Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[C:11](=[O:27])[C@:10]([CH2:29][CH:30]=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl([O-])=[O:33].[Na+].P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.CC(=CC)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)acetaldehyde (Example 110, Step C) (25 mg, 55 μmol) in a mixture of 2-methylpropan-2-ol (1.0 mL) and 2-methyl-2-butene (55 μL, 2.0 M soln in THF, 0.11 mmol) was added a solution of sodium chlorite (37 mg, 0.55 mmol) and sodium dihydrogen phosphate (4.8 mg, 50 μmol) in 550 μL of water at room temperature. The reaction mixture was stirred for 1 hour before it was quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (10% MeOH/DCM) provided the title compound as a colorless solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28]#[N:29])=[C:11]([CH3:30])[O:10][N:9]=1>CS(C)=O>[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28](=[N:2][OH:3])[NH2:29])=[C:11]([CH3:30])[O:10][N:9]=1
Reactant: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C(N)=NO
Temperature: 65 °C
Yield: 24 %

Procedure:
A neutral 2 M solution of hydroxylamine hydrochloride and NaOH in water (0.5 mL, 1.0 mmol) was added to 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 0.017 mmol) in DMSO (0.5 mL) and stirred at 65° C. over night. Crude LCMS on the reaction mixture show 41% product, 38% amide and 21% starting material. Purification using preparative HPLC gave E5 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carboximidamide (1.42 mg, 24%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 356.2 (M+H), 354.21 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.11 m 2H, 6.85 m 2H, 2.77 nm 2H, 2.11 s 3H, 1.88 s 3H, 1.75 m 2H, 0.98 t (7.5 Hz) 3H.
Reaction SMILES: FC(F)OC1C=C2C(=CC=1)N(CCCN(C)C)N=C2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([NH:49][C:50]3([CH3:53])[CH2:52][CH2:51]3)=[O:48])=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:22]2=[N:21][CH:20]=1.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>ClCCl>[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58].[CH3:53][C:50]1([NH:49][C:47]([C:25]2[C:23]3=[N:24][CH:19]=[CH:20][N:21]=[C:22]3[NH:27][CH:26]=2)=[O:48])[CH2:51][CH2:52]1
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC2(C)CC2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(NC(=O)c2c[nH]c3nccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.3 mmol) in 3 mL of dichloromethane was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature overnight. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 245-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide trifluoroacetate (20 mg, 7%) as a yellow solid. LCMS: (M+H)+=484; 1H NMR (300 MHz, CD3OD): δ 9.04 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.61 (d, 1H, J=9.0 Hz), 7.29 (dd, 1H, J1=9.0 Hz, J2=2.1 Hz), 6.78 (t, 1H, J=73.8 Hz), 4.56-4.52 (m, 2H), 3.19-3.12 (m, 2H), 2.79 (s, 6H), 2.39-2.33 (m, 2H), 1.47 (s, 3H), 0.93-0.89 (m, 2H), 0.76-0.72 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH2:30])[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])([OH:21])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:9][CH:8]=1)=[O:6])[O:3][CH3:4].C([O-])=O.[NH4+]>[Pd].O1CCCC1.C(O)C>[CH3:1][N:2]([C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:30])[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])([OH:21])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:11][CH:12]=1)=[O:6])[O:3][CH3:4]
Reactant: C=C(c1ccc(C(=O)N(C)OC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CON(C)C(=O)c1ccc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Yield: 54.6 %

Procedure:
A mixture of N,O-dimethyl-4-(2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]-3-buten-3-yl) benzene hydroxamic acid (0.9 g, 2.2 mmol-see Preparation 50), 10% palladium on charcoal (0.2 g) and ammonium formate (0.68 g, 11 mmol) was suspended in a tetrahydrofuran/ethanol (1:1, 40 ml) solution and heated under reflux for 3 hours. The cooled suspension was filtered through "Arbocel" and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with saturated sodium carbonate solution (20 ml) and brine (20 ml), then dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by gradient elution with dichloromethane followed by dichloromethane/methanol (39:1). Fractions containing the desired product were combined and evaporated under reduced pressure to yield the title compound (0.5 g, 55%) as a colourless foam.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]([C:10]1[N:11]=C(C(O)=O)[S:13][CH:14]=1)([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[CH:7]([C:10]1[N:11]=[C:1]([C:2]([Cl:4])=[O:3])[S:13][CH:14]=1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1csc(C(=O)O)n1
Solvent: Cc1ccccc1
Product: CC(C)c1csc(C(=O)Cl)n1
Temperature: 25 °C

