Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:12][CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[C:5]1([C:3]2[N:17]=[C:15]([NH:14][CH2:11][CH2:12][CH3:13])[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: CCCNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCNc1nc(-c2ccccc2)cs1
Yield: 89.7 %

Procedure:
To a solution of 2-chloroacetophenone (4.45 g, 28.8 mmol) and N-propylthiourea (3.40 g, 28.8 mmol) in ethanol (50 mL) was added sodium acetate (3.07 g, 37.4 mmol), and the mixture was heated under reflux for 1.5 hrs. Water was added to the reaction mixture, and crystals were collected by filtration. The obtained crude crystals were recrystallized from diethyl ether-hexane to give the title compound (5.64 g, 92%) as colorless crystals.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.[O:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:30](O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:34][O:33][C:32]1[CH:35]=[CH:36][C:28]([CH:27]=[O:26])=[CH:29][C:30]=1[O:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:25])[F:13])=[CH:20][CH:19]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, diethyl azodicarboxylate (40% toluene solution, 3.80 mL, 8.38 mmol) was added dropwise to a solution of 2-[4-(tri-fluoromethyl)phenyl]ethanol (1.59 g, 8.36 mmol), isovanillin (1.28 g, 8.41 mmol) and triphenylphosphine (2.20 g, 8.39 mmol) in anhydrous tetrahydrofuran (50 mL). After completion of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice, and then allowed to stand overnight at room temperature. The reaction mixture was concentrated and the residue was purified by silica gel column chro-matography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.96 g (72%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[CH3:20][C:21]1[CH2:22][CH:23]([C:26](O)=[O:27])[CH2:24][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:26]([CH:23]1[CH2:24][CH:25]=[C:21]([CH3:20])[CH2:22]1)=[O:27])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC1=CCC(C(=O)O)C1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CC=C(C)C1)C(C)C
Yield: 60.8 %

Procedure:
The coupling of the 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (82 mg, 0.3 mmol) and the 3-Methyl-cyclopent-3-enecarboxylic acid (45 mg, 0.357 mmol) using PPh3 (95.4 mg, 0.363 mmol) and NCS (48.5 mg, 0.363 mmol) furnished the 3-[Isopropyl-(3-methyl-cyclopent-3-enecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 61% yield) 1H NMR (CDCl3, 400 MHz 1:1 mixture of rotamers), 7.68-7.64 (m, 4H), 7.5-7.4 (m, 6H), 7.1 (s, 1H), 7.09 (s, 1H), 5.2 (s, 1H), 5.1 (s, 1H), 5.06-4.98 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.08-3.0 (m, 2H), 2.85-2.76 (m, 2H), 2.5-2.42 (m, 2H), 2.3-2.1 (m, 4H), 1.69 (s, 3H), 1.64 (s, 3H), 1.24 (d, J=6.7 Hz, 3H), 1.23 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 1.007 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[N:10][C:9]([Cl:13])=[N:8]1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[N:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[N:8]=1
Reactant: FC(F)(F)c1ccc(-c2nc(Br)c(C3CC=NC(Cl)=N3)o2)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nc(Br)c(-c3ccnc(Cl)n3)o2)cc1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
A solution of lithium diisopropylamide (1.8 M in THF-heptane-ethylbenzene, 1.4 mL, 2.6 mmol) was added dropwise into a cooled solution of 5-bromo-2-(4-(trifluoromethyl)phenyl)oxazole (620 mg, 2.1 mmol) in dry THF (20 mL) at −78° C. After 2.5 h, 2-chloropyrimidine (292 mg, 2.6 mmol) was added. After 10 min, the reaction flask was raised half way out of the acetone-dry ice bath and maintained for 30 min, after which the reaction was warmed to 10° C. in an ice-water bath and maintained for 1 h. The reaction was quenched with water (1 mL) and concentrated. The resulting mixture was partitioned between EtOAc (70 mL) and water (40 mL), and the layers were separated. The organic phase was washed with water, brine, dried (Na2SO4), and concentrated to give 859 mg of a residue as 4-bromo-5-(2-chloro-4,5-dihydropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole which was used in the next step without further purification: LCMS (m/z): 407.9 (MH+), tR=0.83 min. A suspension of 4-bromo-5-(2-chloro-4,5-dihydropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole (859 mg, 2.12 mmol) and MnO2 (1.8 g, 21.2 mmol) in EtOAc (10 mL) was irradiated at 110° C. for 10 min in a microwave reactor. The reaction was allowed to cool to rt and was filtered through a plastic membrane. The filtrate was concentrated and resulting residue was triturated with EtOAc to afford 234 mg of 4-bromo-5-(2-chloropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole: LCMS (m/z): 406.0 (MH+), tR=1.19 min.
Reaction SMILES: [Mg].O1C[CH2:5][CH2:4][CH2:3]1.C(Cl)C=C.[CH:11]12[CH2:21][CH:17]([C:18](=[O:20])[CH2:19]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C>[CH2:5]([C:18]1([OH:20])[CH2:19][CH:11]2[CH2:21][CH:17]1[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1)[CH:4]=[CH2:3]
Reactant: C1CCOC1
Reactant: O=C1CC2CC1C1CCCC21
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C=CCCl
Product: C=CCC1(O)CC2CC1C1CCCC21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In a one litre reaction vessel, equipped with a stirrer, a cooler and a dropping funnel, 26.4 g magnesium, 100 g tetrahydrofurane and 1 g allyl chloride were heated to about 40° C. to start the reaction. A mixture of 76.5 g allyl chloride, 250 g tetrahydrofurane and 150 g tricyclo [5,2,1,02,6 ] decan-8-one was added in four hours, keeping the temperature at 35°-40° C. The reaction mixture was stirred for an additional 30 minutes and subsequently poured into a mixture of 600 g of ice and 80 g of acetic acid. The layers were separated and the water layer extracted twice with toluene. The combined organic layers were washed with 5% soda solution until alkaline and subsequently with water until neutral. The organic solvent was removed by distillation under reduced pressure. The residue was distilled on a Vigreux head at 2 mm.Hg. The fraction boiling between 93° and 95° C. was collected. Yield: 80%, nD20 : 1.5154.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Product: CC(C)(C)c1ccc(CNC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1507 g, 0.51 mmol) with 4-tert-butylbenzylamine (0.1070 g, 0.66 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 440 (M+H)+; (ESI−) m/z 438 (M−H)−; 1H NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 4.79 (d, J=5.4 Hz, 2H), 6.14 (t, J=5.3 Hz, 1H), 7.32 (dd, J=8.0, 4.6 Hz, 1H), 7.37 (m, 2H), 7.44 (m, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.85 (dd, J=8.1, 1.4 Hz, 1H), 8.03 (dd, J=8.1, 1.4 Hz, 1H), 8.34 (d, J=1.0 Hz, 1H), 8.62 (dd, J=4.4, 1.4 Hz, 1H).
Reaction SMILES: Cl.[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([O:21]C)=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([OH:21])=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH:7]([CH3:9])[CH3:8])[CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)N(C1CCC1)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: -40 °C
Yield: 97.9 %

