Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cncc(-c2ccccc2Oc2ccccc2)c1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5.16 g, 21.8 mmol), water (36.5 mL), toluene (145 mL), ethanol (36.5 mL), 4-phenoxyphenylboronic acid (5.00 g, 23.3 mmol), sodium carbonate (4.9 g, 47 mmol) and tetrakis(triphenylphosphine)palladium (1.25 g, 1.04 mmol) was stirred and heated under reflux for 5 h. After cooling to room temperature, water (150 mL) was added and the aqueous phase separated and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (50 mL), then dried (MgSO4), treated with 3S Black (decolorizing charcoal), filtered, and concentrated by rotary evaporation. The residue was purified by column chromatography, eluting with cyclohexane/ethyl acetate (90/10, v/v) to give 2.3 g (32%) of a white solid, mp 109° C.
Reaction SMILES: [NH:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[NH:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCNCC1
Temperature: 25 °C

Procedure:
A solution of 16.9 parts of ethyl 4-anilino-1-benzylisonipecotate in 150 parts of acetic acid is hydrogenated at normal pressure and at a temperature of 45° C with 1.5 parts of palladium-on-charcoal 10%. After the calculated amount of hydrogen is taken up, the reaction mixture is allowed to cool to room temperature, the catalyst is filtered off and the filtrate is evaporated. The oily residue is taken up in water, alkalized with ammonium hydroxide and the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from acetonitrile, yielding ethyl 4-anilinoisonipecotate; mp. 121.8° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([C:21]#[N:22])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncc(OCc2ccccc2)cc1Br
Temperature: 100 °C

Procedure:
To a solution of 53-(benzyloxy)-5-bromopyridine 1-oxide (from step 2) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give a mixture of two benzoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4ccccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), (pyridin-2-ylmethyl)-amine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(pyridin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 416 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][CH:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: [H][H]
Reactant: Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 17 h