Procedure:
Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The crude material was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:21][C:22]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 0.5 h

Procedure:
6.7 mL (40.32 mmol) of trifluoromethanesulfonic acid anhydride dissolved in 5 mL dichloromethane is added dropwise between −10° C. to −5° C. to a solution of 7.5 g (36.65 mmol) of 3-chlorobiphenyl-4-ol and 6.1 mL (44 mmol) of triethylamine in 100 mL of dichloromethane. Then the mixture is stirred for 30 minutes. The reaction solution is then extracted with water, the organic phase is separated off and filtered through an Alox frit. The filtrate is concentrated by evaporation. Yield: 12 g (97% of theory); C13H8ClF3O3S (M=336.72); calc.: molecular ion peak (M+H)+: 336/338 (Cl); found: molecular ion peak (M+H)+: 336/338 (Cl); Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate (5:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15](=[O:26])/[C:16](/[C:20]3[N:21]=[C:22]([NH2:25])[S:23][CH:24]=3)=[N:17]\[O:18][CH3:19])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].Cl[C:29]1[N:30]([CH3:50])[N:31]=[C:32]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33](=[O:35])[N:34]=1.C(N(CC)CC)C.C(O)=O>CN(C=O)C>[NH2:25][C:22]1[S:23][CH:24]=[C:20](/[C:16](=[N:17]/[O:18][CH3:19])/[C:15]([NH:14][CH:13]2[C:12](=[O:27])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][NH:1][C:29]4[N:30]([CH3:50])[N:31]=[C:32]([O:36][CH:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:33](=[O:35])[N:34]=4)[CH2:4][S:5][C@H:6]23)=[O:26])[N:21]=1
Reactant: Cn1nc(OC(c2ccccc2)c2ccccc2)c(=O)nc1Cl
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 3.5 h

Procedure:
A solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (200 mg.), 2,5-dihydro-3-chloro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazine (160 mg.) was triethylamine (200 ul.) in DMF (4 ml.) at 0° was allowed to stand for 3.5 hours. Formic acid (1 ml.) was added and the solvent was evaporated to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid which was used without further purification. nmr in solvent B:--3.52 (s, 3 H); 3.6 (s, 2 H); 4.04 (s, 3 H); 4.4 (s, 2 H); 5.18 (d, 1 H); 5.84 (d, 1 H); 7.1 (s, 1 H).
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@@H:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:35]2[C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2[C@@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 9.5 %

Procedure:
The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (Aldrich, 32.2 g, 200 mmol) were combined in DMF (50 mL), stirred at 50° C. under nitrogen for 16 hours, cooled and concentrated. The residue was diluted with ethyl acetate, treated with 1M HCl, stirred for 10 minutes and filtered to remove solids. The organic layer of the filtrate was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 1% ethyl acetate/hexane) to give the title compound (1.0 g, 10%) as the second eluting stereoisomer. MS (ESI+) m/z 526 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:22])[NH:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])=[C:9]([N+:19]([O-])=O)[CH:8]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][NH:4][C:3](=[O:22])[C:2]=2[CH3:1])[CH:12]=[CH:11][C:10]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH3:18]
Reactant: CC1=C(c2ccc(-n3ccnc3C)c([N+](=O)[O-])c2)CNC1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(c2ccc(-n3ccnc3C)c(N)c2)CNC1=O

