Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1CO.O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(SC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: CSc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
A mixture of 4-(4′-methylsulfanyl-biphenyl-4-yl)-4oxo-butyric acid, methyl ester (0.3742 g, 0.001190 mol) and 1.0 M aqueous sodium hydroxide (1.3 mL, 0.0013 mol) in tetrahydrofuran-methanol (5 mL/5 mL) was stirred at room temperature for 3 days. The volatiles were rotary evaporated, and the residue was suspended in water. The suspension was acidified with 1.0 M aqueous hydrochloric acid (1.4 mL, 0.0014 mol), and the mixture was extracted with tetrahydrofuran-dichloromethane (50/50 v/v). The organics were washed with brine, dried (Na2SO4) and rotary evaporated to give 0.34 g of crude 4-(4′-methylsulfanyl-biphenyl-4-yl)-4-oxo-butyric acid as an off-white solid. A portion of this material (0.3383 g, 0.001 1 mol) was stirred with hydroxylamine hydrochloride (0.0931 g, 0.00134 mol) in the presence of sodium carbonate (0.1438 g, 0.001357 mol) in absolute ethanol (7 mL) at reflux for 20 hours and allowed to cool. The volatiles were rotary evaporated, and the residue was partitioned between dichloromethane-tetrahydrofuran (50/50, v/v) and 0.10 M aqueous hydrochloric acid (25 mL). The organics were washed with brine, dried (Na2SO4) and rotary evaporated. The residue was dissolved in tetrahydrofuran, silica gel (4.0 g) was added, and the mixture was rotary evaporated to dryness. The resulting powder was chromatographed on silica gel (48 g, 230-400 mesh), eluting with dichloromethane-diethyl ether (24:1, 13×50 mL); dichloromethanemethanol (24:1, 13×50 mL; 20:1, 10×50 mL) to give 0.0525 g of 4-hydroxyimino-4-(4′-methylsulfanyl-biphenyl-4-yl)-butyric acid as a white solid; mp 162-164° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][CH:21]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[N:22][CH:21]=2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-n3cccn3)nc2)cc1
Temperature: 100 °C

Procedure:
Pyrazole (0.34 g, 5 mmol) in 10 mL of DMF was treated with sodium hydride (0.2 g in 60% mineral oil) at room temperature. The mixture was then treated with the product from Example 21A in DMF (20 mL) and heated at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and quenched with water. The mixture was filtered and the filter cake was collected as the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (bs, 1H), 9.01 (dd, 1H), 8.71 (dd, 1H), 8.52 (dd, 1H), 8.07 (d, 1H), 7.7 (m, 1H), 7.65 (m, 2H), 7.4 (m, 2H), 6.6 (m, 1H) 1.25 (s, 9H); MS (ESI+) m/z 321 (M+H)+.
Reaction SMILES: C[OH:2].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[N:8][CH:9]=1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH2:11])=[O:2])=[N:8][CH:9]=1
Reactant: CO
Reactant: N#Cc1ccc(N)cn1
Solvent: O
Product: NC(=O)c1ccc(N)cn1
Temperature: 50 °C

Procedure:
MeOH (30 mL) was added into the mixture of 5-aminopyridine-2-carbonitrile (1191 mg, 10.00 mmol), NaBO3.H2O (2995 mg, 30.00 mmol), and H2O (30 mL), and the mixture was then heated at 50° C. for 16 h. The mixture was then concentrated in vacuo, then treated with water (30 mL), and extracted with EtOAc (4×50 mL). The combined extracts were dried over MgSO4, filtered, and concentrated in vacuo to obtain a yellow solid. The solid was triturated with 40 mL of 40% EtOAc/hexane to yield the title compound as yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=5.86 (s, 2H), 6.89 (dd, 1H, J=2.4 & 8.4 Hz), 7.07 (brs, 1H), 7.59 (brs, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=2.4 Hz). MS (ES+): m/z 138.18 (100) [MH+]. HPLC: tR=0.75 min (ZQ2000, polar—5 min).
Reaction SMILES: [N+]([CH2:4][CH3:5])([O-])=O.ClCCl.[N+]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:16]([C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:20]=1)(=[O:17])[C:15]1[CH:19]=[CH:20][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 40 °C

