Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[Li]CCCC.[CH:14]12[O:20][CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15]2.B(F)(F)F.CCOCC.[Cl-].[NH4+]>C1COCC1>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:19]1[OH:20]
Reactant: C1CCC2OC2C1
Reactant: Cc1cccc(Br)c1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C1CCCCC1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-3-methyl-benzene in THF at −78° C., was added dropwise a solution of nBuLi (1.6M in THF, 12.4 ml) and the reaction mixture was stirred at −78° C. for 30 minutes. After such time, 7-oxa-bicyclo[4.1.0]heptane (3.4 g) was added slowly to the reaction mixture followed by the addition of boron trifluoride etherate (2.5 ml). The reaction mixture was stirred at −78° C. for another 2 hours before allowing it to warm up to room temperature. The solution was then treated with solution of ammonium chloride (25 ml), the phases were separated and then extracted twice with ethyl acetate. The combined organic extracts were then washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography to give 2.9 g of (cis/trans) 2-o-tolyl-cyclohexanol MS(EI) 190.1 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:44][CH:45]=1)[C:10]([NH:12][CH:13]1[C:39](=[O:40])[N:15]2[C:16]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:17]([CH2:21]Cl)[CH2:18][S:19](=[O:20])[C@H:14]12)=[O:11].[I-:66].[Na+].C(O[CH2:72][CH3:73])(=O)C.O>CC(C)=O>[I-:66].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:44][CH:45]=1)[C:10]([NH:12][CH:13]1[C:39](=[O:40])[N:15]2[C:16]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:17]([CH2:21][N+:12]3([CH3:13])[CH2:73][CH2:72][CH2:9][CH2:10]3)[CH2:18][S:19](=[O:20])[C@H:14]12)=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[N+]1(CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3S(=O)C2)CCCC1
Reaction time: 4.5 h

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) in acetone (100 ml) was added sodium iodide (2.5 g) under ice-cooling. The mixture was stirred for 4.5 hours at the same temperature and then poured into a mixure of ethyl acetate (150 ml) and water (150 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was distilled off. To the residue was added tetrahydrofuran (25 ml) and then 1-methylpyrrolidine (0.52 ml) was added thereto under cooling. The mixture was stirred for 1 hour at the same temperature and then the mixture was poured into ice-water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and then subjected to column chromatography on silica gel using methylene chloride and methanol (5:2) as an eluent. The fractions containing the object compound were collected and evaporated to give benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2 -tritylaminothiazol-4-yl)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate-1-oxide iodide (syn isomer) (1.0 g).
Reaction SMILES: C([O-])C.[Na+].[CH3:5][C:6]([CH3:12])([CH3:11])[CH2:7][C:8](=[O:10])[CH3:9].[CH2:13]([O:15][C:16](=[O:22])[C:17](OCC)=[O:18])[CH3:14].Cl>CCO.O>[CH2:13]([O:15][C:16](=[O:22])/[C:17](/[OH:18])=[CH:9]/[C:8](=[O:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH3:5])[CH3:14]
Reactant: CC(=O)CC(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C(O)=C/C(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice-cooled solution of sodium ethanolate (128.5 g, 1.79 mol) in EtOH (2500 ml) under nitrogen atmosphere is added 4,4-dimethyl-pentan-2-one (195.0 g, 1.71 mol). Half an hour later, oxalic acid diethyl ester (231.5 g, 1.71 mol) is added. After being stirred at rt for 24 h, the reaction mixture is diluted with water, and acidified to pH 2.0 by 6N aq hydrochloric acid. The mixture is contracted to about 1 L and extracted with DCM. The combined extracts are washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the product as a brown liquid.
