrous K2CO3 (2.7 g, 19.5 mmol) in acetone (30 mL) is added allyl bromide (1.7 mL, 19.8 mmol). The mixture is heated in a 60° C. oil bath for 2 h. The mixture is cooled to rt, filtered and concentrated in vacuo to afford 2.1 g (92%) of ethyl 4-(allyloxy)-3-formylbenzoate as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.5, 8.5, 8.2, 7.1, 6.1, 5.5, 5.4, 4.8, 4.4, 1.4.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](CC#N)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>O>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:23][C:22]([OH:25])=[O:24])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Temperature: 0 °C

Procedure:
A mixture of 8.6 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile, 18 parts of concentrated sulfuric acid, 10 parts of acetic acid and 10 parts of water is stirred and refluxed for one hour. The reaction mixture is cooled and poured onto 200 parts of ice-water. The product is extracted twice with 160 parts of ether. The combined extracts are washed with 100 parts of diluted sodium hydroxide solution and separated. The aqueous phase is acidified with concentrated hydrochloric acid solution, whereupon the product is separated as an oil. The latter is extracted with ether. The extract is dried and evaporated. The residue is triturated in petroleumether and the crude product is dissolved in chloroform. It is purified by column chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is triturated in petroleumether and the solid product is crystallized from acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]acetic acid; mp. 126°-129° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:20]=1)(C)(C)C>C(Cl)(Cl)Cl>[CH3:26][C:23]1[O:22][C:21]([C:19]2[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2cncc(NC(=O)OC(C)(C)C)c2)o1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cncc(N)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.7 %

Procedure:
TFA (1 ml) was added to a chloroform solution (2 ml) containing tert-butyl(5-(5-methylfuran-2-yl)pyridin-3-yl)carbamate (61 mg) obtained in the 1st step, stirring at room temperature for 2 hours. The solvent was distilled away under reduced pressure, the obtained residue was dissolved in chloroform, and the resultant was washed with water and a saturated aqueous sodium hydrogen carbonate solution. Subsequently, the aqueous layers were combined, followed by extraction with chloroform (×2). The organic layers was combined and dried over anhydrous sodium sulfate. The solvent was distilled away from the obtained organic layers under reduced pressure, and a white solid of 5-(5-methylfuran-2-yl)pyridin-3-amine (46 mg) was thus obtained.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=O)[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[NH2:1][CH:2]([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[S:30])[CH3:11])[CH2:6][CH2:5]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)N1CCN(CC(C)N)CC1
Solvent: CCN(CC)CC
Product: CC(=S)N1CCN(CC(C)N)CC1

Procedure:
To a solution of 1-[4-(2-amino-propyl)-piperazin-1-yl]-ethanone (149 mg, 0.4 mmol) and triethylamine (TEA, 118 μl, 0.8 mmol) was added Lawesson's reagent (162 mg, 0.4 mmol) at RT. The reaction mixture was heated at reflux for 3 h to provide 1-[4-(2-aminopropyl)-piperazin-1-yl]-ethanethione (intermediate IVa). The solvent was evaporated and the residue was partitioned between ethyl ether and HCl (1 N), the organic layer was discarded and the aqueous layer was basified by addition of a saturated solution of K2CO3. The aqueous solution was extracted with ethyl acetate four times. The organic layers were combined, dried over sodium sulfate and evaporated. The crude mixture was used for the next coupling reaction. M+=202.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:8][CH:9]([CH3:17])[C:10](=O)[CH2:11][C:12](OC)=[O:13].[OH-].[Na+]>C(Cl)Cl>[Br:8][CH:9]([C:10]1[N:7]=[C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]2[C:12](=[O:13])[CH:11]=1)[CH3:17]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1csc2nc(C(C)Br)cc(=O)n12
Temperature: 110 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mL beaker was added 4-methyl-1,3-thiazol-2-amine (Aldrich, 16 g, 140 mmol), followed by methyl 4-bromo-3-oxopentanoate (34.9 g, 167 mmol). The mixture was heated with stirring at 110° C. for 5 h. After cooling, the dark slurry was transferred into 300 g of ice. The pH of the mixture was adjust to 6-7 with 10% sodium hydroxide. The aqueous layer was discarded and the dark oil layer was diluted with methylene chloride and washed with 1N NaOH, brine, dried over magnesium sulfate, and evaporated to dryness to yield the desired product (16.2 g, 42.6%). LCMS calculated for C9H10BrN2OS (M+H)+: m/z=273.0. Found: 273.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][CH:4]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.ClCCl>CC#N>[F:12][C:2]([F:1])([F:11])[C:3]1[N:8]=[C:7]2[NH:9][C:15](=[O:16])[NH:10][C:6]2=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1N
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: ClCCl
Product: O=c1[nH]c2ccc(C(F)(F)F)nc2[nH]1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of the pyridine-2,3-diamine (160 mg, 0.9 mmol) from step (b) above and N,N′-disuccinimidyl carbonate (250 mg, 0.9 mmol, Aldrich) in MeCN (5 mL) was stirred at room temperature for 13 h. Another batch of N,N′-disuccinimidyl carbonate (125 mg, 0.5 mmol, Aldrich) was added and the reaction mixture was heated at 75° C. for 90 min. The reaction mixture was cooled to room temperature and dichloromethane (20 mL) was added. The precipitate was filtered and dried under vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 204 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH2:10])=[O:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[NH:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3](=[O:4])[NH:13][C:12]1=[O:11]
Reactant: COC(=O)c1ccsc1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2ccsc2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.2 %