Procedure:
A solution of polymer in a suitable solvent (nitroethane, dichloromethane, chloroform) was treated with 4-nitro benzoyl chloride (1 eq) and aluminium chloride (1.2 eq). The solution was stirred at room temperature or at 40° C. then quenched with water. The organic layer was collected and washed with 1M HCl and 1M NaOH solutions sequentially. Concentration of the organic layer yielded the product.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)S(C(F)(F)F)(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1ccc(-c2ccc(-c3ccc4c(c3)CC(CCCCCCCC)C4)cc2)cc1
Temperature: 0 °C
Yield: 41.3 %

Procedure:
0.55 g (2.01 mM of 2-octylindan-5-boronic acid, 0.80 g (1.81 mM) of 4-(4-decylphenyl)phenyl triflate, 1.5 ml of ethanol, 2.8 ml of toluene, 2.8 ml of 2M-sodium carbonate aqueous solution and 0.09 g of tetrakis(triphenylphosphine)palladium (O) were mixed and heat-refluxed for 4 hours under stirring. After the reaction, the reaction mixture, water and toluene were added to followed by filtration under reduced pressure. The toluene layer was washed with a common salt aqueous solution followed by drying with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the mixture and the resultant mixture was evaporated to obtain a residue. Ethyl acetate was added to the residue and cooled with ice water to precipitate a crystal. The crystal was recovered by filtration and purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/ethyl acetate). The resultant crystal was further purified by silica gel column chromatography (eluent: toluene/hexane=2/1) and recrytallized from a mixture solvent (toluene/hexane) to obtain 0.39 g of 2-octyl-5-[4-(4-decylphenyl)phenyl]indan (Yield: 41.3%). ##STR312##
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[N:23]=[CH:22][C:21]([CH:24]([CH3:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.N1CCCCC1>ClCCl>[OH:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[N:23]=[CH:22][C:21]([CH:24]([CH3:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)nc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A solution of (RS) Methyl 3-{6-[2-(3-acetoxy-4-nitrophenyl)-acetylamino]-pyridin-3-yl}-butanoate (1.5 g, Reference Example 16) in dichloromethane (50 mL) was treated with a piperidine (5.0 mL). After stirring at room temperature for 1.5 hours the reaction mixture was washed with aqueous acetic acid (1M), then and dried over magnesium sulphate and then evaporated. The residual light brown oil was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (1.26 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11]Br)=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][N:15]=[N+:16]=[N-:17])=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
4-(2-Bromo-acetyl)-benzoic acid methyl ester (15.5 mmol) was dissolved in ethanol (120 ml) and acetic acid (4.8 ml). Sodium azide (31 mmol) was added and the reaction stirred at 4° C. overnight. The ethanol was removed and the mixture diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2'50 ml) and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid, which was re-crystallized from ethanol to give the title compound as a pale yellow solid (2.6 g). IR 2117 cm−1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH:25]1([CH2:24][C:4]([CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)C(C)c1ccccc1
Reactant: BrCC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 2-phenyl-propionic acid methyl ester (3.0 g, 18.27 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with the lithium hexamethyldisilazide (21.9 mL, 1M in tetrahydrofuran, 21.9 mmol) and stirred for 1 hour. Bromomethyl-cyclohexane (3.09 mL, 21.92 mmol) was added to the reaction and the reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 2.5% ethyl acetate in hexane, and 5% ethyl acetate in hexane to give the title compound (4.02 g, 84%). 1H NMR (300 MHz, CDCl3): δ ppm 1.11 (m, 10H) 1.55 (m, 4H) 1.80 (m, 1H) 2.04 (m, 1H) 3.64 (m, 3H) 7.29 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[ClH:22].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[CH3:17])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CN(C)CCCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 74.6 %

