Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A1 (110.65 mg, 0.5 mmol) in dry dichloromethane (3 mL) at 0° C. was added triethylamine (0.086 mL, 0.55 mmol) and 2-fluorobenzenesulfonyl chloride (66.88 μL, 0.50 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using ethyl acetate/hexane (2:5) as the eluent, gave 14a; (105.42 mg, 65.2%). [α]D25: −11.7 (c=0.24, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.82 (dd, J=1.8, 7.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.27-7.21 (m, 4H), 7.16-7.09 (m, 3H), 5.27 (d, J=9 Hz, 1H), 4.41 (m, 1H), 3.20-3.06 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.41, 160.51, 157.15, 136.54, 134.91, 134.80, 129.48, 129.31, 128.18, 126.68, 124.15, 117.04, 116.76, 57.31, 38.36; HRMS (ESI): calcd for: C15H14FNO4S [M+H]+=324.0690, obsd [M+H]+=324.0700.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1>C1COCC1>[OH:2][CH:1]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cnccc2-c2cccc(C#N)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 1.0 M 3-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(3-methoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: CN([CH:4]=[C:5]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:6]=O)C.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].[O-]CC.[Na+].C(OC(=O)C)(=O)C>O.C(O)C>[C:23]([C:25]1[C:26](=[O:27])[NH:28][CH:4]=[C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=1)#[N:24]
Reactant: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: N#Cc1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (cis and trans mixture) (4.00 g), 2-cyanoacetamide (2.31 g), sodium ethoxide (4.67 g) and ethanol (40 ml) was refluxed for 2 hours. After cooling the reaction mixture was added acetic anhydride (24 ml) and water (120 ml) and stirred at room temperature. The resultant precipitates were collected and recrystallized from a mixture of N,N-dimethylformamide and water to give 3-(3-cyano-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.08 g).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[NH:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([CH3:30])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][N:22]=[C:21]([NH:26]C(=O)C)[CH:20]=3)[CH:12]=[CH:13][C:14]=1[F:15]>CCO>[NH2:26][C:21]1[CH:20]=[C:19]2[C:24]([CH:25]=[C:16]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([NH:8][C:7]([NH:6][CH2:5][CH2:4][C:3]([CH3:32])([CH3:2])[CH3:33])=[O:31])[CH:10]=3)[C:17]([CH3:30])=[N:18]2)=[CH:23][N:22]=1
Reactant: CC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(N)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Add HCl (3M, 4 mL, 12 mmol) to a suspension of N-(3-(3-(3-(3,3-dimethylbutyl)ureido)-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)acetamide (70 mg, 0.160 mmol) in EtOH (4 mL), stir at RT for 1.5 h, then heat at 50° C. for 4 h. Cool to RT, remove the organics under reduced pressure and filter the aqueous residue. Add satd. NaHCO3 to the filtrate until pH=8, extract with THF (3×), wash the combined organics with brine, dry over MgSO4 and concentrate to dryness. Suspend the material in 4:1 MeCN/H2O, collect the solid via filtration and dry to afford the title compound (47 mg, 74%) as a golden-tan solid. MS (ESI) m/z: 396.2 (M+H+).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16](=[CH:24]O)[C:17](=O)[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[CH:24]=[N:3][N:2]([CH3:1])[C:17]=2[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: Cn1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using methyl hydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](O)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:27][CH3:26])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a stirred solution of compound (vii) (2.2 g, 5.5 mmol) in pyridine (45 mL) was added methyl amine (8.2 mL, 2 M solution in THF, 16 mmol). The reaction mixture was cooled to 0° C. and POCl3 (2.88 g, 19 mmol) was added dropwise at the same temperature. After 1 h TLC and LCMS showed the absence of SM and formation of product. The reaction mixture was quenched in ice water and the precipitate was filtered and crystallized from MeOH to give 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-nitro-2H-indazole-3-carboxamide (viii) (1.25 g, 55%). ESI-MS m/z calculated for [M+H]+: 415.04/417.04; found: 415.15/417.15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[Cu][C:22]#[N:23]>CN(C=O)C>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: O=c1[nH]nc(Cc2ccc(F)c(Br)c2)c2c1CCCC2
Solvent: CN(C)C=O
Product: N#Cc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 160 °C