Procedure:
(R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (1.76 g, 5.34 mmol) was dissolved in anhydrous CH2Cl2 (45 mL) and cooled to -40° C. To the solution was BBr3 (1.3 mL, 13.4 mmol), dissolved in anhydrous CH2Cl2 (7 mL), added dropwise. The cooling-bath was removed and after 2 h at room temperature the reaction was complete. The reaction was poured out onto an ice/2M NH3 solution and the CH2Cl2 portion was separated, the aqueous layer re-extracted, twice, with CH2Cl2. The combined CH2Cl2 portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 30% ethyl acetate/hexane) gave 1.46 g (98% yield) of the title compound as a gum [α]21D =-95.7° (C=0.1; CHCl3) GC-MS (70 eV) M=279 (0.7%). The hydrochloride salt was made by dissolving the pure base in ether and dropping an excess of an ethereal HCl solution. The salt was washed with diethyl ether to give a white solid Mp: 120° C. sinters.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.Cl.[O-:9][C:10]#[N:11].[K+]>O>[NH:4]1[C:3]([NH:2][C:10]([NH2:11])=[O:9])=[N:7][N:6]=[N:5]1
Reactant: Nc1nnn[nH]1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1nnn[nH]1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
5-Aminotetrazole hydrate (10.3 g, 0.1 mole) was slurried into 150 ml of water containing 10 ml of 37 percent HCl. A solution of potassium cyanate (10 g, 0.12 mole) was added at ambient temperature over the course of one hour. When a slight exotherm began, the solution was cooled to 10° C. The mixture was stirred two hours, filtered and recrystallized from ethanol.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.Cl[C:30]1[N:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C1(C)C=CC=CC=1.O>[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CC(C)(N)Cc1ccc(Oc2ccc(C#N)cn2)cc1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (22.53 g, 100 mmol), powdered K2CO3 (34.55 g, 250 mmol) and DMAC (275 ml) was heated to 100° C. Toluene (94 ml) was added and the mixture slowly heated to reflux. The reflux temperature was raised by distillation of toluene and water until it reached 140° C. The mixture was then cooled to below 100° C. and 2-chloronicotinonitrile (13.86 g, 100 mmol) added with a toluene rinse (50 ml). The mixture was again heated to reflux and the reflux temperature raised to 140° C. as before. Then the water trap was filled with toluene and the reflux continued for 40 min., at which point HPLC showed no 2-chloronicotinonitrile remained but the reaction was not complete. After cooling the reaction below reflux, additional 2-chloronicotinonitrile (0.63 g, 4.5 mmol) was added and reflux continued for 90 min. The reaction was cooled to room temperature and the solids filtered with a toluene wash. The filtrate was concentrated on a rotary evaporator to 41 g of syrup which was dissolved in EtOAc (200 ml). This solution was washed with water (200 ml) and the aqueous layer back-extracted with EtOAc (50 ml). The combined organic layers were washed with water (3×200 ml) and concentrated in vacuo to 26.93 g of solid, ˜100% of theory. HPLC indicated 94.3% purity. 1H NMR (300 MHz, DMSO-d6) was consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1.C(OP([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+]>C1COCC1>[C:26]([O:25][C:23](=[O:24])[CH:22]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[CH:9][N:8]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(OC)c1ccc(C=O)nc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C=CC(=O)OC(C)(C)C)nc1
Yield: 89.2 %