Procedure:
To a suspended solution of 4-(3-indolyl)piperidine (1.0 g, 5.0 mmol) and a 96% 3-dimethylaminopropyl chloride hydrochloride (0.91 g, 5.5 mmol) in acetonitrile (50 mL) was added potassium carbonate (2.07 g, 15 mmol) and sodium iodide (0.82 g, 5.5 mmol), and the resulting mixture was refluxed for 5 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and water (40 mL) was added to the filtrate and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; ethyl acetate) to afford a free form (1.2 g) of the title compound as pale red crystals. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (1.2 g, yield: 69%) as pale yellow crystals.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=3[C:22]3C(OC)=NC=[CH:26][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C=CC(C(N)=O)=CC=3C3CC3)CC3CC(CC(C3)C1)C2.CS(Cl)(=O)=O.[CH3:59][N:60]([CH3:65])[S:61](Cl)(=[O:63])=[O:62]>>[C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:19][S:61](=[O:63])(=[O:62])[N:60]([CH3:65])[CH3:59])=[O:18])=[CH:15][C:14]=3[CH:22]3[CH2:26][CH2:27]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Agent: NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzamide and methanesulfonyl chloride with dimethylsulfamoyl chloride, the title compound was obtained as a colorless solid (0.19 g, 34%): 1H NMR (300 MHz, CDCl3) δ 8.65 (br s, 1H), 7.64-7.56 (m, 1H), 7.41-7.35 (m, 1H), 6.85-6.77 (m, 1H), 3.57 (s, 2H), 3.01 (s, 6H), 2.19-2.08 (m, 1H), 2.02 (br s, 3H), 1.79-1.58 (m, 12H), 0.99-0.91 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z: 431.2 (M−1).
Reaction SMILES: I[C:2]1[C:3]2[NH:16][CH:15]=[CH:14][C:4]=2[C:5]2[C:10]([CH:11]=1)=[N:9][C:8]([NH2:12])=[N:7][C:6]=2[NH2:13].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([C:2]2[C:3]3[NH:16][CH:15]=[CH:14][C:4]=3[C:5]3[C:10]([CH:11]=2)=[N:9][C:8]([NH2:12])=[N:7][C:6]=3[NH2:13])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1nc(N)c2c(cc(I)c3[nH]ccc32)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Nc1nc(N)c2c(cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3[nH]ccc32)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
A solution of 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (322 mg, 0.99 mmol) in ethylene glycol dimethyl ether (3.0 mL) and ethanol (3.0 mL)at 25° C. was treated with 3,5-bis(trifluoromethyl)benzene boronic acid (510 mg, 1.98 mmol), a saturated aqueous sodium bicarbonate solution (1.5 mL), and tetrakis(triphenylphosphine)-palladium (0) (115 mg, 0.1 mmol). The resulting mixture was heated to 80° C. for 18 h, cooled, filtered and the isolated solids washed with ethyl acetate. The filtrate was pre-absorbed onto silica gel and purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10/1 methylene chloride/methanol/ammonium hydroxide) to give 6-(3,5-bis-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (218 mg, 53.5%) as a yellow solid; EI-HRMS m/e calcd for C18H11F6N5 (M+) 411.0918. Found 411.0921.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 83.3% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[OH:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1[C:10]2[N:11]([C:7]([C:4]3[CH2:3][CH2:2][N:1]([C:29](=[O:31])[CH3:30])[CH2:6][CH:5]=3)=[CH:8][N:9]=2)[C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][CH:13]=2
Reactant: CC(=O)Cl
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
To a solution of 3-[1-(1,2,3,6-tetrahydro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino]-propan-1-ol prepared in the previous example (50.0 mg; 0.132 mmol; 1 eq) in anhydrous dichloromethane (660 μL) are successively added N,N′-dimethylaminopyridine (16.1 mg; 0.132 mmol; 1 eq) and acetyl chloride (9.4 μL; 0.132 mmol; 1 eq). The solution is allowed to stir for 17 hours at room temperature until completion of the reaction. The reaction mixture is concentrated under vacuum and the resulting residue is taken-up in ethyl acetate (10 mL). The resulting organic solution is washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The resulting residue is passed through a silica gel column (dichloromethane/methanol 95:5) to afford the title compound as an off-white solid (20 mg; 0.048 mmol; 36%)
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=[O:6].CO.O1CCCC1>[Pd].C(O)C>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 101.6 %

