Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:44])[CH2:19][C:20]2[N:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:44])[CH2:19][C:20]2[N:21]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(CC(O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(CC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a cold (−70° C.) solution of oxalyl chloride (0.27 mL, 3.06 mmol) in dichloromethane (15 mL) is added DMSO (0.32 mL, 6.11 mmol) followed by the alcohol 256 (1.28 g, 2.48 mmol) in dichloromethane (5 mL). The mixture is stirred for at −70° C. solution 15 min., and triethylamine (1.03 mL, 13.9 mmol) is added and the mixture is allowed to come to RT and is stirred for 4 h. The reaction mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue is recrystallized from Et2O to give 1.02 g of the product 257. 1H NMR (CDCl3) δ 10.60 (s, 1 H), 8.10-7.95 (m, 2 H), 7.10-6.90 (m, 12 H), 6.90-6.70 (m, 2 H), 5.40 (s, 2 H), 1.25 (s, 9 H); MS: m/z 459 (M++1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]([OH:22])[CH2:10][C:11]2=[O:21])[CH2:3]1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:23][C@H:6]1[CH:5]=[C:4]2[C@:17]([CH3:20])([CH2:18][CH2:19][C@H:2]([O:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3]2)[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:21])[CH2:10][C@@H:9]1[O:22][C:11](=[O:21])[C:12]([CH3:14])([CH3:13])[CH3:8]
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H](OC(=O)C(C)(C)C)CC(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
One gram of 3β,7β,15α-trihydroxy-5-androsten-17-one is dissolved at room temperature in 20 ml of pyridine; 2 ml of pivalic acid chloride as well as 100 mg of 4-dimethylaminopyridine are added to the reaction mixture, and the latter is agitated at room temperature for 48 hours. The reaction mixture is then poured into 250 ml of ice water, stirred for 2 hours at room temperature, the resultant precipitate is vacuum-filtered, washed with water, and dried for 8 hours in a vacuum drying cabinet at 50° C., yielding 1.38 g of 7β-hydroxy-3β,15α-dipivaloyloxy-5-androsten-17-one, mp 195°-197° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])(C)(C)C.S(C)C.C1C[O:22]CC1>CCCCC>[OH:22][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10]
Reactant: C1CCOC1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: CSC
Solvent: CCCCC
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (7.07 g, 36.1 mmol) in 225 mL of THF at -78° C. is added a 1.7 M solution of tert-butyl lithium (45.6 mL, 77.6 mmol) in pentane. After 5 minutes, CuBr.SMe2 (15.9 g, 77.6 mmol) is added. The resulting solution is stirred for 10 minutes, then O2 is slowly bubbled through the reaction mixture for 30 minutes. After this time, the solution is allowed to warm to ambient temperatures. The solution is stirred for 16 hours. The solution is then poured into 100 mL of H2O. The solution is diluted with EtOAc. The layers are separated. The organic layer is washed with saturated (NH4)2SO4 solution. The organic layer is then extracted with 10 N NaOH. The collected aqueous basic layers are acidified to pH=6 with 6N HCl. The solution is then extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The title compound is obtained as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([Cl:13])[C:4]=1[CH2:5][NH2:6].C[Al](C)C.[CH:18]1([CH:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH:18]1([CH:24]([CH2:28][CH2:27][OH:26])[C:25]([NH:6][CH2:5][C:4]2[C:3]([Cl:2])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=2[Cl:13])=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(Cl)c(CN)c(Cl)c1
Reactant: O=C1OCCC1C1CCCCC1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(CNC(=O)C(CCO)C2CCCCC2)c(Cl)c1
Yield: 80.5 %

