Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][N:27]=1)[C:19](N(OC)C)=[O:20].BrC1C=C(C(C2C3C(Cl)=NC=NC=3N(C(C)C)C=2)=O)C=NC=1>>[Cl:11][C:9]1[C:10]2[C:2]([C:19]([C:18]3[CH:25]=[CH:26][N:27]=[C:16]([Cl:15])[CH:17]=3)=[O:20])=[CH:3][N:4]([CH:12]([CH3:14])[CH3:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Agent: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2ccnc(Cl)c2)c2c(Cl)ncnc21

Procedure:
The title compound was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.5 g, 23.7 mmol) and 2-Chloro-N-methoxy-N-methyl-isonicotinamide (5.7 g, 28.4 mmol) by procedures analogous to those described for the preparation of (5-Bromo-pyridin-3-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone. MS: 295.8 (MH−); HPLC Rf: 2.0 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=1.Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28].[OH-].[Na+]>O>[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=1)(=[O:29])[CH3:28]
Reactant: NC(=O)c1ccc(OCCNCC(O)COc2cccc(N)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(OCC(O)CNCCOc2ccc(C(N)=O)cc2)c1

Procedure:
An aqueous mixture consisting of 10 g. of 1-(3-aminophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol in 150 ml. of water was adjusted to pH 4-5 with dilute hydrochloric acid and then stirred vigorously for several minutes in order to effect complete solution. At this point, 3 g. of acetic anhydride were added to the mixture in a dropwise manner and the pH of the resulting solution was simultaneously maintained within the aforestated pH range by means of dilute aqueous sodium hydroxide. After further stirring the spent reaction mixture for a period of 1 hour, it was subsequently basified with additional dilute aqueous sodium hydroxide solution and the resulting solid precipitate with formed at this point was thereafter collected by means of suction filtration to give 1-(3-acetamidophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol as a white crystalline base, m.p. 164°-165°C. The analytical sample was then recrystallized from aqueous ethanol, but the melting point remained constant.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35](C1N=C(C(O)=O)C(NC)=C(C)N=1)C.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH2:32]([N:31]([CH3:35])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: CCc1nc(C)c(NC)c(C(=O)O)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CCN(C)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-(Ethyl-methylamino)-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-ethyl-methylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy}-propyl]-acetamide; LC-MS: tR=0.98 min; [M+H]+=471.26.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][O:9]C(C)(C)[O:7][C@H:6]1[CH:13]=[CH2:14])C=C.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:9][CH2:10][C@H:5]1[C@H:6]([OH:7])[CH:13]=[CH:14][CH2:1][O:4]1
Reactant: C=CCO[C@@H]1COC(C)(C)O[C@H]1C=C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@@H]1OCC=C[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (48 mg, 0.28 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc.
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:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].Cl.C(O)C>O>[N+:17]([C:20]1[CH:21]=[C:22]([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:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3 mg, 2 mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2 mmol), concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL) was reflued for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→3:1) to give the title compound (631.5 mg, 94.7%) as a light yellowish white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[OH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N+:1]([O-:20])=[CH:2][CH:3]=[CH:4]2
Reactant: Oc1cccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
8-Quinolinol (351 g, 2.42 mol) was dissolved in dichloromethane (3.5 L) and, under ice-water cooling, meta-chloroperbenzoic acid (675.3 g, 2.74 mol) was added thereto in portions, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration and was washed with dichloromethane. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue, 2% aqueous ammonia (2.1 L) was added and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with purified water, and dried under reduced pressure to obtain 8-hydroxyquinoline-N-oxide (318.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].C(N)(=[S:15])C>Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]([NH2:7])=[S:15]
Reactant: COc1ccc(C#N)cc1OC
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=S)cc1OC
Temperature: 90 °C
Yield: 61.9 %