Reaction SMILES: [H-].[Na+].C(COC)OC.P(=O)([O-])O[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17](C)C.[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[C:38]([CH:39]=O)=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])([O:25][CH3:26])=[O:24]>C(O)(=O)C>[CH3:44][O:43][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38](/[CH:39]=[CH:11]/[C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)CCCCC(=O)CO[PH](=O)[O-]
Reactant: COC(=O)CCCCCCc1c(OC)ccc(OC)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/c1c(OC)ccc(OC)c1CCCCCCC(=O)OC
Temperature: 85 °C

Procedure:
To a slurry of 278 mg. of a dispersion of sodium hydride in mineral oil in 40 ml. of dimethoxyethane is added a solution of 1.33 g. of dimethyl(2-oxoheptyl) phosphonate in 40 ml. of dimethoxyethane and the mixture is stirred for one hour. 1.41 g. of the aldehyde in 40 ml. of dimethoxyethane is added and the mixture heated at 85° C. for eighteen hours. The mixture is then cooled and neutralized with acetic acid and the solvent is removed in vacuo. The residue is then chromatographed on a silica gel column to yield 1,4-dimethoxy-2-(6-carbomethoxyhexyl)-3-(3-oxo-trans-1-octenyl)benzene as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0 mmol) to afford after chromatographic purification the title compound (196 mg, 83%). 1H NMR (CDCl3, 300 MHz) δ7.21-7.26 (m,2H), 7.01-7.05 (m, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 3.90-4.30 (m, 3H), 3.86 (s, 3H), 3.3.64-3.75 (m, 1H), 3.25-3.50 (m, 4H), 3.05-3.12 (m, 1H), 2.85-2.95 (m, 1H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 475 [M+H+].
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1cccnc1)c1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1cccnc1)c1ccccn1)NO
Reaction time: 24 h
Yield: 23 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (140 mg, 0.43 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:25) to furnish III as a yellow oil (31 mg, 23%).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg]Cl>C1COCC1>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (3.320 g, 12.2 mmol) in THF (30 mL) was added 15 mL of 3.0 M MeMgCl in THF at −15° C. under N2. After 0.5 h, the mixture was allowed to warm to rt for 4 h. The reaction mixture was then quenched with 40 mL of 1 NHCl and extracted with ethyl acetate (3×), dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude (R)-tert-butyl 3-acetylpiperidine-1-carboxylate was directly used in the next step without further purification. MS ESI +ve m/z 250 (M+Na).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(N)nccc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(O[C@H]3CC[C@@H](N)CC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of cis-[4-(1-aminoisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester (14 mg) in dichloromethane (900 μl) and trifluoroacetic acid (100 μl) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo then purified by prep-HPLC to give gave cis-6-(4-aminocyclohexyloxy)isoquinolin-1-ylamine (8.1 mg), EI-MS: m/z=258.5 [M+H]+. 1H NMR (methanol D4) δ1.55-1.80 (6H, m), 2.05-2.15 (2H, m), 2.75-2.85 (1H, m), 4.65-4.75 (1H, obscured broad s), 6.88 (1H, d), 7.08-7.15 (2H, m), 7.64 (1H, d), 7.99 (1H, d).
