Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H].[Na].I[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>O.CN(C=O)C>[F:3][C:4]([F:13])([F:14])[CH:5]([O:12][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F

Procedure:
Into 200 ml of dry DMF containing 2.0 g of sodium hydride (purity 60%), were added dropwise 9.2 g of S-form oa 1-trifluoromethyl-heptanol, at room temperature with such a speed not causing too rapid generation of hydrogen, to prepare sodium salt (alkoxide) of S-form oa 1-trifluoromethyl-heptanol. After the addition was over, stirring was continued further an hour at room temperature, followed by adding thereto 12.4 g of p-iodo-nitro-benzene and then refluxing for 2 hours. After cooling, the product was introduced into iced water, and extracted with hexane. The hexane phase was washed subsequently with water, 1N-hydrochloric acid aqueous solution and then water, followed by purifying with silica gell column to obtain 7.7 g of oily oa p-(1-trifluoromethylheptyloxy)- nitrobenzene.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52](OCC#N)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (200 mg, 0.314 mmol) in water (6.25 ml) and a solution of (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (454 mg, 1.26 mmol) in THF (3.15 ml) were added to buffer A (113 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then lyophilized. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-A) (129 mg, 46%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[CH:27]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[C:46]2[O:47][C:48]([CH3:51])([CH3:50])[O:49][C:45]=2[CH:44]=[C:43]([C:52](Cl)=[O:53])[CH:42]=1.[C:55]1(=O)[CH2:58]C[CH2:56]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[CH:27]=[C:23]1[CH2:22][N:21]([CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH:13]1[CH2:58][CH2:55][CH2:56]1)[C:52]([C:43]1[CH:42]=[C:41]([O:40][CH3:39])[C:46]2[O:47][C:48]([CH3:51])([CH3:50])[O:49][C:45]=2[CH:44]=1)=[O:53]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2o1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2
Reaction time: 2 h

Procedure:
Experimental conditions analogous to Example 15, from 0.27 g (0.62 mmol) of (S)-2-{[(benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetic acid salt, was dissolved 1 mL dichloromethane, 216 μL (1.55 mmol) of triethylamine, and 0.16 g (0.68 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride were added to this mixture. The crude mixture was filtered through silica and the Boc-deprotection was conducted in 4 mL 10% trifluoroacetic acid/dichloromethane in 2 hours, followed by aqueous sodium bicarbonate quench and submitting the crude material to reductive amination reaction in dichloromethane using 0.24 g (3.1 mmol) of cyclobutanone and 0.657 g (3.1 mmol) of sodium triacetoxyborohydride. After 5 hours the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The residue from the organic layer was purified using flash chromatography (7N ammonia in methanol, 0-3% in dichloromethane), gave 49 mg off-white solid as a free base solid. LC-MSD, m/z for C29H34N2O5 [M+H]+: 491.2. 1H NMR (400 MHz, CDCl3/HCl): δ 1.7 (s, 6 H), 1.8-2.1 (m, 6 H), 2.1-2.2 (m, 1 H), 2.3-2.4 (m, 1 H), 2.5-2.7 (m, 2 H), 2.8-2.9 (m, 1 H), 3.5-3.7 (m, 1 H), 3.7-3.9 (m, 3 H), 3.9 (s, 3 H), 4.0-4.1 (m, 1 H), 4.8-5.0 (m, 2 H), 6.8 (s, 1H), 6.9 (s, 1 H), 7.0 (s, 1 H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1 H), 7.5-7.6 (m, 1 H), 12.0-12.1 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:20][CH2:21][O:22][CH3:23])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 10 mg, 0.42 mmol) in DMF (3 mL) was added NaH (60%, 28 mg, 0.122 mmol). After stirring at room temperature for 15 minutes, 1-bromo-2-methoxyethane (25.4 mg, 0.183 mmol) was added and the reaction mixture was stirred at 80° C. for 60 minutes. The reaction was diluted with brine and extracted with EtOAc, the organic layers were dried with Na2SO4 and concentrated in vacuo to afford the title compound that was used in the next step without further purification (15 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13]I.O>CN(C)C=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cnc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension stirred at 0° C., under an inert atmosphere, of 0.48 g (12.06 mmol) of 60% sodium hydride in 5 mL of dimethylformamide is added dropwise a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 