Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+:5].[O-]S([O-])=O.[Na+].[Na+].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>O>[Na+:5].[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(S(=O)[O-])cc1
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To a solution of 0.26 g (3.2 mmol) of NaHCO3 and 0.4 g (3.2 mmol) of Na2SO3 in water (1.5 mL) were added 0.4 g (1.6 mmol) of 4-(methylsulfonyl)-benzenesulfonyl chloride. The reaction was heated at 80° C. for 3 h. The solvent was removed under reduced pressure. The crude material was suspended in boiling ethanol (20 mL) and the inorganic solids were removed by filtration. The filtrate was concentrated under reduced pressure to afford 0.14 g of 4-methanesulfonyl-benzenesulfinic acid sodium salt.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([C:20]([O:22]C(C)C)=[O:21])[C@@H:12]([OH:19])[C:13]([O:15]C(C)C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[C:20]([C@@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:12]([OH:19])[C:13]([OH:15])=[O:14])([OH:22])=[O:21]
Reactant: CC(C)OC(=O)[C@@H](CCOCc1ccccc1)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](CCOCc1ccccc1)[C@@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
isopropyl 5-O-benzyl-3,4-dideoxy-3-(isopropoxycarbonyl)-L-threo-pentonate (7 g, 19.8 mmol) was taken in THF (50 mL), cooled to 0° C. and was treated with KOH (5.5 g, 99 mmol) in water (50 mL). The resulting mixture was stirred at RT for 3 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was then further extracted with EtOAc (2×100 mL), washed with water, dried over Na2SO4 and then concentrated to give the title product as colorless liquid (3.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)nn1
Product: c1ccc(-c2ccc(-c3ccc(-c4ccccn4)nn3)nn2)nc1

Procedure:
Specifically, it was envisioned, firstly, to use the 6,6′-dichloro-3,3′-bipyridazine dimer 17, which, when subjected to Stille heterocoupling in the presence of two equivalents of 2-tributylstannylpyridine 18, should produce the expected 6,6′-bis(pyridin-2-yl)-3,3′-bipyridazine 19.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:40]([NH:39][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)=[O:41])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)Nc2cc3cc(c2)Nc2nc(ncc2Cl)Nc2cccc(c2)CC3)cc1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 52% yield. LCMS for C26H21ClN7O (M+H)+: m/z=482.2. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 9.49 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.12 (s, 1H), 7.86 (m, 1H), 7.67 (m, 2H), 7.59 (m, 2H), 7.33 (m, 1H), 7.23 (m, 1H), 7.05 (m, 2H), 6.83 (m, 2H), 2.82 (m, 4H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH:11]S(C1C=CC(C)=CC=1)(=O)=O>ClC1C=CC=CC=1Cl>[C:1]1([NH:7][C:8]([NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Solvent: Clc1ccccc1Cl
Product: NC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate (1.19 g, 0.01 mol) and N-methyl-4-methylbenzene sulfonamide (1.85 g, 0.01 mol) were dissolved in 1,2-dichlorobenzene (20 ml) and refluxed for 40 hrs. After cooling, the solvent was evaporated in vacuo to give a viscous oil that crystallized on standing to give N-methyl-N-4-methylphenyl-N*-phenyl urea mp 63–65° C. MS m/z 304. (M+ calcd for C15H16N2O3S=304). H NMR (300 Mhz, CDCl3) d 2.43 (s, 3, CH3), 2.65 (s, 3, CH3), 7.33 (m, 5, aromatic), 7.48 (m, 1, aromatic), 7.75 (m, 3, aromatic).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([N:22]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)c(F)c1
Yield: 90.3 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (300 mg, 1.18 mmol), 3,4-difluoroaniline (0.13 ml, 1.3 mmol) and p-toluenesulfonic acid (25 mg) in toluene (80 ml) was heated to reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude dark orange solid (700 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(3,4-difluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (370 mg, 90%) as a white solid: mp (DSC) 151° C. Anal Calc'd. for C18H15NSO2F2 : C, 62.24; H, 4.35; N, 4.03. Found: C, 62.08; H, 4.52; N, 4.05.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])[CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12
Yield: 88.9 %

Procedure:
0.50 g (12.6 mmol) of 60% strength sodium hydride in paraffin oil is introduced under argon into 20 ml of THF at room temperature. A solution of 2.0 g (8.40 mmol) of 5-bromo-3-isopropyl-1H-indole (Example X) in 20 ml of THF is added dropwise and the mixture is stirred until evolution of gas can no longer be detected. 2.03 g (13.44 mmol) of tert-butyl(chloro)dimethylsilane are subsequently added dropwise. After a short reaction time a precipitate deposits. The batch is stirred for 3 h at room temperature. It is treated with 200 ml of water. The aqueous phase is extracted twice with ethyl acetate, and the combined org. phases are dried and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent: cyclohexane). 2.63 g (89%) of 5-bromo-1-[tert-butyl(dimethyl)silyl]-3-isopropyl-1H-indole are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:28][O:27][C:26]4=[O:25])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)c(F)c3)CC2)c(C)c1
Yield: 13.8 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.96 g) described in Preparation Example 66 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.33 g), the title compound (367 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH:17]1[CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:19][CH2:18]1
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: C1CN1
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])c(N2CC2)c([N+](=O)[O-])c1

