Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:9]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=3)=[O:10])=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][N:15]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(C(F)(F)F)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-(4-fluorophenoxy)-5-(trifluoromethyl)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.90 (1H, d, J=2.7 Hz), 8.45 (1H, s), 8.01 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz), 4.78 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]/1=O)C.[ClH:21].[NH2:22]N>C(O)C.C(O)(=O)C>[ClH:21].[CH3:11][C:8]1([CH3:12])[C:9]2[NH:22][N:2]=[CH:4][C:5]=2[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7]1
Reactant: CN(C)/C=C1\C(=O)C(C)(C)CC1c1ccc(C#N)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccc(C#N)cc2)c2cn[nH]c21
Temperature: 80 °C
Yield: 42 %

Procedure:
To (+/−)-4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclopentyl]benzonitrile (3.2 g, 20 mmol) in ethanol (100 mL) and acetic acid (4 drops) is added hydrazine hydrochloride (4.17 g, 60 mmol) and the reaction is heated to 80° C. for three hours. The reaction is then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers are separated and the organic is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash chromatography eluting with 1:2 ethyl acetate:pet ether. The resulting material is treated with HCl in ethyl acetate to provide the title compound (2.3 g, 70%). ES/MS (m/z) 238.2 (M+1).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:20])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 25.5 h
Yield: 284.8 %

Procedure:
(Biphenyl-4-yl)-phenylamine (35.0 g) and DMF (700 ml) were added and dissolved in a nitrogen-substituted reaction vessel, and N-bromosuccinimide (8.5 g) was added under ice-cooled conditions. The reaction temperature was raised to room temperature while adding N-bromosuccinimide (17.0 g) in two separate portions. After being stirred for 25.5 hours, the reaction solution was dropped to water (3,500 ml), and the precipitated solid was collected by filtration. Toluene (2,500 ml) was added to dissolve the solid, and the solid was dried over magnesium sulfate. After filtration, the filtrate was concentrated. The resulting concentrate was dispersed and washed by addition of n-hexane (500 ml), and dried overnight under reduced pressure to obtain a reddish solid of (biphenyl-4-yl)-(4-bromophenyl)amine (44.1 g; yield 95.4%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([CH2:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2cccc(C(F)(F)F)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3-Trifluoromethyl-phenyl)-ethylamine. MS (ESI): 501.4 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].ClC(F)C(N(CC)CC)(F)[F:36]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([F:36])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(F)CS[C@H]12

Procedure:
To a solution of 325 mg. (0.7 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 10 ml. of methylene chloride was slowly added an equivalent amount of N-(2-chloro-1,1,2-trifluoroethyl)diethylamine. The reaction mixture was heated for 30 minutes under gentle reflux and was then evaporated to dryness in vacuo. The residue was dissolved in a mixture of ethyl acetate-water and the organic layer was separated. The organic layer was washed with 5% hydrochloric acid, water and brine and was then dried. The dried reaction product solution was concentrated to a small volume and n-hexane was added to precipitate, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylate.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13](=[N:3]/[NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Product: O=C(O)c1ccccc1N/N=C/c1ccccc1

Procedure:
The title compound was prepared from 2-hydrazinobenzoic acid hydrochloride (1.89 g, 10.0 mmol) and benzaldehyde (1.06 g, 10.0 mmol) according to the procedure of Fischer, E. and co-workers described in Chem. Ber., 35, 1902, 2318 (2.4 g, quantitative yield). MS (DCI) m/z 241 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](CC(=O)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][C:15](C)=[O:16]>>[CH2:15]([O:16][C:6]([C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[N:3][CH:4]=1)=[O:7])[CH3:14]
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Reactant: CC(C)=O
Product: CCOC(=O)c1ccc(C)nc1

