Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[O:41]=[C:42]1[CH2:48][CH:47]2[NH:49][CH:44]([CH2:45][CH2:46]2)[CH2:43]1.O>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:49]2[CH:44]3[CH2:45][CH2:46][CH:47]2[CH2:48][C:42](=[O:41])[CH2:43]3)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nc(N3C4CCC3CC(=O)C4)ncc2C(=O)NCc2ccccc2)cc1Cl
Yield: 19.8 %

Procedure:
In DCM were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)pyrimidine-5-formamide (222 mg, 0.5 mmol) and DIEA (0.25 mL, 1.35 mmol). 3-oxo-8-azabicyclo[3.2.1] octane hydrochloride salt (90 mg, 0.6 mmol) was dissolved in THF and added to the reaction mixture at 0° C. The reaction was conducted at ambient temperature, followed by addition of water and extraction with ethyl acetate. The organic phase was washed sequentially with water and brine, and dried over sodium sulfate. The solvent was removed by rotary evaporation. Purification was performed by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give a white solid (50 mg, 19% yield).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:3]([OH:9])[CH:4]([CH:6]1[CH2:8][CH2:7]1)[F:5].[C:17]([O:21][C:22]([N:24]1[CH:28]=[C:27]([CH2:29][C@H:30]([NH:34][C:35](=[O:52])[C@@H:36]([CH2:44][S:45]([C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](O)=[O:32])[N:26]=[CH:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[C:48]([S:45]([CH2:44][C@@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:35]([NH:34][C@@H:30]([CH2:29][C:27]1[N:26]=[CH:25][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH:28]=1)[C:31]([NH:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[F:5])=[O:32])=[O:52])(=[O:47])=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: NC(CC1CCCCC1)C(O)C(F)C1CC1
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](F)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 147 mg (0.64 mmol) of (1S or R,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1-fluoro-2-butanol, 365 mg (0.7 mmol) of (S)-1-(tert-butoxycarbonyl)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 71 mg (0.7 mmol) of triethylamine, 114 mg (0.7 mmol) of HOOBT and 285 mg (0.7 mmol) of HOBTU in 15 ml of dimethylformamide is stirred at room temperature overnight under argon. Thereafter, the dimethylformamide is evaporated in a high vacuum and the residue is taken up in 50 ml of ethyl acetate. The ethyl acetate phase is washed with 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-3-fluoro-2-hydroxypropyl]-1-Boc-imidazole-4-propionamide as a yellowish foam.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([C:11]1([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12]1)([CH3:10])[CH2:8][CH3:9].S(C1C=CC(C)=CC=1)(O[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])(=O)=O.O>CCCCCC.O1CCCC1.O1CCCC1.CCCCCC>[CH3:28][N:27]([CH2:26][CH2:25][C:15]1[C:11]([C:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])([C:7]([CH3:6])([CH3:10])[CH2:8][CH3:9])[CH:12]=[CH:13][CH:14]=1)[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CCC(C)(C)C1(C(C)(C)CC)C=CC=C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)(C)C1(C(C)(C)CC)C=CC=C1CCN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Twenty-five mL of a 1.6 molar solution of n-butyllithium in hexane was added dropwise to a cooled (0° C. ) solution of di-(1,1-dimethyl-propyl)cyclopentadiene (8.25 g; 40.0 mmol) in dry tetrahydrofuran (125 ml) under a nitrogen atmosphere in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, a solution of 2-dimethylaminoethyl tosylate (40.0 mmol) prepared in situ in tetrahydrofuran/hexane was added. After 18 hours of stirring, the conversion was found to be 91%, and water (100 mL) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and boiled down. The residue was purified on a silica gel column, which resulted in 9.1 grams (82%) of (dimethyl-aminoethyl)di(1,1-dimethyl-propyl)cyclopentadiene.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[N:32][N:31]=[CH:30]2.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([O:37][CH2:38][C:39]([F:41])([F:42])[F:40])=[N:32][N:31]=[CH:30]2
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)COc1nncc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(OCC(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
A mixture of 4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (19, 143 mg, 0.42 mmol), 6-bromo-1-(2,2,2-trifluoroethoxy)phthalazine (20, 117 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (22.0 mg, 0.019 mmol) in 2 mL of Dioxane and 0.5 mL of 2 N aqueous solution of Na2CO3 in a sealed glass tube was heated at 120° C. for 20 min in a Personal Chemistry microwave. The mixture was treated with 3 mL of 1 N NaOH and extracted with EtOAc (2×10 mL). The combined EtOAc layers were dried and concentrated. Purification of the residue on a 24 g ISCO column (eluted 75-100% EtOAc in Hexanes) provided the title compound 21 as an off-white solid. MS (ESI, pos. ion) m/z: 442.1 (M+1).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[O-]CC.[Na+].[C:15](OC)(=[O:18])[CH:16]=[CH2:17].Cl>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:3]2[CH2:17][CH2:16][C:15](=[O:18])[NH:4]2)[CH:6]=1
Reactant: C=CC(=O)OC