Procedure:
Add 5-(3-methyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.18 g, 0.61 mmol), to a mixture of 10% Pd/C (0.045 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 298 (M+). HPLC (ISO80-10M) t=1.00 (98%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20]>CS(C)=O.C(O)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH3:20])=[C:4]([Cl:11])[N:3]=1
Reactant: CCI
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
2,6-Dichloropurine (378 mg, 2.0 mmol) was dissolved in dimethylsulfoxide (10 mL), and dry potassium carbonate (345 mg, 2.5 mmol), and iodoethane (312 mg, 2.0 mmol) added. The mixture was stirred at room temperature for 16 hours, then the mixture was diluted with ice, acetic acid was added to adjust the pH to 5, and the solution was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was purified by flash chromatography, eluting initially with cyclohexane-EtOAc (75:25) to give 2,6-dichloro-9-ethylpurine (280 mg, 65%), a compound of formula (2). mp 100–103° C.; UV λmax (MeOH) 214 nm (ε 22900), 274 (ε 9500), (pH 1) 213 nm (ε 22800), 273 (ε 9500), (pH 12) 214 nm (ε 17900), 260 (ε 7800), 266 (ε 8100); 1H NMR (Me2SO-d6) δ 1.45 (t, 3H, J=7.2 Hz, CH2CH3), 4.28 (q, 2H, J=7.2 Hz, CH2CH3), 8.77 (s, 1H, H-8). Anal. (C7H6Cl2N4) C, H, N.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)=[O:8])(=[O:4])=[O:3].[Br:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>CCOC(C)=O.C(#N)C>[Br-:24].[CH3:1][S:2]([NH:5][CH:6]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7]([O:9][C@@H:10]1[CH:15]2[CH2:14][CH2:13][N+:12]([CH2:25][C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:17][CH2:16]2)[CH2:11]1)=[O:8])(=[O:3])=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CS(=O)(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(methylsulfonamido)-2-phenylacetate (C76) (38.9 mg, 0.11 mmol) in EtOAc (1 ml) and acetonitrile (0.5 ml), was added 2-bromo-1-phenylethanone (25.2 mg, 0.13 mmol). The mixture was stirred at RT for 2 hours, and then the solvent was evaporated. The crude was triturated with Et2O to obtain (3R)-3-(2-(methylsulfonamido)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (40 mg; 64.7% yield).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>S(Cl)(Cl)=O.CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:14])=[CH:15][CH:16]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 4-(4-bromobenzoyl)benzoic acid (87 mg, 0.29 mmol; described in: Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39(14), 2053-2056) in thionyl chloride (1 mL) at 50° C. was added a few drops of N,N-dimethylformamide. The clear solution was stirred at 50° C. for 30 min. The excess of thionyl chloride was removed under reduced pressure, and by evaporation with several portions of toluene. The residue was dissolved in dichloromethane (10 mL) and a large excess of triethylamine was added until basic pH. A solution of diethylamine (23 mg, 0.31 mmol) in dichloromethane (2 mL) was added and the mixture was stirred at room temperature for 3.5 h. The red solution was partitioned between water and additional dichlorormethane. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using heptane/ethyl acetate, 70:30, affording 70 mg (68% yield) of the title compound as a colorless oil, which partly solidified upon standing in refrigerator: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2 H), 7.70-7.63 (m, 4 H), 7.49 (d, J=8.1 Hz, 2 H), 3.59-3.57 (m, 2 H), 3.27-3.25 (m, 2 H), 1.30-1.25 (m, 3 H), 1.15-1.11 (m, 3 H); 13C NMR (400 MHz, CDCl3) δ 195.4, 170.5, 141.7, 138.0, 136.3, 132.2, 132.0, 130.5, 128.3, 126.7, 43.7, 39.7, 14.7, 13.3; MS (ESP) m/z 360 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH2:60])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]>CN(C=O)C>[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH:60][C:12]([C:4]2[C:3](=[O:15])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([CH3:10])[CH3:11])[CH:5]=2)=[O:14])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 270 mg, 0.99 mmol), TBTU (316 mg, 0.99 mmol) and DIPEA (513 μL, 2.97 mmol) in DMF (3.00 mL) is stirred for 10 min at room temperature. Then, a solution of (4-(N-cyano-S-methylsulfonimidoyl)phenyl)methanamine (preparation 6, 247 mg, 1.18 mmol) in DMF (1.00 mL) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 70 mg (15% of theory); ESI mass spectrum: [M+H]+=465 (bromine isotope pattern); r.t. HPLC: 0.86 min (Z017_S04).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.C(OC1C=CN(C2C=CC([O:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43]C3)=CN=2)C(=O)C=1)C1C=CC=CC=1.C(O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.FC1C=CC(C(O)C)=CC=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][N:14]([C:52]3[CH:51]=[CH:50][C:49]([O:38][CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:54][CH:53]=3)[C:13](=[O:17])[CH:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(Oc1cc[nH]c(=O)c1)c1ccc(F)cc1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cn1
Agent: CC(O)c1ccc(F)cc1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(Oc1ccn(-c2ccc(OCCN3CCCC3)cc2)c(=O)c1)c1ccc(F)cc1

