Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].S(Cl)(C)(=O)=O>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCN(CC)CC
Reactant: CCN(CC)C(CO)c1cccc2c(C)c(C)oc12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCN(CC)CC(c1cccc2c(C)c(C)oc12)N(CC)CC
Temperature: -30 °C
Yield: 50.8 %

Procedure:
0.8 g (2.7 mmol) of 2,3-dimethyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran, 2.67 ml (19.2 mmol) of triethylamine and 50 ml of dichloromethane are placed in a 100 ml round-bottomed flask. The solution is cooled to -30° C. using a dry ice bath and 99 ml (12.8 mmol) of mesyl chloride are added dropwise. The temperature is allowed to return to 0° C. and the solution is concentrated under vacuum. 20 ml of diethylamine are added to the residue and the solution obtained is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature and concentrated under vacuum, 50 ml of water are added and extraction is carried out with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 10% methanol in dichloroethane). 0.434 g (Yield: 55%) of 2,3-dimethyl-7-[1,2-di(diethylamino)ethyl]benzofuran is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:14][CH2:15][C:16](=O)[CH2:17]Cl>>[Cl:14][CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[O:7][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2nc(CCl)co2)c1
Temperature: 130 °C
Yield: 67.3 %

Procedure:
3-(Trifluoromethyl)benzamide (0.300 g, 1.59 mmol) and 1,3-dichloro-2-propanone (0.201 g, 1.59 mmol) were heated to 130° C. for 0.5 h. Then another 0.201 g of 1,3-dichloro-2-propanone (1.59 mmol) was added and the mixture was heated again at 130° C. for 1 h. After being cooled down, the residue was purified by radial chromatography (0-30% EtOAc-hexanes gradient) to afford the title compound (0.280 g, 67% yield): 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.58 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:22][N:23](C)C)[C:14](=O)[CH:15]3[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:27]N>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:22]=[N:23][NH:27][C:14]=2[CH:15]3[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-2-dimethylaminomethylene-4-methyl-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (1 mL) followed by hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-7-methyl-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.72, Method [1], MS (ESI) 352.0 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.47-7.43 (m, 2H), 7.27 (s, 1H), 5.2 (b s, 1H), 4.09 (d, J=4.94 Hz, 1H), 2.89 (q, J=7.14 Hz, 1H), 1.82-1.60 (m, 3H), 1.42-1.34 (m, 3H), 1.19 (d, J=7.14 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 149.9, 140.7, 139.0, 129.6, 128.7, 126.4, 115.6, 55.83, 48.6, 34.1, 31.1, 30.9, 21.8, 15.6 ppm.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[CH3:12]>C(O)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]([CH3:18])=[CH:16][C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:21])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 3-bromophenylhydrazine hydrochloride (2 g, 8.9 mmol) and ethyl-2,4-dioxovalerate (1.69 g, 10.7 mmol) in acetic acid (44 ml) was refluxed for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product, thus obtained, was purified by silica-gel column chromatography (4.8:0.2 hexanes/ethyl acetate) to give the product (2.34 g, 84%) as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:22])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[O:21])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1cc(N)ccc1Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)c(C)c2)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 5.58 g of 4-bromo-3-methylaniline in 20 ml of toluene and 5 ml of methylene chloride was added to a solution of 5.91 g of p-toluenesulfonyl isocyanate in 50 ml of toluene and 10 ml of methylene chloride under a nitrogen atmosphere. The mixture was stirred overnight and filtered, providing 9.19 g of the title product, m.p. 178°-180° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (88.0 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.CS([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=O)=O>CN(C=O)C>[F:3][C:4]([F:16])([F:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:26]2[CH:25]=[CH:24][N:23]=[CH:22][CH:27]=2)=[CH:11][CH:12]=1
Reactant: OCCc1ccc(OCC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(CCOc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of about one gram of 60% NaH (dispersion in oil) in 20 mL of dry DMF was added 5.2 g (0.023 m) of 2-[4-(2,2,2-trifluoroethoxy)phenyl]ethanol. The mixture was stirred at room temperature for 40 minutes, then 3.1 g (0.02 m) of methylsulfonyl pyridine was added. The mixture was stirred at room temperature overnight, then DMF was evaporated in vacuo, and the residue was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was separated, washed with saturated NaCl solution and filtered through phase separating paper. The product was concentrated to yield 6.2 g of crude product, which was adsorbed onto silica gel and chromatographed over silica gel 60 (230-400 mesh) using CH2Cl2 →50% EtOAc/CH2Cl2 to give the title product as an oil. Yield 2.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15](OCC)(=O)[C:16]([NH2:18])=[O:17].C[O-].[Na+]>C(O)CO>[N:1]1[C:2]2=[N:3][C:4]3[C:9]([CH:10]=[C:11]2[C:12](=[O:13])[NH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: CCOC(=O)C(N)=O
Reactant: NC(=O)c1cc2ccccc2nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: OCCO
Product: NC(=O)c1nc2nc3ccccc3cc2c(=O)[nH]1
Temperature: 170 °C