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=C1CCN(c2cccnc2)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a four-neck round bottomed flask (250 mL) which contained 3-hydrazinopyridine dihydrochloride (18.2 g, 0.100 mol) was added sodium ethoxide (21 wt % in ethanol, 107 g, 0.330 mol). The temperature of the slurry rose to 33° C. over 5 minutes. The mixture was stirred at room temperature for 1.25 hours. To the light red tinted slurry was added methyl acrylate (18.0 mL, 0.200 mol) over 10 minutes, with the temperature rising from 25° C. to 35° C. The color of the slurry changed from light red to brown/green. The mixture was heated at 55° C. for 3 hours. After stirring at room temperature overnight, the mixture was neutralized to pH ˜7 with hydrochloric acid (4 M in 1,4-dioxane, 32.6 g, 0.130 mol). The dark gray slurry was concentrated to a dark, paste like solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:8][C:9]1[C:16]([OH:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:10]=1[CH2:11]O)(=O)[CH3:6].[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.[Na+].[Cl-]>C1(C)C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[CH3:6][C:5]1[O:17][C:16]2[C:15]([O:18][CH3:19])=[CH:14][CH:13]=[C:10]([CH2:11][C:20]#[N:21])[C:9]=2[N:8]=1
Reactant: COc1ccc(CO)c(NC(C)=O)c1O
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC#N)c2nc(C)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (40 ml) is slowly added at 0° C. with stirring to a suspension of 2-acetamido-3-hydroxy-4-methoxybenzyl alcohol (2.5 g, 12.0 mmol) and anhydrous CH2Cl2 (30 ml). After the reaction mixture has warmed to RT, it is stirred for 1 h and then stirred at 50° C. for a further 1.5 h. The reaction solution is concentrated in vacuo and then coevaporated with toluene (3 times). The residue obtained is dissolved in a mixture of toluene and DMF (8:1, 45 ml) and added dropwise to a solution of KCN (1.0 g, 15.4 mmol) in 18-crown-6 (4.07 g, 15.4 mmol) and absolute DMF (55 ml). The reaction solution is stirred overnight at RT and then poured into a half-concentrated aqueous NaCl solution, extracted with ethyl acetate (5 times), dried over MgSO4, filtered off and concentrated in vacuo. For further purification, the crude product is filtered through a silica gel column [petroleum ether/ethyl acetate (6:4)]. The title compound is obtained as colorless crystals (1.28 g). TLC, silica gel (glass plates), petroleum ether/ethyl acetate (6:4), Rf=0.32.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCCC4)nc23)CC1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution of 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 1.0 mL pyridine was heated to 50 ° C. To this solution were then added 0.0064 mL (0.048 mMol) cyclohexanecarbonyl chloride and the reaction mixture stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and a solution of the residue in methanol passed over a VARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which had been preactivated with 10% acetic acid in methanol. The column was washed thoroughly with methanol and then the desired product eluted with 2M ammonia in methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.013 gm (87.2%) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([OH:18])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si](CC(N)=O)(C)C.[NH2:33][CH:34]1[C:51](=[O:52])[N:36]2[C:37]([C:48]([OH:50])=[O:49])=[C:38]([CH2:41][S:42][C:43]3[S:44][CH:45]=[N:46][N:47]=3)[CH2:39][S:40][C@H:35]12.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([NH:33][CH:34]1[C:51](=[O:52])[N:36]2[C:37]([C:48]([OH:50])=[O:49])=[C:38]([CH2:41][S:42][C:43]3[S:44][CH:45]=[N:46][N:47]=3)[CH2:39][S:40][C@H:35]12)=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
Phosphorus oxychloride (2.3 g.) was added at a time to a suspension of 2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (3.4 g.) in dry tetrahydrofuran (30 ml.) at -3° C. and the mixture was stirred for 20 minutes at the same temperature. Trimethylsilylacetamide (2.4 g.) and tetrahydrofuran (5 ml.) were added dropwise thereto and the resulting mixture was stirred for 20 minutes at the same temperature. Phosphorus oxychloride (2.3 g.) was added thereto and the mixture was stirred for 30 minutes at 0° to 3° C. Dry dimethylformamide (1.1 g.) was added thereto at a time at 0° to 3° C. and the mixture was stirred for 1 hour at the same temperature to give a clear solution. On the other hand, trimethylsilylacetamide (12.7 g.) was added to a stirred suspension of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.0 g.) in dry ethyl acetate (60 ml.) and the solution was stirred for 1 hour at ambient temperature. To this stirred solution was added the above-obtained tetrahydrofuran solution at a time at -20° C., and the resulting mixture was stirred for 2 hours at -5° to -15° C. To the reaction mixture were added a saturated aqueous solution of sodium chloride (50 ml.). An organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.0). The extract was washed with ethyl acetate, treated with an activated charcoal and adjusted to pH 4.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.03 g.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]3[CH:5]=[C:4]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:3][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(-c3ccccc3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 16.9 %

