Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1>[C:1]1([C@H:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a stirred solution of methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoate (I14, 2.27 g, 4.50 mmol) in THF (23 mL) was added an aqueous solution of lithium hydroxide (2.0 M, 9.0 ml, 18.0 mmol). The mixture was stirred at RT for 16 hours. The pH of the reaction mixture was adjusted to 6 by the addition of 4M aqueous hydrochloric acid. The mixture was then extracted with 10% methanolic ethyl acetate (×2), the organic extracts were combined and the solvent was removed in vacuo. The residue was then dissolved in ethanol and re-evaporated at reduced pressure to afford the title compound as a pale yellow solid (1.85 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[N:13]=1
Reactant: C[C@@H](N)CO
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(N[C@H](C)CO)nc21

Procedure:
The product of Example 44, and (R)-2-aminopropan-1-ol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.81 (m, 6H), 1.30 (m, 2H), 1.96 (m, 2H), 2.36 (m, 2H), 3.71 (m, 2H), 4.25(m, 1H), 5.31 (m, 0.5H), 5.56 (m, 0.5H), 5.71 (br s, 1H), 6.26 (br d, 1H, J=9.6), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.54 (m, 4H). LC MS (m/e)=401 (MH+). Rt=2.07 min
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH3:15]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH3:15])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 70 °C
Yield: 88.8 %

Procedure:
A mixture of 4-nitro-3,5-dibromopyrazole (2) (20.0 g; 73.8 mmol) in DMF (160 ml) was added over 20 minutes to a suspension of NaH (3.3 g, 82.5 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (160 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of bromoethane (19.3 g; 177.1 mmol) in DMF (35 ml) was added over 5 minutes. The reaction mixture was heated to 70° C. for 4 hours and the DMF was then evaporated off under reduced pressure (oil pump) while heating the reaction medium to 80° C. A DCM/water mixture (200 ml, 1/1) was added. The aqueous phase was washed with DCM (100 ml) and the combined organic phases were then washed with water (50 ml). The organic phase was dried over NaSO4 and the solvent was evaporated off under reduced pressure. The crude 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (19.6 g, 89%) is obtained in the form of a solid. This product is used without purification in the following step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH2:17][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=CC1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccccc4)CC3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 702.8 %

Procedure:
To a solution of 1.46 g (5.6 mmol) of 1-benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine and 0.13 g (0.67 mmol) of 4-(4-fluorophenyl) piperidine (Example 1, Step 1) in 30 mL of dichloroethane at rt was added 2.37 g (11.2 mmol) of sodium triacetoxyborohydride. After stirring for 18 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone:hexanes, 1:8) to give 1.98 g of the title compound. 1H NMR (key peaks) (CDCl3) δ7.28-7.37 (m, 5H), 7.19-7.22 (m, 2H), 7.01 (t, 2H, J=8.5 Hz); Mass Spectrum (ESI) m/e=421 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[CH:5][C:4]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@:38]1([CH3:45])[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[O:19]=[C:9]1[NH:10][C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]1[CH:20]=[CH:21][C:3]([F:2])=[C:4]([CH:5]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:42]([C@@:38]2([CH3:45])[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:43])[CH2:26][CH2:25]1)=[O:23]
Reactant: O=C(c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)N1CCN(C(=O)c2cc(Cn3c(=O)[nH]c(=O)c4ccccc43)ccc2F)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione hydrochloric acid (30b, 37 mg) was suspended in acetonitrile (1.5 mL), treated with (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (40a, 30 mg), HATU (47 mg), and Et3N (0.5 mL) sequentially. The reaction mixture was stirred at ambient temperature (25° C.) for 19 hrs. The reaction mixture was directly purified by flash chromatography with MeOH—CH2Cl2 (0-20% gradient elution) to afford the desired product, (R)-tert-butyl 2-(4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carbonyl)-2-methylpyrrolidine-1-carboxylate (40b) as the major fraction (colorless oil, 50 mg). MS (ESI): m/z=594 (M+H+)
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Yield: 50.1 %

Procedure:
A mixture of 955 mg of 3-carboxymethylrhodanine, 516 mg of sodium acetate, 10 ml of acetic acid and 637 mg of benzaldehyde was heat-refluxed for 2 hours. To the reaction mixture was added 20 ml of water, and the precipitated crystals were filtered. The resulting crystals were recrystallized from ethanol to obtain 699 mg of the titled compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH2:62]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:62][CH2:61][CH2:60][N:59]([CH3:63])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethylethylenediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 2H) 1.27-1.51 (m, 2H) 1.51-1.86 (m, 6H) 2.17 (s, 6H) 2.39 (t, J=7.8 Hz, 2H) 3.31 (s, 3H) 3.38 (m, 2H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.48 (d, J=8.0 Hz, 1H) 7.52 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.34 Hz, 1H) 8.35 (br. s., 1H). [M+H] calculated for C26H35F2N7O3, 532. found 532.
Reaction SMILES: [F:1][C@@:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]([CH3:37])([CH3:36])[S:3]2(=[O:39])=[O:38]>C1COCC1>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][CH2:12][C@@:2]3([F:1])[S:3](=[O:39])(=[O:38])[C:4]([CH3:37])([CH3:36])[C:5]([N:21]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:6][C@:7]3([CH3:20])[C:8]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@@]2(F)S(=O)(=O)C1(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@@]2(F)S(=O)(=O)C1(C)C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A mixture of tert-butyl N-[(4aR,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (490 mg, 0.857 mmol) and pd/c (274 mg, 0.257 mmol) in THF (5.7 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (460 mg, 0.850 mmol, 99% yield) as a white foam. MS m/z=564.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:18]#[N:19].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:18]#[N:19])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl (35.0 g, 0.105 mol) and sodium cyanide (5.4 g, 0.110 mol) were dissolved in a mixture of ethanol (228 ml) and water (25 ml), then heated at 50° C. for 3 hours. The solution was concentrated under vacuum and the residue was suspended in ethanol/water 1/1 v/v (35 ml) and cooled at 0-5° C. for 30 minutes. The obtained solid is filtered and dried at 40° C. under vacuum. The crude product was suspended in ethanol (56 ml) at 20 to 25° C. for 30 minutes, filtered and dried at 40° C. under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-cyanomethyl-biphenyl was obtained as a light brown powder (16.8 g, 57% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:27]2)=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Yield: 95.2 %