Procedure:
The 6-methylnicotinoyl-acetone which is mentioned as the starting substance in Example 6, can be obtained in a known manner from α-picoline-5-carboxylic acid ethyl ester and acetone, or from 5-acetyl-α-picoline (prepared in accordance with Angew. Ch. 67, page 398) and ethyl acetate: 270 g of 5-acetyl-α-picoline, 5 1 of anhydrous toluene, 387 g. of ethyl acetate and 537 g of potassium tert.-butylate are stirred at 40° for 20 hours and the mixture is subsequently decomposed by means of a mixture of 3 1 of ice water and 288 ml of acetic acid. 283.5 g of 6-methylnicotinoyl-acetone, boiling point 108°-117° /0.2 mm Hg, which rapidly crystallises and, after recrystallisation from ligroin, melts at 57°-58°, is obtained in the usual manner from the toluene solution.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([Cl:28])=[O:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccc([C@H]2CC[C@H](C(=O)O)CC2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCOc1ccc([C@H]2CC[C@H](C(=O)Cl)CC2)cc1

Procedure:
0.6 g of the thus obtained trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylic acid was heated in toluene with 5 ml of thionyl chloride. Then, toluene was distilled off to obtain trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylic acid chloride. The thus obtained acid chloride was dissolved in 40 ml of carbon tetrachloride to obtain a solution, to which added were 5 ml of pyridine and a solution prepared by dissolving 0.56 g of (S)-3-hydroxy-4-(1-oxo-2-methylbutyl)phenol in 10 ml of carbon tetrachloride. The admixture was stirred at the room temperature for a day to proceed the reaction. After refluxing for additional one hour, water was added to the admixture, and the organic phase was separated. The separated organic phase was rinsed initially with a dilute hydrochloric solution, then with an aqueous solution of NaHCO3, and finally with a saturated aqueous solution of NaCl. The rinsed organic phase was dried over anhydrous Na2SO4 by allowing the same to stand for one night. The solvent was distilled off from the dried organic phase to obtain crude (S)-4-(1 -oxo-2-methylbutyl)-3-hydroxyphenyl trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylate. The thus obtained crude product was recrystallized from ethanol for two times to obtain 0.04 g of a recrystallized product which was identified by infra-red absorption spectrum (IR) and nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To 2.0 mL of a methanol solution containing 0.25 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2.0 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added and stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to afford 0.18 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B(O)O)[CH:8]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[N:23]=3)=[CH:15][CH:14]=2)[CH:8]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: COc1cncc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Methoxypyridine-5-boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 364.2 (M+1)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:30](O)=[O:31])[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[S:35][C:36]([CH3:49])=[C:37]([CH3:48])[C:38]=1[C:39]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)=[O:40].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:30](=[O:31])[NH:33][C:34]4[S:35][C:36]([CH3:49])=[C:37]([CH3:48])[C:38]=4[C:39](=[O:40])[C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1sc(NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CN(C(=O)OC(C)(C)C)C2)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.438 g, 0.999 mmol), and (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (0.241 g, 0.908 mmol) in DCM (20 mL) at 0° C. was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDC.HCl) (209 mg, 1.090 mmol). The reaction was warmed to rt and stirred overnight, before it was concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc) to give tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)carbamoyl)-azetidine-1-carboxylate as an orange oil (382 mg). LRMS (M+Na)+: 708 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](N)=[O:20])=[CH:14][CH:13]=1)=[O:11].S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:20])=[O:23])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
10.7 g of 4-(2,3-dichlorophenylcarbamoyl)phenylacetamide was dispersed in 100 ml of acetic acid, and 17.5 ml of sulfuric acid was added. Then, a solution obtained by dissolving 3.2 g of sodium nitrite in 17.5 ml of water, was dropwise added to bring the reaction temperature to a level of 20° C.±5° C. Thereafter, the mixture was stirred at room temperature for two hours, and then poured into 400 ml of ice water. The resulting crystals are collected by filtration, thoroughly washed with water and then dried to obtain 9.8 g of desired 4-(2,3-dichlorophenylcarbamoyl) phenyl acetic acid. The yield was 91.3%, and the melting point of this compound was from 184° to 185.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH2:11])=[N:7][CH:8]=1.Br[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C>CN(C=O)C>[CH3:24][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([NH:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][N:7]=3)[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: NCCc1ccc(C(F)(F)F)cn1
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine (200 mg, 1.05 mmol) was added 6-bromo-1-methyl-1H-indole (685 mg, 2.10 mmol), cuprous iodide (10 mg, 0.05 mmol) and cesium carbonate (685 mg, 2.1 mmol) under an argon atmosphere. Then DMF (400 μl) and 2-acetylcyclohexanone (28 μl, 0.21 mmol) were added and the reaction mixture was stirred for 4 h at 120° C. After cooling to ambient temperature the reaction mixture was separated between tert-butylmethylether (2×20 ml) and water (15 ml). The combined organic layers were washed with brine (15 ml) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (114 mg, 34%) as a light brown oil. MS m/e: 320.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:7](Cl)([C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:15]([N:16]([CH3:18])[CH3:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C1(C)C=CC=CC=1>[S:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:15]([N:16]([CH3:18])[CH3:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCNCC3)cccc12
Yield: 168.9 %