Procedure:
25 g of 3,4-dimethyoxybenzonitrile and 23 g of thioacetamide were dissolved in 120 ml of 10% hydrochloric acid-DMF. The solution was heated at 90° C. for 3 hours. The solution was further heated at 130° C. for 5 hours to conduct a reaction. The solvent was removed by distillation. The residue was washed twice with 100 ml of diethyl ether. Similar washing was conducted with 100 ml of water. The resulting crystals were collected by filtration and dried. Recrystallization from methanol was conducted to obtain 18.7 g of 3,4-dimethoxythiobenzamide as light brown columnar crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)[CH3:2].[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:1]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:2]=[CH:16]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
15 g of 3-acetylbenzoic acid is converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([NH2:34])=[N:36][CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.20 g, 73%). MS (ISP) 559.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:29](Cl)=[O:30])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:29]([C:26]3([C:21]4[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=4)[CH2:28][CH2:27]3)=[O:30])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Solvent: c1ccncc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (0.3 mL of a 0.324 M solution in pyridine 0.1 mmol) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 M solution in pyridine, 0.2 mmol) was added in one portion. After the mixture was stirred at room temperature for 3 d, the reaction was purified by hplc to afford the title compound. MS(ES) m/e 439 [M+H].
Reaction SMILES: C[C@H]1[O:12][C:10](=[O:11])[C:9]2[C:4](=[C:5](Cl)[CH:6]=[C:7]([C:14](N[C@H](C(O)=O)CC3C=CC=CC=3)=[O:15])[C:8]=2[OH:13])[CH2:3]1.C[O:30]C(C(C(OC)=O)CC(=O)CC)=O.OC=CC(=O)C.[Na]>>[OH:13][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[C:4]([CH3:3])[CH:5]=[CH:6][C:7]=1[C:14]([OH:15])=[O:30]
Reactant: C[C@@H]1Cc2c(Cl)cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)c(O)c2C(=O)O1
Reactant: CCC(=O)CC(C(=O)OC)C(=O)OC
Agent: CC(=O)C=CO
Agent: [Na]
Product: Cc1ccc(C(=O)O)c(O)c1C(=O)O

Procedure:
A method of synthesis of Ochratoxin A comprising: reacting dimethyl-3-oxo-pentane-dicarboxylate with sodium hydroxymethyleneacetone to provide the dimethyl ester of 2-hydroxy-4-methylbenzene-1,3-dioic acid;
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:40]>CO.C1COCC1>[ClH:40].[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)[C:25]([C:22]2[N:23]=[C:24]3[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[N:26]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCN(C)C)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CCN(C)C)c2c1
Reaction time: 3 h

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(1-(2-(dimethylamino)ethyl)-6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (127 mg, 0.23 mmol) in 5 mL of methanol and 1 mL of THF was added 1 mL of concentrated HCl, then stirred for 3 hours. The precipitate was filtered and filter cake was washed with 2-methoxy-2-methylpropane (5 mL) to give 25 mg of 2-(1-(2-(dimethylamino)ethyl)-6-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride. LCMS: (M+H)+=436; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 10.19 (s, 1H), 9.18 (s, 1H), 8.47 (d, 1H, J=8.1 Hz), 8.37 (s, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.17 (d, 1H, J=8.4 Hz), 4.93 (s, 2H), 3.70-3.63 (m, 4H), 2.89 (s, 6H), 2.50 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:27][CH3:28])[C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:23]([C:22]1[CH:25]=[C:18]([CH:17]([O:16][CH3:15])[O:27][CH3:28])[CH:19]=[CH:20][C:21]=1[F:26])[OH:24]
Reactant: COC(OC)c1ccc(F)c(C=O)c1
Reactant: c1ccc2scnc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1ccc(F)c(C(O)c2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A total of 1.08 g of benzothiazole was dissolved in 15 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 6.4 ml of 1.56 M solution of n-butyllithium in hexane was added. After stirring for 5 minutes, 8 ml of a solution of 1.35 g of 5-(dimethoxymethyl)-2-fluorobenzaldehyde in dry tetrahydrofuran was added, followed by stirring for 10 minutes. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 1.8 g of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:28][OH:29])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Yield: 51.2 %

Procedure:
13 g (39.5 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were stirred with 7.5 g (71 mmol) of sodium carbonate and 5.7 g (82 mmol) of hydroxylamine hydrochloride in 200 ml of ethanol and 40 ml of water at 50° for 1 hour and at 75° for 10 minutes. After dilution with 50 ml of water the suspension was suction filtered, whereupon the crystals were dried. There were obtained 7.33 g (51%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of m.p. 265°-266°.
Reaction SMILES: C[O:2][C:3](=[O:51])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[N:52]([C@@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])=[C:53]=[O:54]>C(Cl)Cl>[CH:45]1([CH2:44][O:43][C:40]2[CH:41]=[CH:42][C:37]([C@H:35]3[CH2:34][O:33][C:29]4=[CH:30][C:31]5[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]6[CH:7]=[CH:8][C:9]([C:12]7[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=7[CH3:19])=[CH:10][CH:11]=6)[C:3]([OH:2])=[O:51])=[O:22])[N:24]([C:53](=[O:54])[NH:52][C@@H:55]([C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=6)[CH3:56])[CH2:25][C:26]=5[CH:27]=[C:28]4[O:36]3)=[CH:38][CH:39]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester in DCM was added ((R)-1-isocyanato-ethyl)-benzene (5 eq.) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 824.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].CS(C)=[O:22]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(F)cc1