Procedure:
Reaction of 4-chloro-3,5-dinitrobenzamide (Ullman et al., Annalen, 1909, 366, 82) with aziridine in EtOAc as above for 2 h gave 19: mp 228-231° C., 1H NMR [(CD3)2SO] δ8.68 (s, 2H, H-2,6), 8.33, 7.75 (2 br s, 2H, CONH2), 2.36 (s, 4H, aziridine-H), 13NMR 163.77 (s), 145 16 (s), 143.40 (s), 128.43 (d), 125.89 (s), 30 61 (t). Anal. Calcd for C9H8N4O5: C, 42.86;H, 3.20, N, 22.22. Found: C, 43.15,H, 2.98; N, 22.13%.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: CC(C)O
Product: CC(C)c1ccccc1

Procedure:
The isopropanol obtained in this way was fed directly into a circulation reactor into which benzene was also fed. The alkylation took place in this circulation reactor at a pressure of about 45 bar abs, and the reactor had a temperature profile of from 200 to 230° C. In a downstream phase separation vessel, the reaction mixture was separated into an organic phase and an aqueous phase. The aqueous phase, which is saturated with organic constituents, was distilled and the water-isopropanol azeotrope which was distilled off was recirculated to the circulation reactor. The organic phase from the phase separation vessel was partly recirculated to the circulation reactor, with the circulation ratio of recycled organic parts of the reaction mixture to starting materials fed into the reactor being 5:1. The other part of the organic phase of the reaction mixture was passed to three distillation columns connected in series. In the first distillation column, low boilers such as propene, benzene and unreacted isopropanol were separated off from the organic phase. These low boilers were fed back into the circulation reactor as alkylation reagent. The bottoms from this column were passed to the next column in which cumene was separated from the remaining organic phase. This cumene was fed directly to the oxidation for preparing cumene hydroperoxide (CHP). The bottoms from the distillation column were fed into the third distillation column in which diisopropylbenzene and/or polyisopropylbenzenes were separated from the remaining organic, high-boiling compounds. The bottoms were passed to thermal utilization. The multiply alkylated benzenes were conveyed to a tube reactor into which benzene was also fed. A transalkylation reaction was carried out at a temperature of about 220° C. and a pressure of 40 bar abs in the presence of zeolites as catalyst to form cumene from benzene and multiply alkylated benzenes. The reaction mixture from this reactor was conveyed back to the first distillation column after the alkylation reactor so as to be able to separate unreacted benzene from the reaction mixture once again, then to separate the cumene from the reaction mixture in the next distillation column and to feed it to the oxidation.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([F:18])[CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, off-white solid (69 mg, 81%), MS (ISP) m/z=343.4 [(M+H)+], mp 225° C., was prepared in accordance with the general method of example 1 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH2:17](O)C>[Pd]>[NH2:8][C:5]1[C:4]([CH3:17])=[C:3]([S:11]([N:14]([CH3:15])[CH3:16])(=[O:12])=[O:13])[CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Reactant: CCO
Agent: [Pd]
Product: Cc1c(N)cccc1S(=O)(=O)N(C)C
Reaction time: 16 h
Yield: 98 %