Procedure:
Using 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:13]Br>Cl>[Br:13][C:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: BrBr
Agent: Cl
Product: Brc1cnc(N2CCNCC2)nc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To an ice-cooled solution of 1-(2-pyrimidinyl) piperazine (16.4 g, 0.1 mole) in 1N HCl (100 mL) was added dropwise bromine (15.98 g, 0.1 mole). After stirring at 0° for 0.5 h. the mixture was heated to 100° C. until dissipation of the red color had occurred. The mixture was filtered, cooled, made alkaline with 50% NaOH and extracted with Et2O. The dried extract (MgSO4) was concentrated in vacuo to provide 14.5 g (62%) of product, m.p. 73°-75° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH3:10]C1C=CC(S(N)(=O)=O)=CC=1>CO>[CH3:10][O:8][C:7](=[O:9])[CH2:6][C:2](=[CH2:1])[C:3]([OH:5])=[O:4]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Solvent: CO
Product: C=C(CC(=O)OC)C(=O)O
Temperature: 40 °C
Reaction time: 48 h
Yield: 6533.8 %

Procedure:
To a solution of 2-methylenesuccinic acid (5.0 g, 38.4 mmol) in MeOH (200 mL) was added p-toluenesulfonamide (100 mg). The mixture was stirred at 40° C. for 2 days. The mixture was concentrated to dryness. To the residue was added DCM (200 mL). The precipitate was removed by filtration and the filtrate was concentrated to dryness to give the product as a white solid (5.5 g, 99% yield). ESI MS: m/z 145.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 11.17 (bs, 1H), 6.48 (s, 1H), 5.85 (s, 1H), 3.71 (s, 3H), 3.36 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: COCCOC
Product: CN(Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.4 %

Procedure:
A mixture of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give the title compound as an oil (yield 275 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CI.[CH2:26](I)[CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:26][CH3:27])[C:11](=[O:23])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(c1cccc(Br)c1)=NCC(=O)N2
Reactant: CCI
Solvent: CI
Product: CCN1C(=O)CN=C(c2cccc(Br)c2)c2cc(OC)c(OC)cc21
Yield: 17 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 5-(3-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIak), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 17%. M: 122–126° C. 1H-NMR (CDCl3, 300 MHz): d 1.14 (s, 3H, CH3), 3.79–3.85 (m, 4H, 1H CH2+OCH3), 3.99 (AB system, ? d=0.62, JAB=13.9, 2H, —NCH2), 4.04 (s, 3H, OCH3), 4.78 (m, 1H, CH2), 6.65 (s, 1H Ar), 6.86 (s, 1H Ar), 7.26–7.31 (m, 2H Ar), 7.52–7.62 (m, 2H Ar), 7.86 (s, 1H Ar).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: O=S([O-])([O-])=S
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 287 %

Procedure:
Vanadium(IV) acetylacetonate (40 mg) was dissolved in ethanol (150 ml), to which 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20.0 g) was added and then 35% aqueous solution of hydrogen peroxide (6.14 g) was added dropwise at 20°-25° C., and the mixture was allowed to react at 20°-25° C. for about 5 hours. After completion of the reaction, a solution of sodium thiosulfate (2.7 g/16 ml) was added to the reaction mixture and stirred vigorously for about 10 minutes. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (8:2). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), heated (60°-70° C.), and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (18.1 g). (yield: 91.0%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][NH:16][C:3]1=[O:4]
Reactant: NN
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Solvent: O
Solvent: CCO
Product: CC1CC(c2ccccc2)=NNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid was added to a 100 ml single-necked round bottom flask followed by 3.0 ml (60 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (100%, 95% of ethanol should be fine also). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 C (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45° C. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of 2N NaHCO3, then washed with 60 ml Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give 7.15 g of white crystals (Syn. ID, WH-8-004). Yield, 95%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])SC.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12].C(N(CC)CC)C.Cl>CN(C=O)C>[NH2:10][C:9]1[C:6]([C:7]#[N:8])=[C:3]([S:2][CH3:1])[C:13]([C:11]#[N:12])=[C:14]([SH:15])[N:16]=1
Reactant: N#CCC(N)=S
Reactant: CSC(SC)=C(C#N)C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1c(C#N)c(N)nc(S)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 g (58.74 mmol) of [bis(methylthio)methylene]malononitrile and 6.5 g (64.61 mmol) of cyanothioacetamide are initially charged in 20 ml of DMF, and 16.4 ml (117.5 mmol) of triethylamine are added dropwise at room temperature. The mixture is stirred at room temperature for 8 h and allowed to stand for a further two days. The mixture is then added to 250 ml of 3 N hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and acetone and dried. This gives a yellow powder.