Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](O)=[O:13].Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:25][O:24][N:23]([CH3:22])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:8])[CH:10]=1
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (7.6 mL, 54.65 mmol) was added slowly to a mixture of 3-methyl-4-nitrobenzoic acid (5 g, 27.33 mmol), N,O-dimethylhydroxylamine hydrochloride (2.99 g, 30.06 mmol), and EDCI (6.28 g, 32.79 mmol) in DCM (30 mL). The mixture was stirred at room temperature overnight, quenched with saturated aqueous NaHCO3 and stirred at room temperature for 30 minutes. Water (50 mL) was added followed by additional DCM. The mixture was stirred for 10 minutes and layers were separated. The aqueous layer was again extracted with DCM. The combined organic layer was dried over Na2SO4, then filtered. The solvent was removed and the residual oil chromatographed (DCM/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCOCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Ammonium chloride (2 g) and iron powder (18.9 g) were added to a mixed solvent of water (65 ml) and ethanol (197 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-morpholinobenzonitrile (19.7 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (12.9 g), melting point: 147–148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 3 h
Yield: 151.5 %

Procedure:
A mixture of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (0.73 g) and Lawesson's reagent (0.49 g) in tetrahydrofuran (30 mL) was stirred at 55° C. for 3 h. The reaction mixture was concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (691 mg, 91%) as light yellow prisms. MS 375 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([NH2:33])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[NH:33])[CH3:29]
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: CCN(CC)C(N)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=N)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,N-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(NC(C)=O)c2nc1OC
Yield: 100 %

Procedure:
Acetyl chloride (5.71 mL, 6.30 g, 80.3 mmol) was added to a vigorously stirred suspension of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 26, 20.49 g, 64.8 mmol) in toluene (500 mL) and the resulting mixture was heated under reflux for 2 hours. After being cooled, the product was collected by filtration, washed with toluene and dried by suction for 15 hours to yield 5-acetamido-6,7-dichloro-2,3-dimethoxyquinoxaline (20.49 g, 89%) as a beige solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)(O)CCCCCl
Reactant: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22 g (0.1 mol) of the xanthine from stage (a) are reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide under the experimental conditions described in Example 2, and the mixture is worked up. The reaction product is obtained in pure form without prior column chromatography, by recrystallization once from ethyl acetate with the addition of petroleum ether, at the boil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.N1C=CC=CC=1.[OH-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.8 g (40 mmol) of 2-bromofluorene, 40 mL of pyridine, and 1.5 mL of tetrabutylammonium hydroxide (1.0 mol/1 methanol solution) were put into a 200 mL three-neck flask. This solution was stirred under air at room temperature for 24 hours. After completion of a reaction, 40 m/L of glacial acetic acid was added to the reaction solution and stirred for 1 hour. Then, the reaction solution was washed with water and a water layer was extracted with ethyl acetate. The extracted solution and an organic layer were combined and washed with saturated saline, and then dried with magnesium sulfate. After drying, this mixture was subjected to suction filtration, and a filtrate was concentrated. When an obtained solid was recrystallized with ethanol, 7.9 g of a yellow, powdery solid of 2-bromo-9-fluorenone that was a target matter was obtained with the yield of 76%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[CH:5]2[C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[CH2:32]=[O:33].O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]2([C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[CH2:32][OH:33]
Reactant: C=O
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
A mixture of 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one (3.64 g, 8.41 mmol), para-formaldehyde (2.52 g, 84.1 mmol) and lithium hydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL) and water (10.0 mL) was stirred at 0° C. for 4 h. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous HCl (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (50%) to give the title compound (0.65 g, 59%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.12 (d, 1H), 6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d, 2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01(ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 160.5; MS (ES+) m/z 466.2 (M+1), 448.2 (M−17).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(N(CC)CC)C>ClCCl>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCC(F)(F)F)ncc2c(=O)[nH]1
Reaction time: 96 h

