Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[N:7]([C:20]1[N:21]([C:25]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([O:34]CC3C=CC=CC=3)=[CH:27][C:26]=2[O:42]CC2C=CC=CC=2)[N:22]=[N:23][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:50])[N:7]([C:20]1[N:21]([C:25]2[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([OH:34])=[CH:27][C:26]=2[OH:42])[N:22]=[N:23][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1cc(-n2nncc2N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(-n2nncc2N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c(O)cc1O
Reaction time: 1 h

Procedure:
Pd(OH)2/C (0.02 mmol) was added to [3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-(4-morpholin-4-yl-phenyl)-carbamic acid t-butyl ester (135 mg, 0.2 mmol) dissolved in EtOH (5 ml) and the mixture was subjected to one atmosphere of H2 for 1 hour. The catalyst was filtered off through Celite® pad and ethanol was removed under reduced pressure. The crude reaction mixture was used in the next reaction without any purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CCOC(C)=O>C1COCC1>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:6]2[C:7]([CH3:9])=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[O:11])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (1.68 g, 7.51 mmol) in 3 mL THF was added dropwise to a solution of 4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol) in THF (15 mL) at 0° C. The solution was stirred for 10 min., poured into EtOAc and washed with saturated aq. NaHCO3 (2×), and brine. The organics were dried (Na2SO4) and concentrated. The crude product was suspended in iPrOAc/Et2O (10 mL, 1:1), stirred at 0° C. for ½ hr, and collected by suction filtration to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (2.04 g, 5.21 mmol, 88% yield) as a white solid: TLC Rf=0.28 (35% EtOAc/Hex); 1H NMR (CDCl3, 400 MHz) δ 8.88 (bs, 1H), 8.41 (d, 1H), 7.96 (dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22 (m, 1H), 2.75 (s, 3H); MS (Q1) 392 (M)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Reaction time: 0.5 h

Procedure:
4-Nitrobenzimidazole (41.7 moles, 6.8 g) was dissolved in 200 ml DMF. Sodium hydride (47.5 moles, 1.9 g of 60% in mineral oil) was added portionwise. The reaction was stirred for 30 minutes. Ethyl 2-bromooctanoate was added. The reaction stirred at room temperature for 3 hours and concentrated. Ethyl acetate and water were added; and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The intermediate was purified by HPLC over silica gel eluted with a gradient of 0-50% ethyl acetate in hexane. The reaction yielded 10.3 g of ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate. (MS)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[NH:30][CH2:31][CH2:32][N:33]=2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH:30]1[CH2:31][CH2:32][N:33]=[C:29]1[C:25]1[CH:24]=[C:23]([O:1][C:2]2[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=3)=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Clc1ccnc(C2=NCCN2)c1
Reactant: CC(C)c1cccc(NC(=O)/C=C/c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(NC(=O)/C=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)c1
Temperature: 100 °C

Procedure:
To a solution of (E)-3-(3-hydroxyphenyl)-N-(3-isopropylphenyl)acrylamide (3.20 mmol) in DMF (40 mL) was added 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine (11.2 mmol) and cesium carbonate (16.0 mmol). The heterogeneous mixture was heated at 100° C. for 18 h and then cooled to rt. The mixture was diluted with water and extracted with EtOAc. The combined organic solutions were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (90:10:1 DCM:MeOH:NH4OH) to give B-2. 1H NMR (300 MHz, d6-DMSO): δ 10.13 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 7.56-7.61 (m, 3H), 7.50-7.54 (m, 2H), 7.44-7.47 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.20-7.29 (m, 2H), 7.17 (dd, J=6.8, 2.8 Hz, 1H), 6.93-6.99 (m, 2H), 6.85 (d, J=15.6 Hz, 1H), 3.32 (s, 4H), 2.85 (sept, J=6.8 Hz, 1H), and 1.18 (d, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Product: Cc1ccc(C=CC(=O)O)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 2h30) between 3-fluoro-4-methyl-benzaldehyde (10.519 g; 76.154 mmol) and malonic acid (15.056 g; 144.694 mmol) gave the product 3-(3-fluoro-4-methyl-phenyl)-acrylic acid as a colorless solid (11.860 g; 86%). LC-MS: tR=0.84 min; [M+H]+: no ionisation.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To 30 ml of N,N-dimethylformamide was added, with stirring, 2.8 g (10 mmole) of N-benzoyl-2-oxindole-1-carboxamide, followed by 2.9 g (24 mmole) of 4-(N,N-dimethylamino)pyridine. The mixture was cooled in an ice-bath and then to it was added, dropwise, with stirring, during 10 minutes, a solution of 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of N,N-dimethylformamide. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture prepared from 250 ml of water and 8.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 75 ml of acetic acid to give 2.94 g of the title compound as yellow-brown crystals, mp 190° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=[CH:12][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 2.78 mmol) in THF (9 mL) was added NaH (136 mg, 3.42 mmol) at 0° C. After 10 minutes, SEMCl (0.59 mL. 3.33 mmol) was added slowly to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (810 mg, 94% yield). 1H NMR (600 MHz, CDCl3) δ 10.62 (s, 1H), 8.90 (s, 1H), 7.52 (d, J=3.6 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 5.76 (s, 2H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][NH:22][CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH:25](Br)([CH3:27])[CH3:26]>>[CH:25]([N:22]1[CH2:23][CH2:24][C:9]2[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[N:11][C:10]=2[CH2:21]1)([CH3:27])[CH3:26]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1CCNC2
Reactant: CC(C)Br
Product: CC(C)N1CCc2c(nc(-c3cnc(N)nc3)nc2N2CCOC[C@@H]2C)C1