Procedure:
Example 12 was repeated except that 4-[1-(4-fluorophenyl)ethoxy]-1H-pyridin-2-one as obtained by repeating Steps (1) and (2) of Example 1 in which benzyl alcohol was replaced with 1-(4-fluorophenyl)ethanol, was used in place of 4-benzyloxy-1H-pyridin-2-one, to provide the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.CON(C)[C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:20][C:18]1[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]([CH2:13][C:26](=[O:28])[CH3:27])[CH:19]=1
Reactant: CON(C)C(C)=O
Reactant: CSc1nc(C)cc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nc(C)cc(CC(C)=O)n1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (1.6 M in hexanes, 67 ml, 107 mmol) is added dropwise to a stirred solution of diisopropylamine (15 ml, 107 mmol) in dry THF (90 ml) under argon at −78° C. After 15 minutes at −78° C. to 50° C. the mixture is cooled to −78° C. and a solution of 4,6-dimethyl-2-methylsulfanyl-pyrimidine (15 g, 97.4 mmol) in dry THF (45 ml) is added dropwise. The reaction is stirred for 2.5 hours at −78° C. then N-methoxy-N-methylacetamide (10.4 ml, 97.4 mmol) is added dropwise. The reaction is allowed to warm to room temperature over 1 hour followed by quenching with saturated aqueous ammonium chloride solution (10 ml). The mixture is concentrated to remove most of the THF then partitioned between water (200 ml) and DCM (200 ml). The organic extract is separated, dried (MgSO4), and the solvent is removed to afford the titled compound. The material is a mixture of keto and enol forms as observed by 1H nmr (CDCl3)
Reaction SMILES: CS(C)=O.C1C=CC=CC=1.[F-:11].[K+].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[F:11][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1F
Temperature: 140 °C
Yield: 22.1 %

Procedure:
A mixture of 120 ml of dimethylsulfoxide, 80 ml of benzene, 35 g of potassium fluoride and 50 g of 2,5-dichloronitrobenzene was heated with stirring to 140° C. and was then heated at 180°-185° C. for three hours and then cooled. The water vapor was entrained and the distillate was extracted with isopropyl ether. The combined organic phases were dried and distilled at 40° C. under reduced pressure and were rectified at 14 mm Hg to obtain 10.1 g of 2-fluoro-5-chloro-nitrobenzene with a refractive index of nD20 =1.5558.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][C:15]([C:17](OCC)=[O:18])=[N:14][N:13]=1)=[CH:8]2.O1CCCC1.[BH4-].[Na+]>CO>[OH:18][CH2:17][C:15]1[S:16][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:13][N:14]=1
Reactant: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3nnc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a mixture of ethyl 5-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3,4-thiadiazole-2-carboxylate (1.38 g), tetrahydrofuran (20 ml) and methanol (4 ml) was added sodium borohydride (0.26 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and water was added to the residue. The resulting crystals were collected by filtration, washed with water, and dried to give the title compound (1.18 g, yield 94%) as colorless crystals. melting point 259-260° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[N:15]=[C:14]([C:24]([OH:26])=O)[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:23][C:19]1[CH:18]=[C:17]([N:16]2[C:12]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=3)=[CH:13][C:14]([C:24]([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=[O:26])=[N:15]2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OC(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
40 mg (0.10 mmol) of the compound of Example 53A is reacted analogously to the synthesis of the compound of Example 4 with 11 mg (0.11 mmol) of 2-oxopiperazine. 39 mg (80% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1]Br.[O:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[N:12]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[O:3][C:4]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:5][C:6]2=[N:7][CH:8]=1
Reactant: BrBr
Reactant: c1cnc2nc(N3CCN4CCC3CC4)oc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1

Procedure:
Bromine (0.12 mL, 2.29 mmol) was added to a solution of 4-oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane (560 mg, 2.29 mmol, prepared in Example 27) and sodium acetate (2.26 g, 27.5 mmol) in water (12 mL) and acetic acid (12 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled and extracted with ethyl acetate (3×). The combined organic layers were washed with water (2×) and brine (1×) and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) using a gradient elution from 4% MeOH/CHCl3 containing 0.1% NH4OH to 8% MeOH/CHCl3 containing 0.1% NH4OH giving 578 mg (78%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 8.23 (d, 1H, J=1.7 Hz), 7.50 (d, 1H, J=1.7 Hz), 4.51 (br s, 1H), 3.92 (br s, 2H), 3.16-3.04 (m, 4H), 3.02-2.94 (m, 2H), 2.17-2.01 (m, 2H), 1.83-1.74 (m, 2H); MS (Cl) m/z 325.0/323.0 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:23][C@@H:24]1[O:28][CH2:27][C@@H:26]([S:29][C:30](=[O:32])[CH3:31])[CH2:25]1)(=O)=O>C(Cl)Cl>[O:7]([CH2:23][C@@H:24]1[O:28][CH2:27][C@@H:26]([S:29][C:30](=[O:32])[CH3:31])[CH2:25]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)S[C@@H]1CO[C@@H](COc2ccccc2)C1
Reaction time: 0.83 h
Yield: 60.9 %