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.72 g), 2,2,2-trifluoroethylamine hydrochloride (0.97 g) and triethylamine (0.73 g) in dichloromethane (15 ml) was stirred at ambient temperature for 48 hours and allowed to stand for 4 days. A yellow solid had formed which was collected by filtration and washed with dichloromethane. The filtrate was washed with dilute hydrochloric acid (15 ml) then water (10 ml) and the aqueous layers extracted with dichloromethane (2×7.5 ml). The combined organic layers were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product. This was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield a residue which was recrystallized from isopropanol to yield the title compound, 0.13 g, m.p. 214-215.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH3:19])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:40]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH:19]=[O:40])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3-(benzyloxy)-6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (18.72 g, 36.3 mmol) and selenium dioxide (14.42 g, 130 mmol) in dioxane (200 ml) was heated to 100° C. with attached reflux condenser for 16 hr. Added more selenium dioxide (3.35 g, 30.2 mmol) and continued to heat to 100° C. for 4.5 hr. Cooled to RT, filtered through celite, eluted with EtOAc, concentrated filtated in vacuo, took up residue in DCM, filtered through celite, eluted with DCM, concentrated filtrate in vacuo and purified via flash chromatography (0-100% EtOAc/Hex) to provide 3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde. MS: [M+H]+ m/z 530.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:10]([N:8]3[CH2:9][CH:6]([O:5][C:26]4[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=4)[CH2:7]3)=[O:11])=[N:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(O)ccc1C=O
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Yield: 67 %

Procedure:
Using a similar protocol as described in Example 71A employing 73B and 4-hydroxy-2-methylbenzaldehyde as starting materials afforded 9.4 g (67%) of 73C as a solid. 1H NMR (500 MHz, CDCl3): δ 2.67 (s, 3H), 3.89 (s, 3H), 4.37 (m, 1H), 4.70 (m, 1H), 4.78 (m, 1H), 5.15 (m, 2H), 6.65 (s, 1H), 6.74 (d, 1H), 7.02 (d, 2H), 7.78 (d, 1H), 8.11 (d, 2H), 10.2 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]([F:15])([F:14])[C:12]#[N:13]>CC(C)([O-])C.[K+]>[C:3]([C:2](=[C:12]([NH2:13])[C:11]([F:15])([F:14])[F:10])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)F
Yield: 61.9 %

Procedure:
To a 1 liter, four-necked flask equipped with nitrogen inlet, thermometer, and mechanical stirrer was charged 499.74 g (490 ml, 3.84 mol) of ethyl acetoacetate and 12.9 g (0.115 mol) of potassium t-butoxide. The resulting mixture was stirred while 391 g (4.04 mol) of trifluoroacetonitrile was added. The reaction mixture was washed with hexane and the resulting solid was dried in vacuo affording 535 g (62%) of the enamine as a yellow solid; mp 63°-65° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]3[OH:17])[CH:13]=[N:14][C:7]=12.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][O:23][C:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:47][CH:46]=4)[C@@H:18]([OH:19])[C@H:16]3[OH:17])[CH:13]=[N:14][C:7]=12
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
Compound 11 (99 mg, 0.29 mmol) was azeotroped three times with anhydrous pyridine and then dissolved in pyridine (3.0 ml). To this solution, 4,4′-dimethoxytrityl chloride (106 mg, 0.31 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 5% aqueous NaHCO3 and then extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous sodium chloride, dried over Na2SO4, and then evaporated under reduced pressure to remove the solvent. The product was purified by silica gel column chromatography (1% methanol-CH2Cl2) to give Compound 12 (131 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[C:6]2[CH:19]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10][CH2:9][NH:8]1
Reactant: Fc1ccccc1C1NCCNc2ccc(Br)cc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1C1NCCNc2ccc(-c3ccncc3)cc21
Temperature: 160 °C
Yield: 40.2 %

