Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[CH:10][C:9]=1[NH:20][CH3:21].C(N(CC)CC)C.[F:29][C:30]([F:48])([F:47])[C:31]1[CH:32]=[C:33]([C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43])[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.O>ClCCl>[F:39][C:37]([F:40])([F:38])[C:35]1[CH:34]=[C:33]([C:41]([CH3:46])([CH3:45])[C:42]([N:20]([C:9]2[CH:10]=[N:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:21])=[O:43])[CH:32]=[C:31]([C:30]([F:48])([F:29])[F:47])[CH:36]=1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCOCC2)cc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
8.56 g (28.1 mmol) [4-(2-Chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-methyl-amine were dissolved in 50 ml dichloromethane in the presence of 5.5 ml (1.4 eq.) triethylamine and cooled to 0° C. A solution of 10.8 g (1.05 eq.) 2-(3,5-bistrifluoromethyl-phenyl)-2-methyl-propionyl chloride (step a) in 10 ml dichloromethane was added slowly and after 2 hours, 80 ml water was added. After 15 minutes stirring, the phases were separated, the aqueous phase was extracted with 2 portions of 80 ml dichloromethane and the combined organic extracts were washed with 80 ml water, 80 ml 2% aqueous NaOH, 80 ml water and 80 ml 5% aqueous NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. Crystallization from 40 ml 2-propanol and 20 ml ethanol at −20° C. yielded 14.2 g (86%) of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide as a white powder of m.p.=134.4-135.5° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:8][P:9]([CH:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:24]([O-:26])=[O:25])([O:11][CH2:12][CH3:13])=[O:10])[CH3:7].Br[CH2:28][CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1.O>CCCCCC.O1CCCC1>[CH2:6]([O:8][P:9]([O:11][CH2:12][CH3:13])([CH:14]1[CH:23]=[C:22]([CH2:28][CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:24]([O:26][CH2:1][CH3:2])=[O:25])=[O:10])[CH3:7]
Reactant: BrCCC1OCCO1
Reactant: CCOP(=O)(OCC)C1C=Cc2ccccc2N1C(=O)[O-]
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1c2ccccc2C(CCC2OCCO2)=CC1P(=O)(OCC)OCC
Yield: 62.7 %

Procedure:
75 ml of a 1.6 M solution of n-butyllithium in hexane is added at -78° C., to a solution containing 33.933 g of ethyl 2-(diethoxyphosphinyl-1(2H)-quinoline carboxylate in 500 ml of tetrahydrofuran. Next 18 ml of 2-(2-bromoethyl)-1,3-dioxolane is added. The reaction medium is allowed to return to ambient temperature, then maintained under agitation for 5 hours. 300 ml of water is added, followed by agitation and decanting. The organic phase is washed with water and dried followed by filtration and elimination of the solvent. 63.45 g of product is obtained which is purified by chromatography eluting with ethyl acetate. In this way the sought product is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[CH2:39][C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[C:39](=[CH:20][C:3]4[NH:4][C:5]5[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]6[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]6)[C:7](=[O:19])[C:6]=5[C:2]=4[CH3:1])[C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 46.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (44 mg, 46.8%) as an orange solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](N)C3)n2)c1
Yield: 37 %

Procedure:
The aforesaid tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 108 (33.9 mg, 37%). 1H NMR (400 MHz, DMSO) δ 9.35-9.30 (s, 1H), 9.13-9.10 (d, J=2.0 Hz, 1H), 9.06-9.02 (s, 1H), 8.66-8.61 (s, 1H), 8.58-8.55 (d, J=2.0 Hz, 1H), 8.35-8.31 (d, J=1.9 Hz, 1H), 7.78-7.70 (t, J=8.1 Hz, 1H), 7.23-7.17 (d, J=7.7 Hz, 1H), 6.84-6.78 (d, J=8.5 Hz, 1H), 4.32-4.14 (dd, J=37.4, 11.8 Hz, 2H), 3.12-3.01 (td, J=12.8, 5.7 Hz, 2H), 2.87-2.70 (ddd, J=15.5, 13.1, 7.6 Hz, 2H), 1.96-1.74 (m, 2H), 1.64-1.51 (dd, J=24.5, 11.5 Hz, 2H), 1.33-1.31 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 414.1 [M+H]+
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:64])([F:52])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: COC(O)C(F)(F)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) was stirred at rt for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layers were washed in succession with saturated aq. brine (100 mL), dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which solidified upon standing. For the title compound:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30](=[O:32])[CH3:31])[CH2:24][C:25]([F:28])([F:26])[F:27])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(CC(F)(F)F)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-fluoro-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCCCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCCC)n1