Procedure:
To a stirred solution of methyl-2-aminothiophene-3-carboxylate (2.03 g, 12.9 mmol) in acetic acid (65 mL) and water (6.5 mL) was added a solution of potassium cyanate (3.14 g, 38.7 mmol) dissolved in water (10.4 mL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HCl to pH=6. The resultant precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 546 mg (25%) of the title compound as an orange-solid which was used without any further purification:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:19][CH:18]=1)CCC>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: Brc1ccc2nnccc2c1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3nnccc3c2)s1
Yield: 73.1 %

Procedure:
The title compound (0.24 g, 60%) was synthesized in a manner similar to that described in Example 253 from 6-bromocinnoline (0.25 g, 1.0 mmol) and tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (0.90 g, 1.5 eq). LCMS (API-ES) m/z (%): 329.4 (100%, M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-chlorophenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[N:11]1([C:17]2[N:18]=[C:19]([CH2:24][C:25](OCC)=[O:26])[NH:20][C:21](=[O:23])[CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C[Al](C)C>O1CCCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:25](=[O:26])[CH2:24][C:19]1[NH:20][C:21](=[O:23])[CH:22]=[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc2C1

Procedure:
The product is prepared according to the procedure described in example 70, using 304 μl of 1,2,3,4-tetrahydroisoquinoline, 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 1.3 ml of a 2M solution of trimethylaluminium, in a mixture of 21 ml of touene and 10 ml of tetrahydrofuran. 130 mg of 2-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a whitish foam, the characteristics of which are the following:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]=[CH:10][C:9]1=[O:19].Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([N:11]=[CH:10][C:9](=[O:19])[N:8]2[CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][CH:14]=1
Reactant: O=c1cnc2ccc(F)cc2n1CCC1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CCCn1c(=O)cnc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (0.6 g, 2.3 mmol) in 1,4-dioxane (6.8 ml) was added 4N hydrochloric acid (24 ml) and the mixture was stirred at room temperature for 5 hours. An aqueous solution of sodium hydrogen carbonate was added thereto and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried under vacuum. 0.6 g (quantitative).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:8]([CH2:10][CH2:11][CH3:12])=[N:9][C:5]=2[N:4]=[C:3]1[CH3:50]>CC(O)=O>[CH3:1][N:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:8]([CH2:10][CH2:11][CH3:12])=[N:9][C:5]=2[N:4]=[C:3]1[CH3:50]
Reactant: CCCc1nc2nc(C)n(C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc2nc(C)n(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
1,6-Dihydro-1,2-dimethyl-5-propyl-6-[(2'-{N-triphenylmethyltetrazol-5-yl}{1,1'-biphenyl}-4-yl)-methyl]imidazo[4,5-d]imidazole prepared as described above in Step F can be deblocked with aqueous HOAc at 50° C. as described for a related procedure (see Example 11, Step F) to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:23][C:22](=[O:24])[O:21][N:20]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.Br[CH2:37][CH2:38][Cl:39].N12CCCN=C1CCCCC2>CN(C)C(=O)C>[Cl:39][CH2:38][CH2:37][N:23]1[C:22](=[O:24])[O:21][N:20]=[C:19]1[C:9]1[C:8]2[CH:25]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)[nH]3)c2cc1C1CC1)S(C)(=O)=O
Reactant: ClCCBr
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)n3CCCl)c2cc1C1CC1)S(C)(=O)=O
Yield: 30.3 %

Procedure:
A mixture of Example 10G (188 mg, 0.376 mmol), 1-bromo-2-chloroethane (0.033 mL, 0.395 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL, 0.414 mmol) in N,N-dimethylacetamide (6 mL) was heated in a sealed tube at 100° C. for 16 hours, cooled and concentrated. The residue was chromatographed on silica gel eluting with hexane to 3:1 hexane/ethyl acetate to give the title compound as a solid (64 mg, 30%). MS (ESI+) m/z 579 (M+NH4)+.
Reaction SMILES: C(O[CH:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1)(=O)CCC.[OH2:15].[OH-].[Na+]>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH2:7][C@H:8]2[OH:15]
Reactant: O
Reactant: CCCC(=O)OC1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H]1CC2CCN1CC2

Procedure:
The resulting (R) 3-quinuclidinyl butyrate was hydrolyzed with water-NaOH and then recrystallized from toluene to give (R)-quinuclidinol. Specific rotation [α]24D =-45 (1N HCl).