Procedure:
A 5-mL microwave tube was charged with provided 7-bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (25 mg), 4-pyridylboronic acid (50 mg), dichlorobis(triphenyl-phosphine)palladium(II) (10 mg), potassium carbonate (50 mg), dimethylformamide (3.5 mL) and water (0.5 mL). The reaction was heated to 160° C. for 360 seconds using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying agent was filtered and the filtrate was concentrated to an oil. Silica gel purification provided the title compound 5-(2-fluorophenyl)-7-(4-pyridinyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (10 mg) as a white powder. H1 NMR (d6-dmso): 8.42 (d, 2H), 7.46 (m, 2H), 7.30 (m, 3H), 7.18 (m, 2H), 7.02 (d, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.22 (br s, 1H), 3.18-3.3 (m, 1H), 2.78-2.96 (m, 3H), 2.64 (br s, 1H). Mass (ES+)=320.2 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl.[N:13]([O-])=O.[Na+]>O1CCCC1>[I:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[N:13][CH:10]=[C:9]2[OH:11]
Reactant: O=N[O-]
Reactant: CC(=O)c1cc(I)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnnc2ccc(I)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 1-(2-amino-5-iodophenyl)ethanone (as prepared in the previous step, 6.5 g, 24.90 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) and 1N HCl (49 mL, 2.00 equiv) and NaNO2 (2.3 g, 27.06 mmol, 1.10 equiv). The reaction mixture was stirred for 1 h at 0° C., and then was heated to reflux for 2 h. after cooled to room temperature, the solid were collected by filtration and washed with ice water. The title compound was obtained as a brown solid.
Reaction SMILES: [Cl:1][CH:2]([CH2:5][Cl:6])[CH2:3][OH:4].[CH2:7]([O:9][CH2:10]OCC)[CH3:8]>O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:7]([O:9][CH2:10][O:4][CH2:3][CH:2]([CH2:5][Cl:6])[Cl:1])[CH3:8]
Reactant: CCOCOCC
Reactant: OCC(Cl)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: CCOCOCC(Cl)CCl
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A mixture of 516 g (4.0 mol) 2,3-dichloro-1-propanol, 2.0 g toluenesulfonic acid hydrate, and 1500 ml (12.0 mol) diethoxymethane (DEM) was stirred at reflux while distilling out a mixture of ethanol and DEM. After 5 hr, 200ml had distilled and 250 ml fresh DEM was added. The reaction was shut off overnight and resumed the next day for 5 hr, reaching a final internal temperature of 99° C. Base wash and distillation yielded 688 g of C2H5OCH2OCH2CHClCH2Cl, bp 60-70° C./0.3 mm. Of this amount, 210.7 g was fluorinated in PMM as in Example 1 and the product analyzed by 19F NMR as containing C2F5OCF2OCF2CFClCF2Cl in 69% yield, accompanied by the 1,3-dichloride isomer in about 5% yield. Distillation gave the main cut bp 110° C., 96% pure by glc.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([NH2:32])=[O:26])([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid (510 mg, 1.22 mmol) and HATU (1.1 eq, 1.34 mmol, 511 mg) in DMF (10 ml) was added Hunig's base (1.3 eq, 1.60 mmol, 205 mg). After the resulting suspension had been stirred for 1 h, excess ammonia (0.5 M in dioxane, 4.0 ml) was added and the mixture was stirred overnight (14 h). The solvent was removed in vacuo and the resulting residue was partitioned between CH2Cl2 (10 ml) and 1 N HCl (10 ml) with the aid of 2 ml MeOH to assist in the transfer and improve solubility. The aqueous phase was extracted with CH2Cl2 (2×10 ml), the combined organic phases were washed with 1 N HCl (2×10 ml), dried (MgSO4), filtered and evaporated in vacuo to give an off-white solid (455 mg, 90%). MS: 416 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14]3)=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[N:9]=3)[CH:14]=2)[C:18]1=[O:26])[CH3:29]
Reactant: Cc1ccc(-n2cc3cc(-n4c(=O)[nH]c5cccnc54)ccc3n2)nc1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc3nn(-c4ccc(C)cn4)cc3c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
A mixture of 3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31 mg) and iodoethane (15.5 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (5.4 mg).