10 mL of dimethylformamide. The mixture is stirred at 0° C. for 15 minutes and then at 20° C. for 45 minutes. A solution of 0.77 mL (12.06 mmol) of methyl iodide in 5 mL of dimethylformamide is then added to this stirred suspension at 0° C. The mixture is then stirred for 48 hours. After this time, 50 mL of water and 50 mL of ethyl acetate are added to the mixture. The aqueous phase is separated out and then extracted with 3×30 mL of ethyl acetate. The organic phases are combined, washed with 2×50 mL of water and then concentrated under reduced pressure. The resulting product is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 0.97 g of the expected product is thus isolated.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[CH3:22]>>[Cl:15][C:16]1[N:17]=[N:18][C:19]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1cc(Cl)nnc1Cl
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1Cl
Yield: 55 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-4-isoxazolyl)methanol (5.00 g, 26.4 mmol) was converted using 3,6-dichloro-4-methylpyridazine instead of 3-chloro-6-methylpyridazine to the title compound (4.59 g, 55%) which was obtained as a yellow oil. MS: m/e=316.1 [M]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:21]=[C:18]([O:19][CH3:20])[C:16](O)=[C:13]([O:14][CH3:15])[CH:12]=1.[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH3:35])=[CH:27][CH:26]=1.C([O-])(=O)C.[NH4+]>C(O)C>[I-:23].[C:1]([O:9][C:16]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH:10]=[CH:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N+:25]([CH3:24])=[CH:26][CH:27]=2)=[CH:21][C:18]=1[O:19][CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: O=C(O)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=Cc2cc[n+](C)c3ccccc23)cc(OC)c1OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
A mixture of syringaldehyde benzoate (2e)(0.18 g, 0.63 mmol), 1,4-dimethylquinolinium iodide (0.18 g, 0.63 mmol) and ammonium acetate (0.15 g, 1.9 mmol) was dissolved in warm ethanol and heated under reflux. The solution rapidly turned yellow and within 15 min, yellow precipitate formed. The reaction was continued for a further 1 h and then filtered. The collected solid was washed with methanol to give (24e)(0.28 g, 81%) as a fine yellow powder, m.p. decomp.>250° C. (Found: C, 58.86; H, 4.25; N, 2.71. C27H24NO4I calc. C., 58.60; H, 4.37; N, 2.53%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:27]#[N:28])=[N:21][CH:22]=[C:23]([CH:25]=[CH2:26])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:25]([C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:27]=2[NH2:28])=[CH2:26]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: C=Cc1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: C=Cc1cnc2c(N)nc3ccccc3c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-vinylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-vinylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (methanol-d4-CDCl3): δ 8.87 (d, 1H), 8.69 (d, 1H), 8.28 (d, 1H), 7.49-7.58 (m, 2H), 7.32 (dt, 1H), 6.90 (dd, 1H), 6.09 (d, 1H), 5.54 (d, 1H). LRMS [M+H]=222.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[C:13]([N+:25]([O-])=O)[CH:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>[Fe]>[NH2:25][C:13]1[CH:12]=[C:11]([O:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])[CH:16]=[CH:15][C:14]=1[S:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1
Reactant: CC(Oc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(Oc1ccc(Sc2ccc(O)cc2)c(N)c1)c1cccc(Br)c1
Yield: 70.9 %

Procedure:
The product from Example 168c (5.4 g, 12.2 mmol) was reacted with Fe and NH4Cl as described in Example 9E to give the title compound (3.6 g, 76%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1.Cl>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][N:14]([C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[N:31][CH:30]=2)[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(-c2cnc(Cl)nc2)c1-c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.515 g (3 mmol) of copper(II) acetate and 0.306 ml (4 mmol) of pyridine were added to 0.5 g (2 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate in 10 ml of dichloromethane. 0.598 g (4 mmol) of 2-chloropyrimidine-5-boronic acid was then added, and the mixture was stirred at 20° C. for 24 h. The mixture was then added to 1 M HCl and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. This gave 0.015 g of product (2% of theory).