Procedure:
Treat a mixture of 2,6-dichloro-4-methoxy-benzylamine hydrochloride (4.0 g, 16.6 mmol) and toluene (100 mL) with trimethylaluminum (2 M in toluene, 16.6 mL, 33.2 mmol) at room temperature for 10 minutes. To the mixture, add a solution of 3-cyclohexyl-dihydro-furan-2-one (2.51 g, 14.94 mmol) in toluene (50 mL). Stir the reaction at reflux for 6 hours. Cool the reaction and quench with HCl (1 N, 50 mL). Partition the mixture with ethyl acetate and HCl (1 N). Separate the organic layer and wash with water and brine. After drying the organic layer over sodium sulfate and filtration, concentrate the filtrate to afford 4.5 g (81%) of the title compound as white solid. MS (m/z): 374 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>[Fe].C(O)(=O)C.CN(C)C=O>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[O:16][CH3:17])[N:18]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: COc1cc(C=C(C#N)C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Temperature: 90 °C

Procedure:
Iron powder (65.2 g., 1.22 moles) is added over a period of one-half hour to a slurry of α-cyano-β-(2-nitro-4,5-dimethoxyphenyl)acrylamide (75.0g., 0.271 mole) in a 50% solution of acetic acid-N,N-dimethylformamide (750 ml.) at 75°C. When addition of the iron powder is complete, the mixture is heated to 90°C. for 4 hours and then filtered while hot. The filter cake is washed with hot acetic acid (150 ml.). The dark red filtrate is gradually added to IN hydrochloric acid (1500 ml.) and the pink precipitate recovered by filtration and recrystallized from an excess (10%) of aqueous sodium hydroxide. The solid is filtered, washed with cold isopropanol and dried to give the title product as yellow crystals. Yield = 57.1 g. (83.5%); mpp. 274°-275°C.
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.C1COCC1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23](N(OC)C)=[O:24])[CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23](=[O:24])[CH3:4])[CH:18]=1
Reactant: CON(C)C(=O)c1cc(Cl)ccn1
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a 0° C. solution of 1.4 M methyl magnesium bromide in toluene/THF (6.89 mL, 9.65 mmol) in anhydrous THF (8.77 mL) was added a solution of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide (1.06 g, 5.26 mmol) in anhydrous THF (8.77 mL). The reaction mixture was stirred at RT under N2 for 17 h. The volatile solvent was removed under reduced pressure, and partitioned between EtOAc and water. The organic layer was washed with H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 10% EtOAc/Hex to afford 652 mg of 1-(4-chloropyridin-2-yl)ethanone (95.5%) as a white crystalline solid. 1H-NMR (Acetone-d6) δ 8.69 (d, J=5.4 Hz, 1H), 7.95 (dd, J=2.1, 1.0 Hz, 1H), 7.71 (dd, J=5.4, 2.1 Hz, 1H), 2.65 (s, 3H); TLC (10% EtOAc/Hex), Rf=0.26.
Reaction SMILES: [N:1]1([C:6]([C:8]2([C:11]3[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([N+:17]([O-])=O)[CH:16]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.C.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1([C:6]([C:8]2([C:11]3[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([CH:16]=3)[NH2:17])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCC1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(C2(C(=O)N3CCCC3)CC2)ccc1Cl

Procedure:
1.8 g (8.14 mmol) of 5-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-2-chloro-nitrobenzene are dissolved in 30 ml of ethyl acetate and 30 ml of ethanol and after the addition of 0.8 g palladium on active charcoal (10%) hydrogenated for 3 hours at ambient temperature with hydrogen. Then the catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1>CCCCCC.O1CCCC1.O.C(O)(=O)C>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]([OH:36])([CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: CCc1ccncn1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CC(c1ccncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
n-Butyllithium (4.0 ml of a 2.5M solution in hexane) was added to a stirred solution of diisopropylamine (1.01 g) in dry tetrahydrofuran (30 ml) at -70° under an atmosphere of dry nitrogen. The solution was stirred at -70° for 0.17 hour, followed by 0.17 hour at 0° and then re-cooled to -70°. 4-Ethylpyrimidine (1.08 g) was added and the solution was stirred at -70° for 0.75 hour. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g) in dry tetrahydrofuran (30 ml) was added over 0.17 hour. The solution was stirred at -70° for 1 hour and then acetic acid (1 ml) was added. The solution was allowed to reach room temperature and was then diluted with water. The mixture was extracted three times with ethyl acetate and the combined extracts were washed with water then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Initial alution with ethyl acetate/hexane (3:2) gave recovered ketone starting material. Further elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.305 g), m.p. 114°-115.5° (from ether/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:16](=[O:19])[CH2:17][CH3:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromoaniline (5.10 g) and triethylamine (8.3 ml) in THF (40 ml) was added dropwise propionyl chloride (2.8 ml) at 0° C. and the mixture was stirred at 0° C. for 2 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.60 g) as colorless needle crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[C:6]([CH3:20])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:33].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:33].[ClH:33].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[C:6]([CH3:20])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCN(CCO)CCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)ccc1NCCN(CCO)CCO