Reaction SMILES: Cl.[O:2]=[C:3]1[C@@H:9]([NH2:10])[CH2:8][C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]1[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([CH3:38])[C:36]=1[OH:37])[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[O:2]=[C:3]1[C@@H:9]([NH:10][C:31](=[O:32])[C:30]2[CH:34]=[C:35]([CH3:38])[C:36]([OH:37])=[C:28]([CH3:27])[CH:29]=2)[CH2:8][C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]1[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: N[C@H]1CC(=O)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@H]2CC(=O)c3ccccc3N(CC(=O)OCc3ccccc3)C2=O)cc(C)c1O
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 13a and 3,5-dimethyl-4-hydroxybenzoic acid (307 mg, 1.85 mmol) in 5 ml each of DMF and CH2Cl2 was added HOBT (250 mg, 1.85 mmol), EDC (421 mg, 2.2 mmol), and triethylamine (0.64 ml, 4.56 mmol). The reaction was stirred at room temp. for 18 hrs. then diluted with EtOAc (150 ml) and washed with 10% NaHSO4, sat. NaHCO3 and sat. NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford a gum that was purified by flash chromatography eluting with CH2Cl2/EtOAc (7/3) to afford 545 mg (62%) of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccc(C(=O)O)cc1
Product: COc1ccc(C2=NN(c3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinobenzoic acid as described for compound 35. Purified by chromatography and crystallized from ethyl acetate. M.p. 198°-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]2=[O:16])=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=3[F:24])=[CH:10][C:9]2=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Br)ccc1-n1c(C)cc(O)cc1=O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Temperature: 0 °C
Yield: 29 %

Procedure:
1-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (7.35 g, 25.0 mmol) was dissolved in DMF (15 mL) and stirred with potassium carbonate (4.14 g, 30.0 mmol) and 2,4 difluorobenzyl bromide (3.21 ml (25.0 mmol) at room temperature for 2 hours. The reaction was worked up by pouring in to 300 ml ice water under continuous stirring. A white precipitate was obtained which was isolated by filtering and further purified by triturating with ether to give 3.06 g (29%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.65-7.59 (m, 2H), 7.49 (dd, J=8.45, 2.22 Hz, 1H), 7.31 (dt, J=9.79, 2.22 Hz, 1H), 7.16-7.08 (m, 2H), 6.05 (d, J=2.58 Hz, 1H), 5.93 (d, J=2.66 Hz, 1H), 5.08 (s, 2H), 1.93 (s, 3H), 1.77 (s, 3H). ES-HRMS m/z 420.0390 (M+H calcd for C20H17BrF2NO2, requires 420.0411).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](OCC)=O)[CH:19]=[CH:20][CH:21]=1.C(O)C.[H-].[Na+]>O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]1[NH:14][C:12](=[O:13])[C:3]2[CH:4]=[N:5][N:6]([CH:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:2]=2[N:1]=1
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 180 mg (0.91 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxamide and 575 mg (2.72 mmol; 3 equiv.) of ethyl (3-chlorophenyl)acetate are introduced into 3.5 ml of absolute ethanol. At 0° C., 127 mg of sodium hydride (60% dispersion in mineral oil; 3.18 mmol; 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly warmed and stirred under reflux for 18 h. The mixture is worked up by adding 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([CH:14]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:13].OC(C)CNCC(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C)C=O.O>[CH2:12]([CH:14]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][O:16][C:17](=[O:21])[C:18]([C:19]#[N:20])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCC(CC)COC(=O)CC#N
Agent: CC(O)CNCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COC(=O)C(C#N)=Cc1ccc(C(=O)O)cc1

Procedure:
A 250 ml three necked reaction flask, equipped with a reflux condenser combined with a water separator and an oil bath with a magnetic stirrer was charged with 3.8 g (25 mmol) of 4-carboxy-benzaldehyde (Fluka), 6.8 g (33 mmol) of cyanacetic-acid-2-ethyl-hexylester, 0.3 g of bis-(2-hydroxypropyl)-amine and 0.25 g of p-toluene-sulfonic acid in 80 ml of toluene and 20 ml of dimethylformamide. After 22 hours under reflux the reaction mixture was diluted with toluene and washed with aqueous NH4Cl and NaCl solutions, dried with Na2SO4 and concentrated to yield 6.2 g (74%) of whire crystals. M.p. 159-162° C. W(CH2C2) 305 nm (E=811).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of indole-5-carboxylic acid (26.3 g, 163 mmol) in tetrahydrofuran (600 mL), was added a solution of lithium aluminium hydride 1.0M in tetrahydrofuran (200 mL, 200 mmol) drop wise at ambient temperature. A solution of lithium aluminium hydride 2.0M in tetrahydrofuran (22 mL, 44 mmol) was added drop wise at ambient temperature, and then the reaction mixture was carefully heated up to reflux and held there for 1 hour. The reaction mixture was cooled to ambient temperature and then water (13 mL) was added drop wise, followed by an aqueous 10% sodium hydroxide solution (13 mL), and water (20 mL). The suspension was stirred at ambient temperature for 30 minutes, filtered through a bed of celite and the filter cake washed with ethyl acetate (2×200 mL). The filtrate and the washings were combined and the organics were separated, dried (Na2SO4) and concentrated in vacuo, to give a dark red oil. The resultant crude product was suspended in hexane (200 mL), and ethyl acetate (10 mL) was added. This mixture was stirred at ambient temperature for 18 hours, and the solids were separated via filtration and washed with hexane to afford the title compound as a light brown solid, 22.25 g, 93%.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>C(O)C.CCCCCC>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:2]4[CH:6]=[CH:5][N:4]=[CH:3]4)=[CH:15][CH:14]=3)[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Yield: 85 %

Procedure:
By an exactly analogous method to that described in Example 1, starting from 4-(1-imidazolyl)benzoic acid hydrochloride and 1-(6-bromonaphth-2-ylsulphonyl)piperazine was prepared 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazine (444 mg, 85% yield), m.p. 207-209° C. (from ethanol/hexane), 1H NMR (d6DMSO) 3.0-3.2 ppm (broad s,4H), 3.5-3.8 ppm (broad s,4H), 7.1 ppm (s,1H), 7.4 ppm (d,2H), 7.6 ppm (d,2H), 7.75 ppm (s,1H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.3 ppm (s,1H), 8.4 ppm (s,1H), 8.45 ppm (s,1H), the spectrum also contained signals due to ethanol (<0.2 mol eq.); microanalysis, found: C, 55.0; H, 4.3; N, 10.4; S, 6.2%; C24H21N4O3BrS requires: C, 54.9; H, 4.0; N, 10.7; S, 6.1%; MS (M+H)+ 525/527.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:3]=1[NH:4]C(=O)C.O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[C:3]=1[NH2:4]
Reactant: CC(=O)Nc1c(Br)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1c(Br)cccc1C(F)(F)F

Procedure:
2'-Bromo-6'-trifluoromethylacetanilide in 50% aqueous sulfuric acid is warmed on a steam bath for 2 hours, then refluxed for 1 hour. Cooling and dilution with water gives 2-bromo-6-trifluoromethylaniline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([C:15]([NH2:46])=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 25 mg, 45 μmol) in acetonitrile (1.0 mL) is treated with ammonium carbonate (9 mg, 90 μmol), and the mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 3 mg; ESI mass spectrum [M+H]+=441; Retention time HPLC: 0.65 min (X018_S01).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:11][C:10]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:8]=2[CH:9]=1
Reactant: CC(=O)Nc1cc(C(=O)CCC(=O)O)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CC(=O)Nc1cc2c(cc1C)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
In a mechanically stirred 50 L vessel, 4-(3-acetamido-4-methylphenyl)-4-oxobutanoic acid (74) (675 g, 2.87 mol) was dissolved in nitromethane (13.75 L). Thionyl chloride (255 mL, 3.49 mol) was added. The resulting mixture was stirred for about 1.5 h at rt. AlCl3 (973 g, 7.30 mol) was added maintaining a temperature of about 25° C. The resulting mixture was stirred for another about 30 min and then poured onto ice water (30 L). The resulting mixture was extracted with EtOAc (1×60 L then 2×20 L). The organic layers were combined and washed with sat. aq. NaCl (1×10 L), 1 M aq. NaOH (15 L) and sat. aq. NaCl (1×10 L). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(3-Methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (380 g, 65% yield). 1H NMR (300 MHz, DMSO): δ 9.36 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 2.86 (m, 2H), 2.55 (m, 2H), 2.23 (s, 3H), 2.06 (s, 3H), 2.00 (m, 2H).