Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:4]=1[C:5]#[N:6]>CO.[Pd]>[Cl:2][C:3]1[C:4]([CH2:5][NH2:6])=[CH:7][C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(F)c(Cl)nc1Cl
Reaction time: 21 h

Procedure:
To a Parr reaction bottle was added Pd—C (10%, 560 mg, 0.52 mmol), followed by 6 M HCl (50 ml) and a solution of 2,6-dichloro-5-fluoronicotinonitrile (Aldrich, 10.0 g, 52.4 mmol) in MeOH (100 ml). The mixture was placed under 50 psi H2 on a shaker type Parr apparatus for 21 h, filtered and concentrated. The crude was dissolved in EtOAc, basified with aqueous NaOH, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as crude light yellow oil. Used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5](=[O:14])[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]=1[CH3:8].[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.[F-].[K+]>C1COCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5](=[O:14])[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]=1[CH3:8]
Reactant: Cc1cccc(B(O)O)c1F
Reactant: Cc1c(Br)cc([N+](=O)[O-])c(=O)n1CC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc([N+](=O)[O-])c(=O)n(CC(F)(F)F)c2C)c1F
Temperature: 66 °C

Procedure:
A deoxygenated mixture of 5-bromo-6-methyl-3-nitro-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (2.00 g, 6.35 mmol), (2-fluoro-3-methylphenyl)boronic acid (1.95 g, 12.7 mmol), potassium fluoride (2.43 g, 41.9 mmol), and bis(tri-tert-butylphosphine) palladium(0) (0.333 g, 0.652 mmol) in THF (32 mL) was heated at 66° C. for 30 min. The reaction mixture was allowed to cool to 23° C., then partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexane initially, grading to 50% EtOAc in hexanes to give the title compound. MS: m/z=345.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.C([BH3-])#N.[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a stirred mixture of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate (17 g), acetic acid (4.5 g) and ethanol (30 ml) is added sodium cyanoborohydride (3 g) at room temperature. After stirring for 3 hours at room temperature, the mixture is diluted with water (500 ml) and extracted with methylene chloride. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (2:1-1:1) as an eluent to give ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate (11.5 g) as a colorless oil.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19](C(OC(C)(C)C)=O)[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)[C:12]2[C:7](=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:32]=[CH2:33])[CH:11]=2)[N:6]=1)[CH3:3]>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:2]([O:4][C:5]1[CH:14]=[C:13]([O:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)[C:12]2[C:7](=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:32]=[CH2:33])[CH:11]=2)[N:6]=1)[CH3:3]
Reactant: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(OCC)nc2cc1OC
Agent: Cl
Solvent: ClCCl
Product: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(OCC)nc2cc1OC
Reaction time: 1 h

Procedure:
HCl (g) was bubbled for 10 minutes through a solution of the product from Step 1 (3.90 g, 8.25 mmol) in DCM (83 mL). The solution stirred for 1 hour, and the DCM was removed in vacuo to give 3.55 g of the title compound as a white powder. LRMS ESI+ (M+H−2(HCl))+ 373.1, calcd for C20H25N2O5: 373.2.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>C(O)C>[N:13]1[CH:12]=[C:11]([CH2:10][C:6]2[C:7](=[O:9])[N:8]=[C:3]([NH:31][CH2:30][CH2:29][C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:32]=[CH:33][CH:34]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:20]=4)=[CH:28][CH:27]=3)[NH:4][CH:5]=2)[CH:16]=[N:15][CH:14]=1
Reactant: NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (40 mg, 0.171 mmol, 1 eq) and 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (53 mg, 0.188 mmol, 1.1 eq) were dissolved in dry ethanol (300 μl) and stirred at 120° C. for 6 h. Ethanol was evaporated during the reaction and in the mixture was added pyridine (300 μl) and reaction was stirred for 3 h. Pyridine was evaporated and 0.5 ml of EtOH was added. Precipitate was formed and it was starting material. Mother liquor was evaporated and purified via Biotage SP-1 Snap Si 10 g in the gradient of MeOH in DCM: 1% for 1 CV, 1-5% for 18 CV; 5-10% for 20 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product which was not pure enough and it was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 5-pyrimidin-5-ylmethyl-2-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (0.0087 mmol; yield: 5.1%, HPLC-MS/UV: [M+H]+=468.45; rt: 10.90 min; purity: 94.9%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.78 (t, J=7.17 Hz, 2H), 3.41-3.47 (m, 2H), 3.50 (s, 2H), 6.99 (d, J=8.40 Hz, 2H), 7.22 (d, J=8.34 Hz, 1H), 7.24-7.31 (m, 3H), 7.44 (d, J=7.82 Hz, 1H), 7.56 (s, J=7.92 Hz, 1H), 7.60 (s, 1H), 8.66 (s, 2H), 8.94 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH3:16][C:17]([CH3:19])=[O:18]>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:17]([OH:18])([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: Fc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccncc1F
Reaction time: 0.83 h