Procedure:
A mixture of 9.5 g. 3-n-pentylthio-1,2,4-triazole, 8.07 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 68 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-pentylthio-1,2,4-triazole, b.p. 135° C./0.1 mm. (90.6% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13]>C1COCC1>[CH3:9][C:10]([CH3:15])=[CH:11][C:12]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: CC(C)=CC(=O)Cl
Reactant: Sc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Sc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice bath cooled solution of 1.92 g (80 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3×15 ml hexane wash) in 30 ml of dry THF was added slowly under argon a solution of 15.1 g (80 mmol) of 4-bromothiophenol in 60 ml of dry THF over 1 hour. The mixture was stirred at 0 degrees C. for a further 30 min and then treated with a solution of 10.1 g (85 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture then stirred at room temperature for 40 h. The reaction mixture was poured into 200 ml of water containing 2 ml of glacial acetic acid and the organic layer was separated. The organic layer was washed with 2×75 ml of water and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[CH:30]=[CH:29][C:13]([CH2:14][S:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].CCOC(OC(OCC)=O)=O.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[S:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[O:2])=[CH:32][CH:31]=2)=[CH:30][CH:29]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3)n(C)c(=O)c12
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)N5CCN(C)CC5)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (0.320 g, 0.720 mmol) in DMF (5.0 ml) were added DEPC (0.37 g, 2.27 mmol) and 1-methylpiperazine (0.200 ml, 1.80 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol: ammonia=20:1:0.1). The resulting solid was recrystallized from ethanol to provide colorless needles.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C>[OH:12][C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][N:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: Oc1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
The mixture of o-benzoyl benzoic acid (11.3 g; 0.05 mol) and hydrazine (0.15 mol) in ethanol (150 ml) is stirred at room temperature for 5-24 hours to give 1-hydroxy-4-phenyl phthalazine as a white precipitate which is filtered off and is washed with ethanol. (12.3 g)(m.p. 240° C.)
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Mg]Br)=[CH2:29].[Cl-].[NH4+].[CH2:34]1COC[CH2:35]1>>[C:1]([O:20][CH2:21][C@@H:22]([OH:26])[CH2:23][CH2:24][C:25]([CH:28]=[CH2:29])([OH:27])[CH:34]=[CH2:35])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC(O)(C=C)CC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
26.9 g of (5S)-5-[(trityloxy)methyl]tetrahydro-2-furanone was dissolved in 200 ml THF, 300 ml solution of 1 M vinylmagnesium bromide in THF was added thereto at room temperature, and it was stirred for 1.5 hr under heating and reflux. After the reaction was completed, saturated aqueous ammonium chloride was added thereto under ice-cooling, extracted with ethyl acetate, and then washed twice with brine. The solvent was removed and the resulting residue was purified by silica gel column chromatography to give 13.0 g of (2S)-1-(trityloxy)-5-vinyl-6-heptene-2,5-diol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O>C(#N)C>[ClH:12].[Cl:12][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccncc1F
Solvent: CC#N
Product: Cl
Product: Fc1cnccc1CCl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
6.710 g (52.785 mmol) of (3-fluoropyridin-4-yl)methanol was put in 29 ml acetonitrile and heated to 50° C. Then a solution of 7.701 ml thionyl chloride in 14.5 ml acetonitrile was added dropwise and the reaction mixture was stirred for 4 h at 50° C. Then the reaction mixture was concentrated by evaporation and was co-distilled three times with dichloromethane. After drying under high vacuum, 10.27 g of the title compound was obtained, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[CH3:23][S:24]([NH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[CH:8]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-[5-(Methanesulfonylamino-methyl)-naphthalen-2-yl]-benzenesulfonamide. 5-(Methanesulfonylamino-methyl)-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[C:23]1([C:29]2[N:30]=[N:31][N:32]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:36]4[CH2:37][CH2:38][CH:34]([N:32]5[CH:33]=[C:29]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:30]=[N:31]5)[CH2:35]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: Cc1c(F)c(N2CCC(n3cc(-c4ccccc4)nn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (100 mg, 0.37mmol),3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (160 mg, 0.67 mmol) and diazobicycloundecane (102 mg, 0.67 mmol) in (5 ml) pyridine was heated at 90° C. for 24 hrs. The reaction mixture was concentrated and diluted with water. The separated solid was filtered and washed with water followed by ether and was crystallized from methanol. Yield: 89 mg (55%), m.p. 221.4° C. 1H NMR (TFA) δ: 1.20-1.70 (m, 4H), 2.76-3.80 (m, 2H), 4.20-4.96 (m, 5H), 5.74-5.90 (m, 1H), 7.52 (dd, 5H), 8.70 (s, 1H), 9.27 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH3:15]CCCCC.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>>[CH2:25]([O:24][C:21](=[O:23])[CH:22]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[CH3:15])[CH3:26]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCCC2
Product: CCOC(=O)C(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC2
Yield: 43 %

