Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:32]=[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]1[C:23]1[CH:22]=[CH:21][C:20]([NH:19][CH2:2][C:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]([C:13]3[S:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[O:12])[CH2:6]2)=[O:4])=[CH:25][CH:24]=1
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Reactant: O=C(N[C@@H]1CCN(C(=O)CBr)C1)c1ccc(Cl)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCN(C(=O)CNc2ccc(-n3ccccc3=O)cc2)C1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.7 %

Procedure:
7.2 A solution of 250 mg 5-chloro-thiophene-2-carboxylic acid [(R)-1-(2-bromo-acetyl)-pyrrolidin-3-yl]-amide in 2 ml DMF was treated with 110 mg 1-(4-amino-phenyl)-1H-pyridin-2-one (CAS 13143-47-0), 0.12 ml TEA and 110 mg tetrabutylammonium iodide. The reaction mixture was stirred at r.t. for 2 days, then quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 95:5) to give 72 mg 5-chloro-thiophene-2-carboxylic acid ((R)-1-{2-[4-(2-oxo-pyridin-1-yl)-phenylamino]-acetyl}-pyrrolidin-3-yl)-amide. MS 457.5 ([M+H]+)
Reaction SMILES: [OH2:1].[NH2:2][C@@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:4]([OH:6])=[O:5].[C:14](#N)[CH3:15]>>[CH:8]1([CH2:7][C@H:3]([N:2]2[CH2:15][C:14]3[C:9](=[CH:8][CH:7]=[CH:3][CH:4]=3)[C:10]2=[O:1])[C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC#N
Reactant: O
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Product: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of (S)-(+)-α-aminocyclohexanepropionic acid hydrate (5.00 g; 29.2 mmol) and phthalic dicarboxaldehyde (4.21 g; 31.3 mmol) in acetonitrile (120 mL) was refluxed for 20 h under nitrogen. The mixture was allowed to cool to room temperature and further cooled to 0° C. The solid was filtered off and washed once with cold acetonitrile (50 mL) to give 6.54 g (78%) of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C17H21NO3 (M+) 287.1521, found 287.1521.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38](Cl)=[O:39]>C(Cl)(Cl)Cl>[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:35]([Cl:34])[CH:36]=2)[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(N)C12CCCCC2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(NC(=O)c2ccc(Cl)c(Cl)c2)C12CCCCC2
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a stirring suspension of 3.0 g (0.017 mole) of 1-methyl-4-amino-1-azaspiro[4.5]decane of Example 2 and 5.0 g of NaHCO3 in 50 ml of CHCl3 was added dropwise 3.8 g (0.018 mole) of 3,4-dichlorobenzoyl chloride in 25 ml of CHCl3. The reaction was refluxed for 3 hours, cooled to room temperature, filtered, and the solvent evaporated to give an oil. The residue was triturated with boiling hexane and decanted, the hexane solution afforded 2.6 g of 1-methyl-4-(3,4-dichlorobenzamido)-1-azaspiro[4.5]decane on standing. The solid was dissolved in ether and a solution of ethereal HCl was added. The resulting solid was collected and recrystallized three times from ethanol to give 2.2 g (35%) m.p. 227°-228° C. of 1-methyl-4-(3,4-dichlorobenzamido)-1-azaspiro[4.5]decane hydrochloride.