Procedure:
1,5-Dihydro-3-methyl-4-[4-(2-methyl-1H-imidazol-1-yl)-3-nitrophenyl]-2H-pyrrol-2-one (7.3 g, 24 mmol) and tin (II) chloride dihydrate (28 g, 125 mmol) are combined in ethanol (330 mL), and the mixture is heated at reflux under a nitrogen atmosphere for 30 minutes. The mixture is cooled, made basic with saturated aqueous sodium bicarbonate, and filtered through celite. The filter cake is washed with ethanol, and the filtrates are evaporated. Chromatography of the residue on alumina provides the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CN1CCN(C)C1=O>[Cu]Cl.N1C2C(=CC=CC=2O)C=CC=1.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][OH:17])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: OCc1cccc(O)c1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 150 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
A mixture of 4-chlorobenzotrifluoride (27.1 g, 1.5 equiv), 3-hydroxybenzyl alcohol (12.4 g, 1 equiv), copper (I) chloride (0.2 g, 0.02 equiv), potassium carbonate (8.3 g, 0.6 equiv), 8-quinolinol (0.29 g, 0.02 equiv) and 1,3-dimethyl-2-imidazolidinone (50 mL) was stirred at 150° C. under argon for 3 days. After cooling, the residue was poured into water and extracted with ethyl acetate. Drying and evaporation, followed by chromatography (silica, dichloromethane) gave the title compound as a pale liquid (11.3 g). 1H-NMR (CDCl3) δ 1.88 (1H, t), 4.69 (2H, d), 6.97 (1H, m), 7.04 (3H, m), 7.17 (1H, m), 7.36 (1H, m), 7.57 (2H, m); MS (APCI−) found (M−1)=267; C14H11F3O2 requires 268.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([N:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([N:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCCC1
Agent: N
Product: CC(CS)C(=O)N(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0 %

Procedure:
To N-(3-Acetylthio-2-methylpropanoyl)-N-cyclohexylglycine (5.1 g, 16.9 mol) was added 100 ml of ammonia-saturated methanol, and the resulting solution stirred for 2.5 hours at room temperature under nitrogen. The solution was concentrated and the residue dissolved in methanol and passed through a column of AG-50W-X2 cation exchange resin. Those fractions showing a positive nitroprusside test were combined and concentrated. This material was then purified by medium pressure liquid chromatography eluting with ethyl acetate/hexane/acetic acid, 48:48:2 to give 0.7 g of N-(3-mercapto-2-methylpropanoyl)-N-cyclohexylglycine as an oil. The compound was characterized as its DCHA salt, prepared by dissolving the acid in ether and adding DCHA to pH 9. The salt was isolated as a white crystalline solid, m.p. 158°-160°.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([S:27]([OH:30])(=[O:29])=[O:28])[C:9]([CH:12]=[CH:13][C:14]2[C:15]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)([O-:5])=[O:4].[OH-].[K+:32].O=O.Cl>>[N+:20]([C:17]1[CH:16]=[C:15]([S:23]([O-:26])(=[O:25])=[O:24])[C:14]([CH:13]=[CH:12][C:9]2[C:8]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21].[K+:32].[K+:32]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: Cl
Agent: O=O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1000 g of 4.5% strength by weight sodium hydroxide solution and 3 g of 4,4'-dinitrostilbene-2,2'-disulphonic acid are initially taken at 70° C. 124 g of 87.2% strength finely powdered 4,4'-dinitrodibenzyl-2,2'-disulphonic acid and 430 g of 6.19% strength by weight aqueous potassium hydroxide solution are added in small portions (approximately 20 portions) at 70° C. 50 l/hour of oxygen and 20 l/hour of air are passed into the reaction mixture for the whole duration of the experiment. After the mixture has been stirred for a further 2 hours at 70° C., a further 6 g of 100% strength by weight potassium hydroxide solution are added and the mixture is neutralized with 210 g of 30% strength by weight hydrochloric acid. 145 g of moist dipotassium 4,4'-dinitrostilbene-2,2'-disulphonate, corresponding to 124.7 g of dry material are isolated by filtration. The yield is found to be 97.2% of theory according to analysis by means of the HPLC method.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:16]3[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCNC(=O)c1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c1CCN=C2c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Thirty-six (36) grams of 1-(4-chlorobenzoylamino)-2-(2-methylphenyl)ethane was dissolved in 180 ml of xylene and 100 ml of phosphorus oxychloride. While the solution was heated with stirring, 80 g of phosphorus pentoxide was added gradually, and the mixture was heated under reflux. The reaction mixture was poured into ice water. The aqueous layer was separated, and made weakly alkaline with ammonia water. Recrystallization of the precipitated oily product from n-hexane afforded 31 g of 1-(4-chlorophenyl)-5-methyl-3,4-dihydroisoquinoline as colorless prisms having a melting point of 66° to 67° C.
Reaction SMILES: C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3N(C=2C(O)=O)C=CS3)CC1.[CH3:27][C:28]([CH3:42])([CH3:41])[CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.[Br-].[CH2:44]([O:46][C:47]([C:49]1[N:56]2[C:52]([S:53][CH:54]=[CH:55]2)=[N:51][C:50]=1[CH2:57][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:48])[CH3:45].[H-].[Na+]>CS(C)=O>[CH3:27][C:28]([CH3:42])([CH3:41])[CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1/[CH:33]=[CH:57]/[C:50]1[N:51]=[C:52]2[N:56]([C:49]=1[C:47]([O:46][CH2:44][CH3:45])=[O:48])[CH:55]=[CH:54][S:53]2
Reactant: COc1cccc(C=O)c1OCC(C)(C)C
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC(C)(C)C)nc2sccn12
Yield: 73.2 %