Procedure:
Dansylpiperazine was prepared by refluxing a solution of 7.98 g piperazine (9.27 mmol) and 5.00 g dansyl chloride (18.5 mmol) in 100 mL toluene for 6 h. The product was isolated by washing the solution with 5% NaOH and then water and concentrating in vacuo to yield 5.0 g (84%) dansylpiperazine as yellow-green powder. 1H NMR (200 MHz, CDCl3) 2.7-2.9 (4H, multiplet), 2.9 (6H, singlet), 3.1-3.3 (4H, multiplet), 7.1-7.6 (3H, multiplet), 8.2-8.6 (3H, multiplet).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2.S(Cl)([Cl:22])=O>O1CCCC1.CN(C)C=O>[Cl:22][CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 62, step 2, 468 mg, 1.82 mmol) in tetrahydrofuran (10 ml) and N,N-dimethylformamide (5 ml) was added dropwise thionyl chloride (0.20 ml, 2.7 mmol). After stirring at room temperature for 2 h, the mixture was concentrated in vacuo, poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The combined organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1.5 to ethyl acetate only) to give 151 mg (30%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:24][CH3:25])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC(C)C)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC(C)C)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-chloro-3-(isobutyl amino)-2-methylbenzoate (1.0 g, 3.9 mmol) in dry DMF (10 mL), cesium carbonate (2.55 g, 7.82 mmol) and ethyl iodide (6.09 g, 39.1 mmol) were added. The resulting reaction mass was heated at 80° C. for 12 h. On completion, the reaction mass was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give crude material which then used for next step as is (10 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OC1CCCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclohexanone (108.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IId-a (138.5 g, 78.3%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.O.[NH2:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:21][NH2:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: NN
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 72 h

Procedure:
A mixture of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione and hydrazine hydrate is allowed to stand for 72 hours at about 25° C. After evaporation of the ethanol, the solid products obtained are recrystallized from methylene chloride-benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine of melting point 204°-207° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25](C)([CH3:27])C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:27][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.14 g, 2.78 mmol), nitromethane (0.45 mL, 8.34 mmol), NaOH (0.78 g, 1.95 mmol), THF (3 mL) and water (9 mL). Purification: flash column chromatography (25% EtOAc/hexanes): yield 0.42 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.41 (s, 1H), 7.37-7.18 (m, 6H), 7.03 (d, J=7.8 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.28 (dd, J=13.7, 2.7 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.46 (s, 2H), 4.33 (t, J=6.1 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 2.12 (s, 3H), 2.01-1.87 (m, 2H). MS (ESI): m/z=370 (M−1, negative).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:23](=[O:24])[CH2:22][CH2:21][CH:20]1[C:25]#N.C(O)(=[O:29])C>C1C=CC=CC=1.C(OCC)C>[OH:24][CH:23]1[CH2:22][CH2:21][CH:20]([CH:25]=[O:29])[CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: CC(=O)O
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC1CCC(O)C1CCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A solution of diisobutylaluminium hydride (25.6 g., 0.18 mole) in benzene (250 ml.) was added, with rapid stirring, to a solution of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (10 g., 0.045 mole) in dry diethyl ether (250 ml.) at 10°-15°C. Stirring at ambient temperature was contined for 15 minutes and the mixture was added to 2N aqueous acetic acid (300 ml.) at a temperature lower than 15°C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over magnesium sulphate and the solvents were removed in vacuo. The residue was distilled under reduced pressure to give 3-hydroxy-2-(7-hydroxyheptyl)cyclopentanecarbaldehyde (4.5 g., 43%), b.p. 185°-193°C./0.1 mm.Hg, nD22.5 1.4995.