Procedure:
To a 0° C. solution of 0.326 g of phenol, 1.8 ml of Hunig's base, and 2.5 ml of methylene chloride is added, via syringe, 1.07 g of product from Example 22 in 0.50 ml of methylene chloride. The reaction is stirred in an ice bath for 50 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer is dried, concentrated in vacuo, and purified by chromatography (Silica Gel: 30% ethyl acetate/hexane) to give 0.532 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Br[C:13]#[N:14]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13]([NH2:14])=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: CCO
Product: Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
7.6 g (50 mmol) of 4-nitro-ortho-phenylenediamine was dissolved were dissolved in 100 mL of ethanol and 20 mL of H2O. 7.9 g (75 mmol) of BrCN was added in one portion to this stirring solution, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 20 mL then neutralized with saturated NaHCO3 solution to ˜pH 8, and resulting solid 5-nitro-1H-benzoimidazol-2-ylamine collected via filtration was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.C(C1C=NC=CC=1NC(=O)C(C)(C)C)=O.C1([Mg][Cl:38])C=CC=CC=1.Cl.[NH2:40][OH:41]>N1C=CC=CC=1>[ClH:38].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:40][OH:41]
Reactant: Cl[Mg]c1ccccc1
Reactant: NO
Reactant: Nc1ccncc1C(=O)c1ccccc1
Agent: CC(C)(C)C(=O)Nc1ccncc1C=O
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccncc1C(=NO)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of (4-amino-3-pyridinyl)phenylmethanone (17 g prepared from N-(3-formyl-4-pyridinyl)-2,2-dimethylpropanamide by utilizing the reaction scheme described in Example 9, 10 and 11 except that phenyl magnesium chloride was used instead of cyclohexyl magnesium chloride) and hydroxylamine hydrochloride (24 g) in 150 ml pyridine was stirred at 90°-95° for two hours and thereafter cooled and concentrated. The residue was stirred with water, basified with sodium carbonate and extracted with dichloromethane. The dried organic layer was concentrated to 20 g waxy solid. This was triturated with acetonitrile to yield 13.6 g solid, m.p. 177°-179°. The filtrate was concentrated to 4.3 g oil and thereafter eluted with 10% methanol in dichloromethane through silica via flash column chromatography to yield an additional 1.8 g product for a total yield of 15.4 g. Eight grams were again eluted with 10% methanol in dichloromethane through silica via flash column chromatography to yield 6.9 g solid, m.p. 178°-180°. A 4.9 g portion was converted to the hydrochloride salt in methanol/ether to yield 3.3 g crystals, d 238°-240°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1.[CH3:16]I>C(#N)C.[Ag]=O>[CH3:16][O:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]cc(CO)c2c1
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1c[nH]c2ccc(C(=O)OC)cc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A 327 mg portion of methyl 3-(hydroxymethyl)-1H-indole-5-carboxylate was dissolved in 9 ml of acetonitrile, mixed with 385 mg of silver oxide and 3.6 ml of methyl iodide and stirred at 80° C. for 5 hours. A 385 mg portion of silver oxide was further added thereto and stirred overnight at 80° C. A 385 mg portion of silver oxide and 3.6 ml of methyl iodide were further added thereto and stirred at 80° C. for 9 hours. After cooling to room temperature, the insoluble matter was removed, the solvent was evaporated, and then the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6 to 1:5 to 1:4) to obtain 143 mg of methyl 3-(methoxymethyl)-1H-indole-5-carboxylate as a pale yellow solid.