Procedure:
To a stirred solution of 0.130 g (0.465 mmol) (2-amino-5-phenyl-thiophen-3-yl)-phenyl-methanone in 7 ml acetic acid was added 62 mg (0.491 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 110° C. for 20 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 29 mg (17%) cyclopropyl-(6-methyl-2,4-diphenyl-thieno[2,3-b]pyridin-5-yl)-methanone as a light yellow powder. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 5 L three-necked round-bottomed flask, equipped with mechanical stirrer, thermometer with adapter, condenser, and nitrogen inlet (on top of condenser), was charged with 1 (140.7 g, 0.756 mol), 4-bromophenol (130.6 g, 0.755 mol), anhydrous K2CO3 powder (367.6 g, 2.66 mol, 3.5 eq), and acetonitrile (1.3 L). The mixture was vigorously stirred (blade touching bottom of flask) at 80° C. (overnight), followed by dilution with DCM (500 mL) and heptane (200 mL) and filtration through Celite. Evaporation to dryness (rotovap, then high vac) gave 2 as a light yellow oil (216.00 g, yield of 100%, 96.3% AUC, contains 3.7% unreacted bromophenol). This material was used successfully without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.CN(C=O)C>C(Cl)Cl.O>[CH3:13][S:14]([O:12][CH:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11])(=[O:16])=[O:15]
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Yield: 71 %

Procedure:
1-(2,6-dichloro-3-fluorophenyl)ethanol (5.2 g, 24.9 mmol), methanesulfonyl chloride (6.3 g, 55 mmol, 2.2 eq), and triethylamine (6.1 g) were stirred in 50 ml of DCM and 12 ml of DMF at room temperature overnight. Water and DCM were added, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, evaporated and chromatographed (EtOAc/Hexanes 1:10) to give an oil, 5.11 g, in 71% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25](O)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([N:32]3[CH2:33][C:30]([CH3:29])([OH:34])[CH2:31]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: CC1(O)CNC1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CC(C)(O)C3)cc2n1C
Yield: 76 %

Procedure:
The title compound was prepared as a colorless amorphous in 76% yield (71 mg) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (80 mg, 0.21 mmol, STEP 2 of Example 21) and 3-methylazetidin-3-ol hydrochloride (crude 135 mg, STEP 1) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2ccc(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2ccc(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
3.7 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7-chloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 80 cm3 of methanol and 33 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from a 1:2 mixture of ethyl acetate and hexane. Thus, 2.88 g (84%) of the title compound are obtained in the form of yellow ochre solids melting at 200–205° C.
Reaction SMILES: [OH-].[K+].Br[CH:4]1[CH:13]([O:14][CH3:15])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]1=2>CO>[CH3:15][O:14][C:13]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1
Reactant: COC1c2sccc2C(=O)c2ccccc2C1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ccccc2c(=O)c2ccsc12

Procedure:
9 g of potassium hydroxide are added to a solution of 17.5 g of 9-bromo-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one in 400 cc of methanol, and the solution is boiled at reflux for 6 hours. After cooling to 0°-5°, the precipitated crystalline material is filtered off and recrystallized from methanol. The pure 10-methoxy-4H-benzo[4,5] cyclohepta[1,2-b]thiophen-4-one, having a M.P. of 164°-166°, is obtained in this manner. Microanalysis agrees with the formula C14H10O2S. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.N>>[CH2:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNc1nc(N)nc(NCCCC)n1
Reactant: C1CCNCC1
Agent: N
Product: CCCCNc1nc(NCCCC)nc(N2CCCCC2)n1

Procedure:
The same procedures were repeated as in the N-substituted melamine (C1), except that piperidine was employed in place of the aqueous ammonia to obtain 2,4-bis(monobutylamino)-6-piperidino-1,3,5-triazine which is in powder-state.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(Cl)(=O)C(Cl)=O.[N:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[C:19]([CH:23]=1)[C:20]([N:43]1[CH2:44][CH2:45][N:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH2:41][CH2:42]1)=[O:21])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1C(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1C(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
5-(6-Bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoic acid(97 mg) was dissolved in dichloromethane (1 ml.). Oxalyl chloride (126 mg) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was evaporated to give a solid which was redissolved in dichloromethane (1 ml) and added to a solution of N-(4-pyridyl)piperazine (34 mg) and triethylamine (108 mg) in dichloromethane (2 ml). After stirring for 2 hours at ambient temperature the mixture was diluted with ethyl acetate (100 ml), washed with water (2×25 ml), dried (MgSO4) and evaporated to give an oil, which was further purified by chromatography (Mega Bond Elut column, eluted with dichloromethane containing an increasing proportion of methanol, 0-5%) to give 1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine (55 mg);