Procedure:
5-dimethoxymethyl-pyridine-2-carbaldehyde (355 mg, 1.97 mmol) was dissolved in THF (10 ml) and the resulting solution was added to a stirring mixture of tert-butyl diethylphosphonoacetate (547 mg, 2.169 mmol) and NaH (102 mg, 2.56 mmol, 60% oil dispersion) in THF (5 ml). After 15 minutes the reaction was quenched by addition of water and the resulting slurry was extracted with Et2O. The organic phase was dried over Na2SO4 and evaporated under vacuo. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc 95:5) to give 491 mg of 3-(5-dimethoxymethyl-pyridin-2-yl)-acrylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+].[Na].Cl.[OH2:33]>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S@:8](=[O:33])[C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)C[S@](=O)[C@H]12)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (2.59 g) in water (25 ml) was added sodium metaperidoate (1.93 g). The solution was stirred for 30 minutes at ambient temperature and then acidified by the dropwise addition of 2N aqueous hydrochloric acid. The resulting precipitate was collected, washed successively with water, ethanol and ether and then dried in vacuo to afford the title compound as a white powder (1.63 g.), [α]D20 + 113° (c 0.86, Me2SO); λmax (pH6 buffer) 264.5 (ε 17,200) and 279 nm (ε 15,600); νmax (Nujol) 1779 (β-lactam), 1740 and 1716(CO2H), 1688, 1654, 1589 and 1530 (CONH and OCONH2) and 1030cm-1 (S→O), τ (Me2SO-d6)0.60 (d, J 8Hz, NH), 2.11, 3.19, 3.31 (multiplets, furyl protons), 4.08 (q, J5 and 8Hz, C-7H). 4.87 and 5.45 (ABq, J13Hz, CH2OCONH2), 4.96(d, J 5Hz, C-6H), 6.08 (s, OCH3), 6.10 and 6.42(ABq, J 18Hz, C-2 CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH3:17])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8]=2[CH:24]=1)([O-:3])=[O:2].[C:25](Cl)(=O)[CH3:26]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:12][N:13]([CH2:14][CH2:25][CH3:26])[CH2:7][CH2:6][CH3:5])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccn1)=NC2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-nitro-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N'N'-tetrapropyldiaminomethane) are reacted together to give 8-nitro-1-[2-(dipropylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19](I)[CH:18]=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[Cl:44][C:45]1[CH:46]=[C:47]([SH:51])[CH:48]=[CH:49][CH:50]=1>[Cu]I.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([S:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([Cl:44])[CH:46]=4)[CH:18]=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(I)ccc3OC2C1
Reactant: Sc1cccc(Cl)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2c3cc(Sc4cccc(Cl)c4)ccc3OC2C1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. 6-Iodo-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (80.25 mg, 0.200 mmol) was dissolved into anhydrous DMF (2.50 mL) in a one dram vial. The sodium tert-butoxide (58 mg, 0.60 mmol), neocuproine (4.2 mg, 0.020 mmol) and copper (I) iodide (11 mg, 0.060 mmol) were added sequentially at room temperature. 3-Chlorobenzenethiol (63.6 mg, 0.440 mmol) was added neat last. The reaction was shaken at 110° C. overnight. It was cooled to room temperature and concentrated. The residue was partially dissolved into a 2% MeOH in DCM solvent mixture (2.0 mL) with sonication. Silica gel (˜55 mg) was added into a filter plate. The suspension of product was flushed through the dry silica gel using 2% MeOH in DCM. The eluent was then concentrated to yield crude 6-(3-chlorophenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester which was used in the next step without further purification. MS m/z 418 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]2[NH:20][CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccccc2)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2)C2NCCC21
Reaction time: 1 h