Procedure:
5,6,7,8-Tetrahydro-3-nitro-2-naphthol is alkylated according to the general instructions that are mentioned in Example A) with D,L-2-bromopropionic acid ethyl ester. After column chromatography with hexane/ethyl acetate, the nitro compound is obtained in a yield of 43%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[CH2:17][C:18](=[O:21])[CH2:19][CH3:20].O>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:15][CH2:17][C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)CBr
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)COc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
Cesium carbonate (108 g, 0.33 mol) was added in one portion to a stirred solution of 3,5-dichlorophenol (49 g, 0.30 mol) in acetone (900 ml) at room temperature under nitrogen. To this suspension a solution of 1-bromo-2-butanone (30.6 ml, 0.30 mol) in acetone (300 ml) was added dropwise and the resultant suspension was heated under reflux for 2 hours. The suspension was cooled to room temperature, water (200 ml) was added and the acetone was removed under reduced pressure. The mixture was extracted with dichloromethane (2×300 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a clear oil. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:cyclohexane (50:50, by volume) to provide the title compound (65 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:6]=2[CH:17]=1.[C:18]1([S:24]([Cl:27])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:27].[CH3:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[C:6]3[CH:17]=[C:2]([NH:1][S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2coc3ccc(N)cc23)CC1
Product: CN1CCC(c2coc3ccc(NS(=O)(=O)c4ccccc4)cc23)CC1
Product: Cl

Procedure:
Beginning with a mixture of 0.018 gm (0.07 mMol) 5-amino-3-(l-methylpiperidin-4-yl)benzofuran and 27 μL (0.21 inMol) phenylsulfonyl chloride, 0.0056 gm of the title compound were prepared by the procedure of EXAMPLE 18.
Reaction SMILES: C(Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].[C:15]([O:18][CH2:19][CH3:20])(=O)[CH3:16].O>CC(C)=O>[CH2:19]([O:18][C:15]1[CH:16]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:9](=[O:12])[CH2:2][CH2:7]2)[C:20]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 94 %

Procedure:
This product was suspended in acetone (120 mL), and benzyl bromide (10.9 g, 64.0 mmol) and potassium carbonate (12.3 g, 88.9 mmol) were added, and the mixture was heated under reflux under nitrogen atmosphere for 1 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (14.2 g, 94%) as pale-yellow crystals (recrystallized from ethyl acetate).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:16](OC(=O)C)(=O)C>>[CH3:16][O:11][C:10]([C:8]1[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:12]
Reactant: O=C(O)c1ccc(C2CC2)nc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1nc(C2CC2)ccc1C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-cyclopropyl-pyridine-2,3-dicarboxylic acid (D82, 19.8 g, 95.6 mmol) in acetic anhydride (100 ml) was heated at 110° C. for 2 hours and then was concentrated in vacuum. To the residue was added methanol (100 ml) and stirring was continued at room temperature for 2 hours. The reaction mixture was concentrated in vacuum and the residue was purified by column chromatography on silica gel (10% ethyl acetate in petroleum ether) and C-18 reversed phase column (5% methanol/water to methanol) to give D83 (10.7 g) as a yellow solid.