Procedure:
To a solution of 4-(3-bromo-4-fluoro-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (9) (9.53 g, 28.2 mmol), in dry DMF (95 ml) was added copper (I) cyanide (3.5 g, 42.3 mmol) in one portion. The mixture was heated to 160° C. for 18 hours. The reaction was then cooled and filtered through celite and washed though with methanol (30 ml). The filtrate was concentrated in vacuo to afford a brown oil. Main peak in LC-MS, (8.01 g, 66% purity) and was taken through crude to the next transformation; m/z (LC-MS, ESP), RT=3.50 mins (M+H 284.3).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:20])=[C:11]([CH:14]=[C:15]([O:17][CH2:18][CH3:19])[CH:16]=1)[CH:12]=[O:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15]1[CH:16]=[C:9]([OH:8])[C:10]([F:20])=[C:11]([CH:14]=1)[CH:12]=[O:13])[CH3:19]
Reactant: CCOc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(O)c(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)-5-ethoxy-2-fluorobenzaldehyde (7.25 g, 24.3 mmol), prepared according to WO2003066588 A1, which is incorporated herein by reference, in 50 mL THF at 0° C., was added a 1 M solution of TBAF in THF (24.3 mL, 24.3 mmol). The mixture was stirred for 30 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford Intermediate 7.1, contaminated with tetrabutylammonium salts.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C=C(Cl)C=1)N.N1C=CC=CC=1C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[C:6]([Cl:19])[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Clc1cc(Cl)cc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dichloroaniline (48.6 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][C:18]([C:32]#[N:33])=[CH:19][CH:20]=2)[C:15]=1[Br:34])[CH2:9][CH:10]=C(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C[OH:39]>>[C:1]([O:5][C:6]([N:8]([C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]2[C:16](=[CH:17][C:18]([C:32]#[N:33])=[CH:19][CH:20]=2)[C:15]=1[Br:34])[CH2:9][CH:10]=[O:39])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
A solution of 17 (180 mg, 0.345 mmol) in 22 mL (0.016 M) of 20% CH3OH--CH2Cl2 was cooled to -78° C. A stream of 3% O3 /O2 (160 L/min) was bubbled through the solution for 72 s. The reaction was immediately quenched with the addition of 0.81 mL of dimethyl sulfide and the mixture was allowed to stir at -78° C. for 5 min before being allowed to warm to 25° C. and stirred for 5 h. The solvent was removed in vacuo. Chromatography (SiO2, 2×20 cm, 30% EtOAc-hexane) afforded 18 (155 mg, 171 mg theoretical, 91%) as a white foamy solid: 1H NMR (CDCl3, 400 MHz) δ9.76 and 9.73 (two s), 8.63 and 8.61 (two s, 1H), 8.41 and 8.36 (two d, 1H, J=8.7 Hz), 7.64 and 7.60 (two dd, 1H, J=1.4, 8.7 Hz), 7.50-7.34 (m, 5H), 7.17 and 7.14 (two s, 1H), 5.26, 5.29 and 5.17 (one s and two d, 2H, J=11.4 Hz), 4.76 and 4.65 (two d, 1H, J=18.8 Hz), 4.01 and 3.95 (two d, 1H, J=18.8 Hz), 1.31 and 1.52 (two s, 9H); 13C NMR (CDCl3, 100 MHz, major rotamer) δ197.3, 154.1, 140.8, 135.6, 133.4, 132.0, 128.8, 128.7, 128.5, 127.9, 127.6, 127.1, 124.2, 118.7, 113.8, 112.0, 110.5, 81.8, 70.9, 58.9, 28.1; IR (film) vmax 2976, 2229, 1706, 1596, 1415, 1369, 1335, 1259, 1225, 1152, 1096, 848 cm-1 ; FABHRMS (NBA) m/z 495.0922 (M+ +H, C25H23BrN2O4 requires 495.0919).
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[N:6][N:7]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC12CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Temperature: 80 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
To a stirred suspension of Intermediate 350F (0.400 g, 0.956 mmol) in 1,4-dioxane (5 mL) was added K3PO4 (0.500 g, 2.80 mmol), (3-chloro-4-fluorophenyl) boronic acid (0.250 g, 1.435 mmol) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)-CH2Cl2 (0.047 g, 0.057 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 12 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL) The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 3% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 350G as a pale yellow solid (0.29 g, 70%). MS(ES): m/z=421 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.69 (dd, J=7.0, 2.3 Hz, 1H), 7.50 (ddd, J=8.5, 4.6, 2.1 Hz, 1H), 7.33-7.15 (m, 1H), 5.34 (br. s., 2H), 4.97 (br. s., 2H), 4.05 (br. s., 2H), 1.44 (s, 9H), 1.22-1.24 (m, 2H), 1.02-0.79 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:22][C:16]([S:13][C:9]1[N:10]=[N:11][S:12][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Sc1nnsc1Cc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1nnsc1Cc1ccccc1