Reaction SMILES: CS(O[C@@H:6]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH2:9][CH2:8][C@H:7]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])(=O)=O.[Li+].[B-](CC)(CC)CC.CCOC(C)=O.CCCCCC>C1COCC1>[F:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C@@H:7]1[CH2:8][CH2:9][C@@H:10]([O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[CH2:6]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](OS(C)(=O)=O)c2cccnc21)(C(C)C)C(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 21 flask was (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl methanesulfonate (55.2 g, 105 mmol) (azeotroped with dry benzene) in THF (300 mL) to give a tan solution. Superhydride (525 mL, 525 mmol) (1.0M in THF) was added dropwise via dropping funnel under nitrogen, and the mixture was stirred at rt for 4 h. THF was stripped off and the tan oil was partitioned between water (300 ml) and EtOAc (400 ml). The layers were separated and the organic layer was washed with brine, dried and concentrated to a tan oil (close to 60 g). Purification by FCC (2.5 L packed column) up to 30% EtOAc/hexane did not give good purification but did get rid of baseline (not very uv active) junk (use just a silica plug and <10% EtOAc/hexane should be ok too). All the collected less polar fractions were combined and concentrated to a tan oil (33.58 g) and was directly used in the next step. MS (ESI)[M+H+]=432.19.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of finely powdered malonic acid (10.4 g, 0.1 mol), 2,2,2-trichloroethanol (9.6 mL, 0.1 mol) and p-toluenesulfonic acid monohydrate (570 mg, 3% in benzene (30 mL) was stirred under azeotropic reflux for 26 hours, then cooled at room temperature. The unreacted malonic acid (4.6 g) was filtered and washed with benzene (2×10 mL). Water (50 mL) was added to the filtrate followed by portionwise addition of sodium bicarbonate until a basic pH was reached. The aqueous phase was decanted, washed with ether (3×50 mL), then acidified with concentrated aqueous HCl and extracted with methylene chloride (4×50 mL). The combined extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to give 2,2,2-trichloroethyl hydrogen malonate (4.34 g, 18.4 mmol, 18%) that slowly crystallized; m.p. 42°-43°; NMR (CDCl3): δ11.0 (S, CO2H), 4.83 (S, --OCH2CCl3 ), 3.61 (S, --O2C--CH2CO2 --).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[O:26][CH:25]=[N:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[O:26][CH:25]=[N:24][CH:23]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2cnco2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnco2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.200 mmol) was dissolved in 1 ml DMF. Sodium hydride (24 mg, 0.600 mmol) was added at 0° C. and the reaction mixture was stirred at RT for 10 min. 5-(2-methyloxiran-2-yl)oxazole (35 mg, 0.280 mmol) in DMF (1 mL) was added dropwise over 10 min. and the reaction mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. Ice cold water was added to the reaction mixture and then extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (4×10 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain the 20 mg of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(oxazol-5-yl)propan-2-ol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.09 (s, 1H), 7.18 (s, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 6.8 (s, 1H), 4.7 (m, 1H), 4.35 (m, 3H), 3.9 (m, 1H), 3.56 (m, 1H), 3.25 (m, 2H), 3.09 (s, 3H), 2.37 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provides enantiomers II-142a-b.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23][CH2:34][CH2:35][CH2:36][N:13]2[CH2:14][CH2:19][CH2:20][CH2:12]2)[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OCCCN4CCCC4)cc3n2CC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9 mmol) and 3-bromo-1-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br.C(O)(=O)CC>O>[ClH:19].[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCC(=O)O
Product: Cl
Product: Clc1ccc2c(c1)CNC2
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