Procedure:
A suspension of 2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (2.0 g, 8.20 mmol) and Pd/C (0.30 g) in ethanol (40 mL) was stirred under an H2 balloon for 16 h. The suspension was filtered through Celite and washed with methylene chloride. The filtrate was concentrated to provide 3-amino-2-methyl(N,N-dimethyl) benzenesulfonamide (1.72 g, 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:1][C:2]1[C:8]([C:9]2([CH3:12])[CH2:10][CH2:11]2)=[CH:7][C:5]([NH:6][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: CCOC(=O)C=O
Reactant: COc1cc(Cl)c(C2(C)CC2)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(C2(C)CC2)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 4-chloro-2-methoxy-5-(1-methylcyclopropyl)aniline (450 mg, 2.13 mmol) in MeOH (20 mL) at RT, AcOH (3 drops) and ethyl glyoxalate (326 mg, 3.19 mmol, 50% in toluene) were added. The mixture was stirred at RT for 2 h and then sodium cyanoborohydride (403 mg, 6.39 mmol) was added to the mixture. The resulting mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to RT, and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product (636 mg). ESI-MS m/z: 298.2[M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[O:25]=[C:26]1[C:31]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:30]=2[N:29]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:27]1>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([C:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:29]=[C:28]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:27][C:26](=[O:25])[C:31]=3[CH:32]=2)=[O:37])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Reactant: COc1c(-c2ccccc2)cn2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1c(-c2ccccc2)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
2.25 ml (16.12 mmol) of triethylamine and 3 g (13.44 mmol) of 1-methoxy-2-phenylindolizine (according to the method described in WO 03/084956) diluted in 20 ml of dichloroethane are added, under an inert atmosphere at ambient temperature, to 4.22 g (14.78 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carboxylic acid (described in WO 06/097625) in 100 ml of dichloroethane. After stirring overnight at ambient temperature, the reaction medium is filtered, and rinsed with dichloroethane. The filtrate is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is filtered through a silica pâté, elution being carried out with dichloromethane. 4.4 g of a yellow solid are obtained.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O>>[CH3:30][O:29][C:12]1[CH:11]=[C:10]([CH:8]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:28]=[CH:27][C:13]=1[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[C:23]([F:24])([F:26])[F:25]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
The title compound was prepared using rhodanine and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile according to General Procedure B. 1H NMR (400 Hz, CDCl3) δ 9.31 (bs, NH), 7.98 (bs, 1H), 7.68 (dd, 1H), 7.64 (s, 1H), 7.18 (m, 3H), 6.77 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:29](=[O:30])[N:16]3[C:17]([C:26]([O-:28])=[O:27])=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:29](=[O:30])[N:16]3[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)N[C@H]1C(=O)N2C(C(=O)[O-])=C(C3CCCC3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N[C@H]1C(=O)N2C(C(=O)O)=C(C3CCCC3)CS[C@H]12

Procedure:
A solution of 244 mg of the ester of Step A in 2.5 ml of trifluoroacetic acid stood at room temperature for 8 minutes and was then evaporated to dryness under reduced pressure. The residue was taken up in benzene and was evaporated to dryness. The residue was triturated with ether and crystallization was effected. The crystals were vacuum filtered, washed with ether and dried to obtain 174 mg of DL cis 7-p-nitrophenylacetamido-3-cyclopentyl-3-cepheme-4-carboxylic acid melting at 170°C. The product occurred as colorless crystals slightly soluble in ethanol and insoluble in ether and water.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7]>C(#N)C>[N:3]([C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7])=[C:2]=[S:1]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N=C=S)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Potassium thiocyanate (1.08 g) is added to a solution of methyl 4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). After stirring for 1 hour at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The solid obtained is purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) in order to produce the expected compound (2.1 g; 95% yield).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:18]([O:25][CH3:26])(OC)(OC)OC>C(O)(=O)C>[CH2:11]([O:10][C:9]1[C:2]2[N:1]=[C:18]([O:25][CH3:26])[N:4]([CH3:5])[C:3]=2[CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(OCc2ccccc2)c1N
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COc1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-benzyloxy-N-methylaniline (318.5 mg) in acetic acid (3.2 ml) was added tetramethyl orthocarbonate (223.0 μl) at ambient temperature, and the reaction mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo, and to the residue were added ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was triturated with n-hexane-diisopropyl ether to give 4-benzyloxy-2-methoxy-1-methyl-1H-benzimidazole (273.3 mg) as a pale brown solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32](=[N:41][C:42]#[N:43])OOC3C=CC=CC=3)[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2].[CH3:44][NH:45][CH3:46]>C(O)(C)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]([N:45]([CH3:46])[CH3:44])=[N:41][C:42]#[N:43])[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CNC
Solvent: CC(C)O
Product: CCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 6d from 4'-[[2-ethyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and dimethylamine in isopropanol.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(Cl)cc(-c2cccnc2)n1
Temperature: 50 °C

Procedure:
Under inert atmosphere, 27 g 6-hydroxy-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine in 125 mL phosphorous oxychloride is suspended, and 11.5 g potassium carbonate is added portionwise. The mixture is heated to 50° C. for 6 hours under stirring. At the end of the reaction, the suspension is concentrated to residue, it is diluted with water, cooled, and the precipitate is filtrated. Upon drying, 26.6 g of product with HPLC purity of 80% (A %) is achieved, identified through LC-MS and 1H-NMR. Such raw product also contains a by-product, in an amount of about 15% (A %) which, during the following reduction reaction, still yields the desired product (4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine). The raw material, therefore, is employed as is in the example 13.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>CO>[CH:11]1([CH:17]=[C:5]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: O=CC1CCCCC1
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(=CC1CCCCC1)C(=O)C1CC1
Reaction time: 48 h
Yield: 74.6 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-oxopropanoate (3.00 g) and cyclohexanecarboxaldehyde (2.84 g) in MeOH (30 ml) was added piperidine (0.209 ml) at room temperature. The mixture was stirred for 48 h. The solvent was evaporated off, and the residue was chromatographed on a silicagel column chromatography (EtOAc-hexaens, a linear gradient of EtOAc from 0 to 15% over 60 min) afforded methyl 3-cyclohexyl-2-(cyclopropylcarbonyl)acrylate as a colorless oil (3.72 g).