Procedure:
A 500 mL Parr bottle was charged with crude 12 (370 mg, 0.84 mmol) and 5% Pd-on-carbon (50 mg) in reagent grade MeOH (10 mL). The mixture was pressurized to 50 PSI H2 then shaken for 1 h. The catalyst was removed by filtration through Celite® and the solids were washed with MeOH and EtOAc. The filtrate was concentrated in vacuo to afford 256 mg (quant.) of 13 which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([C@@H:13]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[CH2:14]3)[N:10]=[C:11](I)[C:3]=12.C(N(CC)CC)C.[CH2:28]([O:31][CH3:32])[C:29]#C.CO>CN(C=O)C.C(OCC)(=O)C.[Cu]I.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>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH:13]3[O:18][CH:17]([CH2:19][OH:20])[CH:15]([OH:16])[CH2:14]3)[N:10]=[C:11]([C:29]#[C:28][O:31][CH3:32])[C:3]=12
Reactant: C#CCOC
Reactant: Nc1nc(N)c2c(I)nn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC#Cc1nn(C2CC(O)C(CO)O2)c2nc(N)nc(N)c12
Reaction time: 16 h

Procedure:
To a mixture of 4,6-diamino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (4.2 g, 10.71 mmol), CuI (211 mg, 1.10 mmol), Pd(PPh3)4 (635 mg, 0.553 mmol), and triethylamine (2.2 mL) in 20 mL of anhydrous DMF was added methyl propargyl ether (1.82 mL). The mixture was stirred under argon for 16 h. and then evaporated to dryness. The residue was crystallized from methanol: 3.20 g (89%) yield; TLC (30% methanol in ethyl acetate), Rf=0.63; 1H NMR (DMSO-d6) δ 7.44 (2H, br d, amino), 6.32 (1H, t, J=6.6 Hz, 1′-H), 6.33 (2H, br s, amino), 5.20 (1H, d, J=4.1 Hz, 3′-OH), 4.75 (1H, br t, 5′-OH), 4.40 (2H, s, methylene), 4.36 (1H, m, 3′-H), 3.76 (1H, m, 4′-H), 3.47 & 3.32 (2H, 2×m, 5′-Hs), 3.32 (3H, s, methoxy), 2.68 & 2.14 (2H, 2×m, 2′-Hs).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]2)[C:3]([N:5]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:6][CH:7]([O:10]C(=O)C)[CH2:8][CH3:9])=[O:4].[OH-].[K+]>CO>[CH3:1][N:2]([CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]2)[C:3]([N:5]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:6][CH:7]([OH:10])[CH2:8][CH3:9])=[O:4]
Reactant: CCC(CN(C(=O)N(C)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC(O)CN(C(=O)N(C)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
6-{3-[1-Methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}-carbostyril (1.63 g) is added to methanol (10 ml), and thereto is added dropwise a 10% aqueous potassium hydroxide solution (10 ml). The mixture is stirred at room temperature overnight, and concentrated under reduced pressure to remove the solvent. The resultant is poured into water, and extracted with chloroform. The extract is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20: 1), and recrystallized from methylene chloride-diethyl ether to give 6-{3-[1-methyl-3-cyclohexyl-3-(2-hydroxybutyl)ureido]propoxy}carbostyril (0.6 g) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][CH:12]=2)[CH2:7][C@@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[O:28][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([O:17][CH3:18])[CH:16]=4)[CH2:7][C@@H:6]3[CH3:20])=[O:4])[C:27](=[O:29])[O:28][C:24]=2[CH:23]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)ccc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)[C@@H](C)C2)ccc1Cl

Procedure:
Compound 9 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (8), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.75 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 450.4, found, 450.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[O:12]=[CH:13]C(Cl)(Cl)Cl>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:13]=[O:12])[CH3:2]
Reactant: CCNCCc1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Product: CCN(C=O)CCc1ccccc1

Procedure:
N-Ethyl-N-phenethylformamide was prepared from N-ethylphenethylamine and chloral. The boiling point was 107°-108°C/0.4 mm Hg.