1.0 g of 2-(p-toluensulphonyl)-5-chloroisoindoline and 1.0 g of phenol were added to a mixture of 8 ml of 48% hydrobromic acid and 1.4 ml of propionic acid, and then mixture was heated at reflux for 6 hours. The resultant reaction mixture was diluted with 10 ml of water and extracted twice with 50 ml of ethyl acetate. The water layer was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate three times. The extract was concentrated and the crude product was diluted with 4N HCl/dioxane and stirred for 15 minutes before evaporating the HCl and then re-evaporating with toluene three times to give 0.3 g of 5-chloro-2,3-dihydro-1H-isoindole hydrochloride as a black solid. MS: [M+H]+ 153-15
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Li+].[Li+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (10.41 g, 75.4 mmol) in 100 mL of DMF was added lithium carbonate (16.71 g, 226 mmol), followed by benzyl bromide (13.5 mL, 113 mmol). The solution was warmed to 60° C. and stirred for 30 hours. The reaction was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:14]2[S:21][CH:20]=[CH:19][C:15]=2[N:16]=[CH:17][N:18]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:14]2[S:21][CH:20]=[CH:19][C:15]=2[N:16]=[CH:17][N:18]=1)=[O:11]
Reactant: Nc1ncnc2ccsc12
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CC#N
Product: O=C(Nc1c(Cl)cccc1Cl)Nc1ncnc2ccsc12
Yield: 229.1 %

Procedure:
2,6-Dichlorophenyl isocyanate (0.075 g) was added to a mixture of 4-aminothieno[3,2-d]pyrimidine (Tetrahedron, 1971, 27, 487; 0.201 g) and acetonitrile (16 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and washed in turn with diethyl ether and methanol. There was thus obtained the title compound (0.31 g); NMR Spectrum: (DMSOd6) 7.25 (t, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.95 (d, 1H), 8.4 (s, 1H), 8.8 (s, 1H), 11.7 (br s, 1H); Mass Spectrum: M+H+ 339 and 341; Elemental Analysis: Found C, 45.8; H 2.4; N, 16.5; C13H8Cl2N4OS requires C, 46.03; H, 2.38; N, 16.52%.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][F:20])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:21](=[O:24])([O-])[O-].[Na+].[Na+].O.[CH2:28]([OH:30])[CH3:29]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:21]1[O:24][C:2]2[C:1]([C:4]3[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:6]([CH3:7])[CH3:5])[C:5]=3[O:16][CH2:17][CH2:18][CH2:19][F:20])=[CH:3][CH:9]=[CH:4][C:1]=2[CH:2]=1)(=[O:30])[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(B(O)O)c(OCCCF)c(C(C)C)c1
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCCCF)c2o1

Procedure:
A mixture of 1.08 mmol of 3,5-diisopropyl-2-(3-fluoropropoxy) phenylboronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-7-[3,5-diisopropyl-2-(3-fluoropropoxy)phenyl]-benzo[b]furan as a clear yellow pasty solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([Cl:13])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0° C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=1.[CH2:23]([SH:25])[CH3:24]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9]1[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=[C:2]([S:25][CH2:23][CH3:24])[CH:3]=[C:4]2[N:10]=1
Reactant: CCS
Reactant: CC(C)(C)Cc1nc2cc(Br)cnc2n1CCOC(F)(F)F
Product: CCSc1cnc2c(c1)nc(CC(C)(C)C)n2CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-(2,2-dimethylpropyl)-3-[2-(trifluoromethoxy)ethyl]-3H-imidazo[4,5-b]pyridine (Step D) and ethanethiol (Wako Pure Chemical Industries, Ltd.).
Reaction SMILES: C([O:4][C@H:5]1[C@H:11](CC([O-])=O)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH:36]([O:38]C(=O)C)[CH3:37])CO2)(=O)C.[CH3:42][O-:43].[Na+].C(O)(=[O:47])C>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:9]23[O:20][C@@:6]([CH:36]([OH:38])[CH3:37])([CH2:42][O:43]2)[C@@H:5]([OH:4])[C@H:11]([OH:47])[C@H:10]3[OH:16])=[CH:22][C:23]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](CC(=O)[O-])[C@@H]2OC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To a solution of [(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-hydroxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate 31b (1.17 g, 1.98 mmol) in methanol (20 mL) was added sodium methoxide (85 mg, 1.57 mmol) at rt. The mixture was stirred at rt for 4 hours, and then acetic acid (0.1 mL) was added. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 31c as a white foam (0.78 g, 93.