Procedure:
3-Fluoropyridine (11.0 g, 113.0 mmol) in 100 mL of THF was treated with LDA (1.5M, 100.0 mL, 150.0 mmol) at −78° C. for 50 min under argon. Acetone (28 mL) was added and the resulting reaction mixture was stirred at −78° C. to −40° C. for 50 min. The reaction was then quenched with aqueous NH4Cl and extracted with ether. The combined organic layers were washed with H2O and brine, then dried over Na2SO4 and concentrated under vacuum. Purification by MPLC (80 g column, 0 to 40% ethyl acetate in hexane as eluant) afforded the title compound. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.65 (s, 6 H), 7.27 (dd, J=5.57 Hz, 1 H), 8.36-8.39 (m, 2 H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>O1CCCC1.[Cl-].N>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:18][CH:17]=[CH:16][CH2:15]1
Reactant: ClC/C=C\CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: N
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To an ice-cooled solution of diethyl malonate (75.01 g, 468.3 mmol) in tetrahydrofuran (1.5 L) was added sodium hydride (28.1 g, 1.17 mmol) portionwise. After 1 h, (Z)-1,4-dichlorobut-2-ene (75.0 g, 468 mmol) in tetrahydrofuran (500 mL) was added over 40 min at 0° C. After 1 h, the reaction mixture was diluted with saturated aqueous ammonia chloride solution (500 mL), and the resulting mixture was extracted with ethyl acetate (2×2 L). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (petroleum ether) provided product as a yellow oil (85 g, 86% yield).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:32])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:32][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1
Reactant: OC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of cyclohexyl(1-phenyl-1H-indazol-3-yl)methanol (716 mg) synthesized above, pyridine (284 μL) and toluene (20 mL) was added thionyl chloride (256 μL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (767 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2].[CH3:37][NH:38]C>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:38][CH3:37])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CNC
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CNC)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{1-ethyl-4-[2-(3-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and 2M dimethylamine provided the title compound. ESMS [M+H]+: 494.0.
Reaction SMILES: [Cl-].NC1C=CC2N3C4C=CC=CC=4[N+](CC)=C3C=CC=2C=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29](/[CH:31]=[CH:32]/[C:33]3[CH:38]=[C:37]([NH2:39])[C:36]([Cl:40])=[CH:35][C:34]=3Cl)=[N:28][C:27]=2[CH:42]=1>CCO>[Cl-:40].[NH2:39][C:37]1[C:36]([Cl:40])=[CH:35][C:34]2[N+:28]3[C:27]4[CH:42]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=4[S:30][C:29]=3[CH:31]=[CH:32][C:33]=2[CH:38]=1
Reactant: Cc1ccc2sc(/C=C/c3cc(N)c(Cl)cc3Cl)nc2c1
Agent: CC[n+]1c2ccccc2n2c3ccc(N)cc3ccc21
Agent: [Cl-]
Solvent: CCO
Product: Cc1ccc2sc3ccc4cc(N)c(Cl)cc4[n+]3c2c1