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:6]=1[NH:13][C:14](=[O:16])[CH3:15])#[N:2].OO.[OH2:19].C(O)(=[O:22])C>>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:6]=1[NH:13][C:14](=[O:16])[CH3:15])(=[O:22])=[O:19])#[N:2]
Reactant: CC(=O)Nc1c(F)cc(F)cc1SCC#N
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: CC(=O)Nc1c(F)cc(F)cc1S(=O)(=O)CC#N
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
N-(2-Cyanomethylsulfanyl-4,6-difluoro-phenyl)acetamide (0.25 g) was suspended in glacial acetic acid (2 ml). Hydrogen peroxide (35%, 1 ml) was added and the mixture was stirred at 100° C. for 1 h 45 min. Then the mixture was cooled to 0° C. and water (5 ml) was added. After stirring for ½ h a white precipitate was isolated by filtration, washed with water and dried to give the title compound as white needles. Yield 0.17 g (61%); 1H-NMR (DMSO-d6), δ (ppm): 9.81 (br s, 1H, NH), 8.08-7.90 (m, 1H, Ar—H), 7.80-7.65 (m, 1H, Ar—H), 5.23 (s, 2H, CH2), 2.10 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][C@H:44]1[CH:49]2[CH2:50][CH2:51][N:46]([CH2:47][CH2:48]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:46]12[CH2:51][CH2:50][CH:49]([CH2:48][CH2:47]1)[C@H:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)s1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
A mixture of 2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (106 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.82 mmol), 1-hydroxybenzotriazole (110 mg, 0.82 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (101 mg, 0.51 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.23 mL, 1.64 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide (19 mg, 13%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.55 (d, J=7.4 Hz, 1H), 8.15 (dd, J=7.8, 0.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.65 (dd, J=7.2, 1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.89 (dd, J=3.7, 1.0 Hz, 1H), 4.35-4.30 (m, 1H), 3.55-3.48 (m, 1H), 3.16-3.07 (m, 2H), 2.96-2.91 (m, 2H), 2.86-2.82 (m, 1H), 2.60 (s, 3H), 2.18-2.12 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H); MS (ESI+) m/z 368 (M+H); HPLC 98.0% (AUC), tR=12.40 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH2:37][C:38]1[N:43]=[C:42]([CH3:44])[C:41]([Br:45])=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[Br:45][C:41]1[CH:40]=[CH:39][C:38]([NH:37][C:29]([NH:20][C:19]2[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:24])=[O:35])=[N:43][C:42]=1[CH3:44]
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1nc(N)ccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccc(Br)c(C)n4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 6-amino-3-bromo-2-methylpyridine (69 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a larger amount of ether was added to the solution to precipitate a crystal which was then collected by filtration to give 80 mg (yield 48%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.N[C:13](N)=[S:14].[OH-].[Na+].CI>C(O)C>[Cl:8][C:7]1[C:2]([S:14][CH3:13])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: CSc1ncc([N+](=O)[O-])cc1Cl
Temperature: 10 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
2,3-Dichloro-5-nitropyridine (7.90 g, 0.041 mol) (Synthesis, 1990, 499) was dissolved in ethanol (150 ml) and was treated with thiourea (3.43 g, 0.045 mol). The resultant mixture was then heated to reflux with stirring under argon. After 3 h, the reaction mixture was allowed to cool, and was left stirring at room temp. for 16 h. 10% Sodium hydroxide solution (160 ml) was then added and the reaction mixture was heated to reflux with stirring. After 1 h, the reaction mixture was cooled to 10° C., and methyl iodide (2.80 ml, 0.045 mol) was added. After 1 h, the resultant precipitate was filtered off to give the title compound as an orange solid (5.90 g, 70%).
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:39]>>[ClH:39].[ClH:39].[NH:21]1[CH2:22][CH2:23][CH:19]([O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc(C(=NOC2CCNC2)c2cc3ccncc3[nH]2)cc1
Yield: 33 %

Procedure:
Phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-pyrrolidin-3-yloxime dihydrochloride (12.3 mg, 33%) was prepared as an off-white amorphous solid from tert-butyl 3-[[[phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]pyrrolidine-1-carboxylate (Example 90) following the procedure described for Example 77, except 1:1 trifluoroacetic acid/CH2Cl2 was used: 1H NMR (500 MHz, CD3OD) major isomer δ 0.94-0.92 (1H, m), 2.33-2.35 (1H, m), 3.26-3.27 (1H, m), 3.33-3.34 (1H, m), 3.45-3.46 (1H, m), 3.58-3.60 (1H, m), 3.70-3.72 (1H, m), 5.23-5.24 (1H, m), 6.78 (1H, s), 7.53-7.57 (5H, m), 8.08 (1H, d, J=6.4 Hz), 8.22 (1H, d, J=6.5 Hz), 9.01 (1H, s); ESI MS m/z 307 [C18H18N4O+H]+; HPLC (Method A) 96.6% (AUC), tR=12.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8]2.[OH-:16].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[CH2:8][C@@H:7]([CH3:15])[C@H:6]([OH:16])[CH2:5]2
Reactant: [OH-]
Reactant: COc1ccc(OC)c2c1CC=C(C)C2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1C[C@@H](C)[C@H](O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 (5.00 g, 24.5 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and treated with 1 M borane-tetrahydrofuran complex (24.5 mL, 24.5 mmol) and the resulting solution was stirred at room temperature for 4 h. Then, 12 mL of 3 N NaOH solution was added slowly to the stirring reaction solution followed by the addition of 6 mL of 30% aqueous hydrogen peroxide. After stirring for 30 min, the resultant mixture was diluted with 500 mL of ethyl acetate and washed by brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified on silica gel (30% ethyl acetate/hexane) to give 5 as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Li+].C(OCC)C>O1CCCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred mixture of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (900 mg, 2.65 mmol) in tetrahydrofuran (10 mL) and water (3 mL) was added lithium hydroxide (135 mg, 3.19 mmol). After addition was complete the mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and diethyl ether and the layers separated. The aqueous layer was made acidic with 2N aqueous hydrochloric acid and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (710 mg, 82%) as a yellow solid: LR-ES-MS m/z calculated for C16H17F2NO4 [M]+ 325, observed [M+H]+ 326.