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, MeOD) δ(ppm): 7.44 (d, 1H), 7.42-7.34 (m, 2H), 7.03 (d, 2H), 6.70 (d, 2H), 4.17 (d, 1H), 4.06-3.98 (m, 3H), 3.92 (d, 1H), 3.78 (d, 1H), 3.66 (t, 1H), 3.55 (d, 1H), 1.33 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[N:35]1([C:2]2[N:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:20][CH2:19][C:18]4[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]5[CH:23]=[N:22][N:21]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=6)[C:16]=5[CH:17]=4)[CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: C1CNC1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and azetidine. LCMS (Method C): 524 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:10][N:9]=2)[CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:16]1[CH2:15][CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3cccnc3)no2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(Cc2noc(C3CCNCC3)n2)c1

Procedure:
tert-Butyl 4-[3-(pyridin-3-ylmethyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate was treated with 10 mL TFA/DCM (1:1) for 30 min at ambient temperature. The reaction mixture was concentrated to give the di-TFA salt of 3-[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]pyridine as an amber oil (4.0 g, 8.47 mmol, 85%, 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.70 (d, 1H, J=5.0 Hz), 8.51 (br.s, 1H), 8.18 (d, 1H, J=7.9 Hz), 7.75 (m, 1H), 4.30 (s, 2H), 3.44-3.30 (m, 3H), 3.09-3.00 (m, 2H), 2.20-2.16 (m, 2H), 1.93-1.80 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:26]#[N:27])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>[Fe]>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=1)[N:14]=[CH:13][C:12]([C:26]#[N:27])=[C:11]2[NH:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1ccc(Nc2c(C#N)cnc3c(OC)cc([N+](=O)[O-])cc23)cc1O
Agent: [Fe]
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cc(N)cc23)cc1O

Procedure:
Using the method described in Example 196, 0.1 g of 4-(3-hydroxy-4-methoxy-phenylamino)-8-methoxy-6-nitro-quinoline-3-carbonitrile and 0.09 g of iron was converted to the title compound: MP=215° C. (dec)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([O:18][CH3:19])=[O:17].O.O=[CH:22][C:23]([OH:25])=[O:24]>C(#N)C>[CH3:19][O:18][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][CH:22]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:23]([OH:25])=[O:24])=[O:17]
Reactant: O=CC(=O)O
Reactant: COC(=O)c1sccc1N
Reactant: OB(O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of phenylboronic acid (286 mg, 2.35 mmol), methyl 3-aminothiophene-2-carboxylate (369 mg, 2.35 mmol), and 2-oxoacetic acid hydrate (216 mg, 2.35 mmol) in acetonitrile (20 ml) was stirred at room temperature for 2 hours. The reaction was filtered, and the precipitated was washed with little acetonitrile. The solution was concentrated under reduced pressure, and the precipitate was collected again by filtration, washing with little acetonitrile. The combined precipitates were dried under vacuum overnight to obtain 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetic acid (558 mg, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[NH2:8].[Se].[OH2:13].[CH2:14](N(CC)CC)C>O1CCCC1>[NH2:9][C:4]1[CH:5]=[CH:6][C:7]2=[N:8][C:14](=[O:13])[N:1]=[C:2]2[CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O
Reactant: CCN(CC)CC
Agent: [Se]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)=NC(=O)N=2
Temperature: 80 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3,4-Diaminonitrobenzene 1.91 g (12.5 m moles), selenium powder 0.99 g (12.5 m moles), water 1.6 ml (89 m moles), triethylamine 5.0 g (50 m moles) and tetrahydrofuran 100 ml were placed in a 200-ml capacity autoclave, and stirred at a temperature of 80° C. for three hours under carbon monoxide of 20 Kg/cm2. The reaction mixture obtained was worked up in the same manner as in EXAMPLE 1, to provide 5-aminobenzimidazolone 1.80 g (90.0% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.COC1C=C(C2C=NC=CC=2)C=CC=1>>[CH3:15][C:11]1[CH:10]=[C:9]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(Br)c1
Reactant: Brc1cccnc1
Agent: COc1cccc(-c2cccnc2)c1
Product: Cc1cccc(-c2cccnc2)c1

Procedure:
3-(3-methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol) 3-bromopyridine and 120 g (0.70 mol) 3-bromo-toluene as described for the preparation of 3-(3-methoxyphenyl)-pyridine. (Example I7.) B.p. 87°/0.05 mmHg. Yield 61.7 g (69%).