Procedure:
Bis-(4-fluorophenyl) sulphone (100 g; 0.394 mole), potassium hydroxide solution (91.98 g; 0.787 mole KOH) and dimethyl sulphoxide (400 cm3) were stirred together in a stainless steel vessel under nitrogen at 57° C for 24 hours. Two liquid phases remained throughout the reaction. The reaction mixture was diluted with water and twice extracted with diethyl ether to recover non-phenolic material (9 g). The aqueous phase was then acidified and the phenolic component (86 g; m.p. 150°-154° C) was extracted with more ether. By subliming this product under a diffusion pump at 180° C, followed by recrystallisation from toluene (400 cm3), 4-(4-fluorophenylsulphonyl)phenol (72.5 g) was obtained, m.p. 158°-159° C. The potassium salt was obtained from this phenol as a very pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.[Xe](F)[F:21]>C(#N)C.C(OCC)(=O)C>[F:21][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:7]=1[CH:6]=[CH:5]2
Reactant: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)cc3c21
Reactant: F[Xe]F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)c(F)c3c21
Reaction time: 18 h
Yield: 8 %

Procedure:
To a solution of N-{2-[(8S)-2-methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl]ethyl}acetamide (1.01 g, 3.91 mmol) in acetonitrile (39.2 mL) was added xenon difluoride (728 mg, 4.30 mmol) under ice-cooling, and the mixture was stirred for 18 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0) and preparative TLC (methanol/ethyl acetate=10/90) to give the title compound (86.4 mg, yield 8.0%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:21])[CH2:14][O:13][C:12]([CH3:20])([C:15](OCC)=[O:16])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>>[CH2:1]([O:8][CH2:9][C:10]1([CH3:21])[CH2:14][O:13][C:12]([CH3:20])([C:15]([NH2:22])=[O:16])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)C1(C)OCC(C)(COCc2ccccc2)O1
Product: CC1(COCc2ccccc2)COC(C)(C(N)=O)O1

Procedure:
Ethyl 4-benzyloxymethyl-2,4-dimethyl-1,3-dioxolan-2-carboxylate (5.0 grams) and concentrated aqueous ammonia solution (50 milliliters, 0.880 S.G.) were stirred together at room temperature for 3 days. The white solid formed was filtered off, washed with water and recrystallised from cyclohexane to give the desired product as an isomer mixture melting point 72°-92° C.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[N+:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:19]=[C:20]([NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:8][CH2:9][C:10]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: N[C@@H]1CCCc2ccccc21
Product: O=[N+]([O-])c1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 80.2 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.894 g, 12.0 mmol; HPLC: 4.446 min) and (R)-1-aminotetralin (CAS 21966-60-9) (1.767 g, 12.0 mmol; HPLC: 0.390 min) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (3.11 g, 80%, HPLC 2.211 min), MS (ISP) m/e=324.2 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[H][H]>C(O)C.[Pd]>[CH2:13]([C:11]1[NH:12][C:4]2[C:5]([N:10]=1)=[N:6][C:7]([CH2:8][OH:9])=[CH:2][CH:3]=2)[CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc2nc(CO)ccc2[nH]1
Yield: 92.5 %

Procedure:
0.25 g(0.00088 mole) of 6-bromo-2-butyl-5-hydroxymethyl-1H-imidazo[4,5-b]pyridine obtained in step 6 of Example 1 was dissolved in 10 ml of ethanol and to the resulting solution was added 0.03 g of 10% palladium/activated carbon. The resultant was reacted at room temperature for 3 hours under about 3 atm of hydrogen using a hydrogenation apparatus. The reaction solution was filtered through Cellite with washing with 10% methanol/ethyl acetate(10 ml×3) and concentrated under reduced pressure to obtain 0.167 g of the title compound(yield 93%).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].Cl[C:12]1[C:22](Cl)=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1>CN(C=O)C>[CH2:1]([S:3][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)c1cc(Cl)c(Cl)c(-c2cc(C)no2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(SCC)c(-c2cc(C)no2)c1C
Temperature: 0 °C
Yield: 43.2 %

Procedure:
Into a 250-ml round-bottomed flask were placed 0.311 g of ethyl mercaptan, 0.018 g of water and 6 ml of DMF, and then 0.346 g of potassium carbonate and 0.314 g of ethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate were adder The resulting mixture was stirred with a magnetic stirrer at room temperature for 6 hours under the irradiation of 40W fluorescent light. The reaction solution was poured into 25 ml of ice-water, and extracted with 25 ml of diethyl ether. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained crude product was purified on silica gel column chromatography (elution with n-hexane/ethyl acetate=95/5) to give 0.132 g of the title compound as white crystals. Melting point: 39-40° C.