Procedure:
The amino precursors of ABQ-38 and ABQ-95, (E)-7-ethyl-2-(5-amino-2-chlorostyryl)benzimidazole IIv and (E)-5-methyl-2-(5-amino-2,4-dichlorostyryl)benzothiazole IId, respectively, were prepared by the reduction of the corresponding nitro derivatives with hydrazine in the presence of nickel boride in dry methanol, see FIG. 3. (E)-7-ethyl-2-(5-amino-2-chlorostyryl)benzimidazole IIv was photocyclized as described (BQS Method 1) to give 3-amino-7-ethylbenzimidazo[3,2-a]quinolinium chloride (ABQ-38) as a yellow solid: 1H NMR (500.13 MHz, DMSO-d6): δ ppm 9.05 (d, 1H, J=8.50 Hz), 8.88 (d, 1H, J=9.0 Hz), 8.56 (d, 1H, J=9.5 Hz, 8.27 (d, 1H, J=8.5 Hz), 8.23 (d, 1H, J=9.50 Hz), 7.90 (t, 1H, J=7.5 Hz), 7.81 (t, 1H, J=7.5 Hz), 7.43 (dd, 1H, J=8.5, 2.5), 7.27 (d, 1H, J=2.5 Hz), 4.83 (q, 2H, J=7.0 Hz), 1.48 (t, 3H, J=7.0 Hz); UV-vis (95% EtOH) λmax/nm (e): 409 (1410), 351 (8104), 336 (9815) and 271 (20866); HRMS calcd for C17H16N3 (compound without the chloride counter ion) 262.1, found by ESI at m/z 261.9. (E)-5-methyl-2-(5-amino-2,4-dichlorostyryl)benzothiazole IId was photocyclized as described (BQS Method 1) to give 3-amino-2-chloro-10-methylbenzothiazolo[3,2-a]quinolinium chloride (ABQ-95) as a yellow solid: 1H NMR (500.13 MHz, DMSO-d6): δ ppm 9.17 (s, 1H), 8.92 (s, 1H), 8.63(AB quartet, 2H, J=9.5 Hz), 8.48 (d, 1H, J=8.5 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.53 (s, 1H), 6.50 (m, 2H), 2.70 (s, 3H); UV-vis (95% EtOH) λmax/nm (e): 429 (4417), 380 (10 387), 282 (22 568) and 214(2650); HRMS calcd for C16H12ClN2S 299.0 (without the chloride counter ion), found by ESI at m/z 299.0 M+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]#[N:37])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[NH:25]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-trifluoromethoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K24) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (23 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[H-].[Na+].O.C(Cl)Cl>CN1C(=O)CCC1.[Cu].CCCCCC.CCOC(C)=O>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][CH:16]([S:13]([C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:21][CH2:20]1
Reactant: c1nc[nH]n1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(-n2cncn2)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Temperature: 160 °C
Yield: 48.2 %

Procedure:
A mixture of 1,2,4-triazole (0.175 g, 2.5 mmol), 4-(4-bromophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]piperidine (0.54 g, 1.2 mmol), copper bronze (80 mg) and sodium hydride (60%, 100 mg, 2.5 mmol) in NMP (3 ml) was heated under nitrogen at 160° C. for 16 h while stirring. The hot solution was poured into water/CH2Cl2 (10/20 ml) and further extracted into CH2Cl2. The combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield a syrup. Column chromatography [silica, hexane/EtOAc (1:1)] yielded 250 mg of crystalline material. δH (360 MHz, CDCl3) 1.68-1.79 (2H, m), 1.98-2.05 (4H, m), 2.50-2.54 (2H, m), 2.71-2.75 (2H, m), 2.90-2.99 (1H, m), 3.05-3.09 (2H, m), 6.72-6.81 (2H, m), 7.09-7.15 (1H, m), 7.93-8.04 (4H, m), 8.17 (1H, s), 8.72 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[CH2:29][N:23]4[CH:22]=[CH:21][CH:20]=[C:24]4[CH2:25]3)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A mixture of 2.13 g of 4-[(4-methylphenyl)-sulfonyl]benzoyl chloride (Reference Example 42) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with ? ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.3 g of the desired product as a solid. M+H 443.2; M+Na 465.2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([CH:23]=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O:41]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([OH:41])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(C(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.8 %

Procedure:
The procedure of Example 6 was repeated except that 140 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 112 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][S:34][CH3:35]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][S:34][CH3:35])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCl
Reactant: O=C1C(=O)N(Cc2ccc(Nc3ncccn3)cc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 86.45 %

Procedure:
In 40 ml of N,N-dimethylformamide was dissolved 3.0 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine, and 0.372 g of sodium hydride (purity 52%) was added thereto, after which the resulting mixture was subjected to reaction at 80° C. for 30 min. with stirring. The reaction mixture was then cooled, and 0.72 ml of chloromethylmethylsulfide was added thereto, after which the resulting mixture was subjected to reaction at 50° to 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was distilled under reduced pressure and the residue thus obtained was extracted with chloroform and then washed with water. The solution thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 3.0 g (86.45% yield) of white crystalline 1-benzyl-4-{4-[N-methylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 156° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=O)OCC)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Cc2ccc(N)cc2)cc1
Yield: 69 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-methoxy-benzaldehyde. Yellow solid. Yield=69%. MS: m/e=225.9 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:19](=[O:20])[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:19](=[O:20])[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[C:12]2=[O:13])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccsc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccsc2C1=O

Procedure:
The mixture of 1.55 g of N-(4-nitro-o-tolyl)-thiophene-2,3-dicarboximide, 0.7 g of Raney nickel and 180 ml of ethyl acetate is hydrogenated at 2.7 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated and the residue recrystallized from ethyl acetate-diethyl ether to yield the N-(4-amino-o-tolyl)-thiophene-2,3-dicarboximide melting at 237°-240°.