Procedure:
A mixture of 2-aminoquinoline-3-carboxamide (2.0 g., 1.15 millimoles) ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) and sodium methoxide (10 mg.) is heated at 170° C. for 1 hour. The product is precipitated by slow addition of ice methanol (50 ml.) to the hot reaction mixture followed by chilling in an ice bath. It is filtered off, washed with cold methanol and dried in vacuo. Yield = 0.768 g. (28%). M.P. 320° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: COC1(c2ccc(F)c(F)c2)CCNC1
Yield: 78.9 %

Procedure:
Preparation according to Example 1. (+)-1-benzyl-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.202 g, 0.66 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.38 g, 2.66 mmol) refluxed for 1 h, and methanol (20 ml) reflux 1 h Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.111 g, 78%). [a]D=+5.8° (methanol). MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (44), 183 (84), 171 (bp), 141 (45).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].C(OC(N1CCC(CN[C:30]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])=[S:31])CC1)=O)(C)(C)C>>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:30]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])=[S:31])=[O:7])([CH3:1])[CH3:3]
Reactant: CN(C)C=NC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: CN(C)C=NC(=S)NC[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester was prepared from (S)-2-(aminomethyl)-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester according to the procedure described in Example A (4-(3-dimethylaminomethylene -thioureidomethyl)-piperidine-1-carboxylic acid tert-butyl ester). Purified by column chromatography on silica gel (2:1 to 3:1 ethyl acetate/hexane eluant). Yellow solid. MS: 315.4 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=1.COC(=O)[C:21](Cl)([F:23])[F:22].O>CN(C)C=O>[F:22][CH:21]([F:23])[O:14][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
Potassium carbonate (2.42 g, 17.5 mmol) was added to a solution of 5-fluoro-2-nitrophenol (785 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 20 min. Chlorodifluoroacetic acid methyl ester (1.33 mL, 12.5 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 min and then stirred at an external temperature of 90° C. for 3 hr. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to afford 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene as a pale yellow oil (745 mg).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CNC(=O)Cn1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)Cn1ccnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2

Procedure:
Following the procedure for 214, 2-(2-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-imidazol-1-yl)-N-methylacetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki conditions to give 221. MS: (ESI+)=462.2. 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=8.4 Hz, 1H), 8.18 (s, 1H), 8.06-7.99 (m, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.33 (dd, J=8.4, 1.8 Hz, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.11 (d, J=1.1 Hz, 1H), 6.90 (d, J=1.1 Hz, 1H), 5.18 (s, 2H), 4.76 (s, 1H), 4.49 (s, 4H), 4.04 (s, 2H), 2.65 (d, J=4.6 Hz, 3H), 1.10 (s, 6H).
Reaction SMILES: Cl[P:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([CH3:6])([CH3:5])[CH3:4].Cl.C1(C)C=CC=CC=1>CN(C)C=O.[Zn]>[C:3]([PH:2][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)PC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
0.849 g (4.70 mmol) of chloro-di-t-butylphosphine was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at room temperature for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, and the toluene layer was determined by gas chromatography, giving di-t-butylphosphine in 25% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[S-2:24].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][S:24]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCS1
Temperature: 40 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
To a solution of crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) in methanol (25 ml) was added sodium sulfide monohydrate (0.84 g). The reaction mixture was stirred at 40° C. for 3 hours. The methanol was partially removed by distillation. Water was added and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified over silica gel (ethyl acetate/heptanes, from 1:4 to 1:1) to give thietan-2-ylmethyl-carbamic acid tert-butyl ester (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Mg]Br>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[CH3:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C. to a solution of 3-(3,4-dichlorophenyl)-N-methoxy-N-methylpropanamide (569 mg, 2.17 mmol) in ether (10 mL) was added drop wise methyl magnesium bromide (2.17 mL, 6.51 mmol) and the solution was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm up to rt and stirred for 18 h.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:12])[CH2:10][NH2:11])=[CH:4][C:3]=1[Cl:13].[CH2:14]([C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)[C:15]([CH3:17])=O>>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([OH:12])[CH2:10][NH:11][CH:15]([CH3:17])[CH2:14][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:30][CH:31]=2)=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)Cc1ccc(CC2SC(=O)NC2=O)cc1
Product: CC(Cc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1