Procedure:
This compound was prepared as described in Intermediate 1 by the reaction of 2-(2,2-dimethylpropoxy)-3-methoxybenzaldehyde (1.328 g, 5.984 mmol) with 5-ethyloxycarbonylimidazo[2,1-b][1,3]thiazol-6-yl-methyl(triphenyl)phosphonium bromide (3.0 g, 5.440 mmol) in the presence of sodium hydride (0.23 g, 5.984 mmol) in anhydrous DMSO (25 mL) to give 1.650 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 9H), 1.39 (t, J=6.9 Hz, 3H), 3.57 (s, 2H), 3.80 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 6.99-7.02 (m, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.46 (d, J=4.5 Hz, 1H), 7.67 (d, J=15.9 Hz, 1H), 7.94 (d, J=16.8 Hz, 1H), 8.12 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 415.33 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][CH:17]=[C:4]2[CH2:3]1.[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl.O>[I:18][C:17]1[N:16]=[CH:15][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: Cc1cccc2c1C(=O)N(C)Cc1cncn1-2
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc2c1C(=O)N(C)Cc1c(I)ncn1-2

Procedure:
15.85 g (69.7 mmol) of 4,5-dihydro-5,7-dimethyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 95° for 2.5 hours with 67 g (264 mmol) of iodine in 100 ml of N,N-dimethylformamide. The reaction mixture was then poured into 450 ml of water, treated with methylene chloride, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted six times with methylene chloride. The combined organic phases were washed three times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there was obtained 4,5-dihydro-3-iodo-5,7-dimethyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 106°-108°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH:12]([NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:16]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COCC(C)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
21 g (0.15 mol) of 1-fluoro-4-nitrobenzene and 42 ml of 2-amino-1-methoxypropane were introduced into a 150 ml three-necked flask. The mixture was stirred for 15 minutes and brought to the boiling point. After reaction for 2 to 3 hours, the reaction medium was poured onto ice. A yellow precipitate formed. This precipitate was filtered off, washed with water, and then successively washed with a minimum amount of ethanol, isopropyl ether, and petroleum ether. 27.8 g of expected product were isolated.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH2:35][CH:30]=[CH2:31])[C:20]=3[OH:26])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(Cl)cc(NC(=O)Cc2ccc(OC)c(OC3CCCC3)c2)c1O

Procedure:
A solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline (33 grams, 0.079 mol) in 330 milliliters of diphenyl ether was heated at 180° for 6.5 hours. This reaction mixture was combined with a second reaction mixture containing N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline and 250 milliliters of diphenyl ether which had been heated at 180° for 20 hours.