Procedure:
4,4-Dimethyl-2-pentenoic acid (343 g), methanol/tetrahydrofuran=3/1 (150 mL) and ethanol (1240 mL) were mixed. After an addition of 10 w/w % palladium on activated carbon (31 g) to the mixture, the mixture was stirred at RT for 10.5 hr under hydrogen atmosphere (1 atm). The 10 w/w % palladium on activated carbon was filtered off and the filtrate was concentrated in vacuo to give the title compound (354 g) as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH2:22]>C(#N)C.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:22])(=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1=O
Agent: Cl[Ru](Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of (4S)-tert-butyl 4-(3-bromo-5-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (34.6 g, 91 mmol) in acetonitrile (420 mL) under stirring was added NalO4 (29.2 g, 137 mmol), and ruthenium trichloride hydrate (0.359 g, 1.729 mmol), followed by water (320 ml). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was diluted with EtOAc (500 ml), washed with brine (200 ml) twice, dried over Na2SO4, filtered and concentrated to afford the crude product, which was used directly at the next step. 40.3 grams of the crude product was obtained. LC-MS: (MW+Na): 419.9 m/z at 1.01 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH:29][C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:33]1[CH2:34][CH2:35][C:30]([OH:29])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:31][CH2:32]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: OC1(c2ccccc2)CCNCC1
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 17 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 17%; MS: m/z=569 (M+H).
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[CH:9]1[C:13]2=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=[C:12]2[N:11]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]2)[CH:10]=1.C[C:28]([O-:30])=[O:29].[Na+]>CN(C=O)C>[NH2:18][C:14]1[C:13]2[C:9]([C:28]([OH:30])=[O:29])=[CH:10][N:11]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]3)[C:12]=2[N:17]=[CH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: Nc1ncnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)O)cn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 0.17 h

Procedure:
NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added, at room temperature, to a solution of 2'-deoxytubercidin (1.0 g, 4.0 mmol) and NaOAc (0.78 g, 8.0 mmol) in dried DMF (10 ml). The red solution is stirred for 10 minutes and then evaporated. Title compound (38) is obtained as colorless crystals (400 mg, 25%) following flash chromatography (column: 20×5 cm, CH2Cl2 /MeOH, 9:1), evaporation of the more rapidly migrating zone and subsequent recrystallization from isopropanol. Isolation of the more slowly migrating zone yields 5-bromo-2'-deoxytubercidin (130 mg, 10%). Method B: a solution of NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added to a solution of 5-bromo-2'-deoxytubercidin (1.3 g, 4.0 mmol) and NaOAc (0.785 g, 8.0 mmol) in dried DMF (10 ml). Purification, see method A. Yield: 490 mg, 30% of 21. Melting point: 181° C. TLC (silica gel, CH2Cl2 /MeOH, 9:1): Rf 0.40. 1H-NMR (D6 -DMSO): δ=2.12 (m, Hα -2'); 2.50 (m, Hβ -2'); 3.51 (m, 2H, H-5'); 3.84 (m, 1H, H-4'); 4.44 (m, 1H, H-3'); 5.20, (br, 2H, 5'-OH, 3'-OH); 6.42 ("t", J=6.2 Hz, 1H, H-1'); 6.93 (br, 2H, NH2); 8.10 (s, 1H, H-2).