Procedure:
5-[4-[2-[(4-Amino-3,5-dichloro-β-hydroxyphenethyl)amino]propyl]benzyl]thiazolidine-2,4-dione was prepared as a 46:54 mixture of diastereoisomers, mp. 195°-201° C., from 2-(4-amino-3,5-dichlorophenyl)-2-hydroxy ethylamine and 5-(4-acetonylbenzyl)thiazolidine-2,4-dione in an analogous manner to that described in Example 5
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.257 g) in DCM (10 mL) and pyridine (5 mL) was treated with a solution of 2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 96, 0.36 g) in DCM (10 mL) and the mixture was stirred at room temperature overnight. The resultant mixture was evaporated to dryness and the residue was re-dissolved in DCM, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.13 g) as a gum.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:22]Br>[N+](C1C=CC=CC=1)([O-])=O.CO>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8]([Br:22])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)Nc1cccc2c1C(=O)c1c(O)cccc1C2=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: CC(C)Nc1ccc(Br)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
55 g of 1-isopropylamino-8-hydroxy-anthraquinone are dissolved in 110 ml of nitrobenzene at 100°, the solution is cooled to 15°-20° whilst stirring, 40 g of bromine are added over the course of approx. 10 minutes, the mixture is stirred overnight until cold and is diluted with 150 ml of methanol whilst cold, the whole is stirred for some time longer and the product is filtered off, washed with methanol and dried. Yield: 53 g.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[N:10]1[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29]>C(Cl)(Cl)Cl>[O:8]=[C:9]1[N:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[N:10]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 64 h
Yield: 60.6 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of tert-butyl {(55)-2-oxo-5-(propan-2-yl)-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetate (4.44 g) in chloroform (20 mL), and the mixture was stirred at room temperature for 64 hr. Additional trifluoroacetic acid (9 mL) was added thereto, the resulting mixture was further stirred for 1 hr, and the reaction mixture was then concentrated under reduced pressure. A portion (6.5 g) of the residue was dissolved in diethyl ether, followed by extraction with 6M aqueous sodium hydroxide solution and water. The water layer was washed with diethyl ether and then made acidic using 1M hydrochloric acid. After extraction with chloroform, the organic layer was separated out by phase-separation cartridge, and the solvent was distilled off under reduced pressure to afford the title compound (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:21]([OH:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:21]([O:23][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2)c2c1CCc1ccccc1-2
Reactant: CCN(CC)CCCl
Solvent: CC(C)O
Product: CCN(CC)CCOC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCc1ccccc1-2

Procedure:
A mixture of 10 parts of 1-(4-chlorophenyl)-4,5-dihydro-1H-benz[g]indazole-3-carboxylic acid, 5parts of 2-diethylaminoethyl chloride and 160 parts of anhydrous 2-propanol is heated at reflux for 16 hours. The 2-propanol is then removed under reduced pressure and the resulting residue is partitioned in ether and dilute hydrochloric acid. The aqueous layer is separated and washed twice with ether. It is then made alkaline with cold aqueous sodium hydroxide solution and then extracted with ether. The combined ether extracts are dried over potassium carbonate and the solvent is evaporated to leave a residual free base. This is recrystallized from a mixture of benzene and hexane to give 2-diethylaminoethyl 1-(4-chlorophenyl)-4,5-dihydro-1H-benz[g]indazole-3-carboxylate melting at about 102°-103°C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([F:10])[C:17]([O:18][CH3:19])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1ccc(N)cc1F
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1F

Procedure:
(2-amino-4-fluoro-5-methoxyphenyl)-(2-chlorophenyl)-methanone (Xdd) was prepared by reacting 2-chlorobenzaldehyde with 0.0223 moles of 3-fluoro-4-methoxy aniline in a manner analogous to Example 1. MH+/Z=280.