Procedure:
Compound fk was prepared according to the procedure described in Example 2 by reacting (S)-5-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine with isopropylbromide. LC-MS: m/z=+370 (M+H)−.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@H:16]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([CH:25]4[CH2:30][CH2:29][N:28](CC5C=CC=CC=5)[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@H:16]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCNCC3)CC2)cc(C)c1O

Procedure:
A solution of 51 mg (0.07 mmol) (R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate (Example 2.7) in 10 mL MeOH was combined with 5 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure until the reaction came to an end. The catalyst was removed by suction filtering and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.C([O-])(=O)C.[Na+]>C(O)=O>[CH:5]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:7]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: O=CNC1Cc2ccccc2C1
Temperature: 0 °C

Procedure:
Acetic anhydride (40 ml) and formic acid (20 ml) were mixed and heated at 50° for 15 minutes with stirring. 2-Aminoindane hydrochloride (25 g) (see J. Med. Chem., 1980, 23, page 745) and sodium acetate (20 g) were added to this mixture which was then stirred at room temperature for 24 hours. The reaction mixture was poured into ice/water and extracted three times with methylene chloride. The combined organic layers were washed with water and aqueous sodium carbonate, dried (MgSO4) and evaporated in vacuo to give the title compound, yield 17.6 g, m.p. 72°-74°.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]>C1COCC1.O.C1COCC1>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of NaBH4 (0.53 g, 14 mmol) in THF/H2O (4:1) (12 ml) was added dropwise to an ice-cold stirred solution of 4-formylcinnamic acid (2.47 g, 14 mmol) in THF (25 ml), and the mixture was stirred at room temperature for 3 h. The reaction was quenched by adding 4N HCl (20 ml), and the THF was removed by a rotary evaporator. The solid residue was treated with H2O (20 ml), and extracted with EtOAc (4×50 ml). The EtOAc extracts were washed with H2O (50 ml) and brine (50 ml), and dried. The crude product was recrystallized from EtOAc to afford pure 4-hydroxymethylcinnamic acid 124 (1.3 g, 52% yield) as yellow solid. 1H NMR (300 MHz, CD3OD): δ4.62 (s, 2H), 6.45 (d, J=16.2 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.65 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CD3OD): δ63.53, 117.81, 127.17, 128.08, 133.58, 144.25, 144.92, 169.22; MS (ESI): m/z 177 (M−1).
Reaction SMILES: C[C@H](OC1N=C2C(N=C(OC)N2CCCC[NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=C(N)N=1)CCC.Cl[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:44]([O:45][CH3:46])=[N:43][C:42]2[C:37]1=[N:38][C:39]([O:48][C@@H:49]([CH3:53])[CH2:50][CH2:51][CH3:52])=[N:40][C:41]=2[NH2:47].O1CCC(N)CC1>>[CH3:53][C@H:49]([O:48][C:39]1[N:38]=[C:37]2[C:42]([N:43]=[C:44]([O:45][CH3:46])[N:36]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:41]([NH2:47])[N:40]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Agent: NC1CCOCC1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCNC3CCOCC3)c2n1
Temperature: 70 °C

Procedure:
Prepared similarly to Intermediate 36 from 9-(5-chloropentyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and tetrahydro-2H-pyran-4-amine but with heating at 70° C. for an additional 20 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[H-].[Na+].BrCCC[CH2:25][Cl:26].C1C=C2NS(C3=CC=CC(=C23)C=1)(=O)=O>CN(C)C=O>[Cl:26][CH2:25][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17]
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: ClCCCCBr
Agent: O=S1(=O)Nc2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl

Procedure:
2-(4-Chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may be obtained in the following manner: operating as in Example 1 for the preparation of 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide, starting with sodium hydride (4.8 g) in a 50% dispersion in vaseline oil, 1-bromo-4-chlorobutane (11.9 cc) and 1,8-naphthosultam (20.5 in dimethylformamide (250 cc). After purification by flash-chromatography on a silica under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and cyclohexanone (30-70 vol) as eluant, 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (24.6 g) is obtained in the form of a yellow oil which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20].O>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5])=[O:25])(=[O:21])[CH3:20]
Reactant: CCNc1cccc(N)c1C#N
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCNc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (6.7 g) in methylene chloride (100 ml) is added pyridine (4.8 ml), and to the mixture is added dropwise acetoxyacetyl chloride (6.5 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (7.8 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][N:18]([CH2:20][CH2:21][OH:22])[CH3:19].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:22][CH2:21][CH2:20][N:18]([CH3:19])[CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, dimethylaminoethanol and DBU in dioxane. 329 (M{9Br}+H+, 95), 327 (M{10Br}+H+, 100).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1.[Br:16][CH2:17][C:18](Br)=[O:19]>C1COCC1>[Br:16][CH2:17][C:18]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1)=[O:19]
Reactant: O=C(N[C@@H]1CCNC1)c1ccc(Cl)s1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCN(C(=O)CBr)C1)c1ccc(Cl)s1

Procedure:
7.1 A solution of 400 mg 5-chloro-thiophene-2-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example 6.2) in 5 ml THF was treated with 0.31 ml TEA and 0.16 ml bromo acetylbromide. The reaction mixture was stirred over night. The precipitate was filtered and washed with THF. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 98:2) to give 250 mg 5-chloro-thiophene-2-carboxylic acid [(R)-1-(2-bromo-acetyl)-pyrrolidin-3-yl]-amide. Off-white amorphous solid. 353.1 ([M+H]+)
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO.O1CCCC1>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 5 h
Yield: 47.5 %

Procedure:
Add magnesium chloride (27.7 g, 0.29 mol) to 2-methoxyethanol (400 mL) and heat the mixture to reflux. Add a solution of 3-(3,4-Dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (0.29 mol) in 2-methoxyethanol (100 mL) and tetrahydrofuran (40 mL) slowly to the MgCl2 mixture over 1 hour. Upon completion of addition, stir the mixture for 5 hours at reflux, and then concentrate under reduced pressure. Treat the concentrated crude mixture with 2N hydrochloric acid (500 mL) and extract with dichloromethane (3×400 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 20% ethyl acetate/hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as an orange solid (31.6 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.[OH-].[Na+]>C(O)C>[CH:37]1([CH2:36][O:30][C:28]2[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:14]4[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:15]4)[CH2:17][CH2:18]3)=[O:23])[CH:29]=2)[CH2:39][CH2:38]1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCC5CC5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 0.35 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.11 ml (bromomethyl)cyclopropane in 8 ml ethanol is treated with 0.11 ml 10n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 16 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:15])SCC(O)=O)=[CH:5][CH:4]=1.[OH-].[K+].O.[NH2:19][NH2:20].Cl>CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:19][NH2:20])=[S:15])=[CH:5][CH:4]=1
Reactant: NN
Reactant: CSc1ccc(C(=S)SCC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=S)NN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step c) (15.0 g) in methanol (200 ml) was added aqueous potassium hydroxide (58.0 ml, 1M) followed by hydrazine monohydrate (3.1 ml) dropwise over 30 minutes. After stirring at room temperature for 1 hour the mixture was acidified to pH 5 with concentrated hydrochloric acid. The resulting precipitate was filtered off and recrystallised from ethanol to afford the sub-title compound (9.9 g) as pale yellow plates. mp 152°-153°.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:29]=O.O.[OH-].[Na+]>C(O)=O>[CH3:29][N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:4][CH2:5]1
Reactant: OC1(C(CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 1-{2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (590 mg, 1.59 mmol) (see Example 23), in formic acid (3.1 mL) at 50° C., was treated with an aqueous solution of formaldehyde (37% in water, 1.3 mL, 1.94 mmol). The reaction was heated at 70° C. for 1.5 h, after which time the reaction was poured into water (50 mL) and basified to pH=10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3×20 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 442 mg (72%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H29F3N2O2.2.00 HCl, 458.1715; found (ESI), 387.2263.