Procedure:
A solution of 1.99 g of 5-(phenylmethyl)-1,2,3-thiadiazole-4-thiol, sodium salt in 30 ml of ethanol was stirred overnight with 1.96 g of ethyl 2-bromoisobutyrate and then concentrated in vacuo. The residue was taken up in ether, filtered, and evaporated in vacuo. The oily residue was purified as described in Example 50, giving a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 1.22 (t, 3H); 1.67 (s, 2 CH3 's); 4.12 (q, 2H); 4.31 (s, CH2); 7.30 (6s, SH).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][C:31]=1[CH2:32][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cc(CCO)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4Cl)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.294 g) in NMP (2 mL) was treated with acetic acid (0.039 mL) and stirred for 5 minutes. A solution of 2-chloro-5-(2-hydroxyethyl)benzaldehyde (example 61, step c) (0.189 g) in NMP (3 mL) was then added, the resulting solution was stirred for 1 hour and was then treated with sodium triacetoxyborohydride (0.217 g). The mixture was stirred overnight at room temperature, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.238 g.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCCOCc4ccccc4)c4ccccc4)ccc3n2C)cc1
Yield: 73 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide hydrochloride and n-hexyl chloroformate. Yield: 73% of theory, C40H46N6O4 (674.9); Rf value: 0.46 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=675; (M+H+Na)++=349; (M+Na)+=697; (M+K)+=713.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH3:21])[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:13]=2[C:12]([CH3:38])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CN(C)C=O.[OH-].[OH-].[Pd+2]>[CH2:18]([C:15]1[N:14]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:13]2[C:12]([CH3:38])=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=1)[CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCc1nc2c(OCc3ccccc3)ccc(C)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc2c(O)ccc(C)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 57 from 4'-[(4-benzyloxy-2-n-butyl-7-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and hydrogen in methanol/dimethylformamide in the presence of 20% palladium hydroxide on carbon.
Reaction SMILES: Cl.[CH2:2]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[CH:6]2[CH2:5][NH:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.C(N(CC)CC)C>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:4]1[CH2:3][CH2:2][N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[CH:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: BrCCCCCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2N2CCN(CCCCCc3ccccn3)CC12

Procedure:
A solution of 6.2 g. (0.03 mole) of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, hydrochloride, 7.5 g. (0.04 mole) of 5-(2-pyridyl)pentyl bromide hydrochloride, 15 g. potassium carbonate, 5 g. potassium iodide, and 0.5 ml. of triethylamine in acetone (200 ml.) is heated under reflux for 72 hours. The reaction is worked up in the usual manner, yielding the title compound as base. This is converted to dihydrochloride salt by treating an acetone solution of base with dry hydrogen chloride, m.p. 266°-69° C. (dec.).
Reaction SMILES: C([C:4]1[C:5]([N:13]([CH3:15])[CH3:14])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)(=O)N>Cl>[CH3:14][N:13]([CH3:15])[C:5]1[CH:4]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: CN(C)c1nn2ccccc2c1C(N)=O
Agent: Cl
Product: CN(C)c1cc2ccccn2n1
Yield: 50.4 %

Procedure:
A mixture of 3.25g (1.6 × 10-2 mole) of 3-carbamoyl-2-dimethylaminopyrazolo[1,5-a]pyridine and 100 ml of concentrated hydrochloric acid was refluxed for 5 hours. After cooling, the solution was made to alkali and extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was column-chromatographed over alumina. The elution with methylene chloride gave crude product, which was recrystallized from n-hexane to give 1.3g of colorless needles, mp 51°-52° C. Yield 50%.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 4-(4-methoxybenzoyl)-nitrobenzene (150 g, 0.58 mol), glacial acetic acid (500 mL), and hydrobromic acid (48% w/w aqueous solution, 400 mL) was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The crude product as filtered, washed several times with water and dried at about 50° C. under high vacuum. Crystallization from ethyl acetate/hexanes gave 4-(4-hydroxybenzoyl)-nitrobenzene (114 g, 81%), m.p. 190-193° C.; Analysis for C13H9NO4: Calc.: C, 64.20; H, 3.73; N, 5.76; Found: C, 63.95; H, 3.65; N, 5.85; MS m/e (%): 243 (M+; 45).
Reaction SMILES: FC(F)(F)C([N:5]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:9][N:8]=1)[NH2:6])=O.Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH:5]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)=[CH:9][N:8]=1)[NH2:6]
Reactant: NN(C(=O)C(F)(F)F)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NNc1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cn1
Yield: 62.4 %

Procedure:
2,2,2-Trifluoro-N-(5-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2-yl)acetohydrazide (0.17 g) was dissolved in ethanol (5 mL). To the solution, concentrated hydrochloric acid (1 mL) was added at room temperature, and the mixture was heated to reflux for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (Moritex Corporation, elution solvent: ethyl acetate) to obtain the title compound (0.079 g) (yield: 63%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([F:19])([F:18])[S:4]([O:7]S(C(F)(F)C(F)(F)F)(=O)=O)(=[O:6])=[O:5].F[C:23](F)(F)C(F)(F)S(O)(=O)=O.C(=O)(OC)OC>>[F:1][C:2]([F:21])([F:20])[C:3]([F:19])([F:18])[S:4]([O:7][CH3:23])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)C(F)(F)F
Yield: 84.1 %

Procedure:
5.74 g (15.0 mmol) of pentafluoroethanesulfonic anhydride and 0.31 g (1.55 mmol) of pentafluoroethanesulfonic acid are initially introduced in a 10 ml round-necked flask. 1.35 g (15.0 mmol) of dimethyl carbonate are added at room temperature with constant stirring and reflux cooling. The solution is stirred for one hour at a temperature of 60° C. and subsequently for a further 3 hours at 110° C. After distillation, 5.41 g of methyl pentafluoroethanesulfonate are isolated (boiling range: 114-115° C., yield: 84.1%).