Procedure:
The 2-[[2-(4-nitro-2-methylphenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (17) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[C:9]([Cl:29])[CH:8]=1)=[O:5].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.[Pd](Cl)Cl.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>[Cl:29][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=2[C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[CH:26]=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14]
Reactant: OB(O)c1cccs1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-c1cccs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 135.5 %

Procedure:
The 2-bromo-N-[3-chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]benzamide (1.04 g, 2.0 mmol) and thiophene-2-boronic acid (0.32 g, 2.4 mmol), and barium hydroxide octahydrate (0.88 g, 2.8 mmol) was suspended in ethylene glycol dimethyl ether (28.8 ml) and water (4.8 ml). The heterogeneous mixture was stirred at room temperature and purged with nitrogen for ten minutes before bis(triphenylphosphine) palladium (II) chloride (0.17 g, 0.24 mmol) was added. The reaction was capped with a nitrogen balloon and heated in an oil bath at 70° C. After 20 hours, additional thiophene-2-boronic acid (0.13 g, 1 mmol) was added to the reaction. After 24 hours additional bis(triphenylphosphine)-palladium(II)chloride (84 mg, 0.12 mmol) was added to the reaction flask. The reaction was cooled to room temperature and the mixture was extracted into benzene. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a brown solid (1.42 g). The solid was triturated with ethyl acetate and filtered. The filtrate was purified by flash chromatography using silica gel with hexane-ethyl acetate (1:1) as the mobile phase to afford a pale yellow solid (0.59 g, 56%), which was dried under vacuum at 78° C. for two days, m.p. 132°-136° C. MS (EI),m/z: 523 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL) , 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (53%). white solid mp 207° C. , MS: 462.5 (M+H)+.
Reaction SMILES: [CH3:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([OH:24])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1.[OH-].[K+]>C(O)C>[OH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1
Reactant: CCCCCCC(C)Br
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
According to a known method, optically active 2-octyl bromide and 2,7-dihydroxyfluorene were reacted in ethanol in the presence of potassium hydroxide. The resultant reaction mixture was purified by a column chromatography and recrystallization to obtain optically active 2-hydroxy-7-(2-octyloxy)-fluorene.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:9])=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 71 %

Procedure:
As described for example 160c, 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (80 mg; 255 μmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (101 mg, 71%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Cu+2].CS(C)=O>[O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]([F:10])([F:22])[F:23])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccn(-c2ccc(OC(F)(F)F)cc2)c1=O
Temperature: 25 °C
Yield: 22.9 %

Procedure:
In a microwave vial were placed 2-oxo-1,2-dihydropyridine-3-carbaldehyde 1-1 (200 mg, 1.62 mmol), 4-trifluoromethoxyphenylboronic acid 4-1 (660 mg, 3.25 mmol), and anhydrous Cu(OAc)2 (295 mg, 1.62 mmol). To the mixture was added DMSO (3.20 mL) followed by Et3N (0.45 mL, 3.25 mmol). The mixture was irradiated in microwave apparatus (Biotage) at 100° C. for 15 minutes and cooled to room temperature. The mixture was concentrated and the residue was purified by silica gel chromatography (0-20% EtOAc in hexane) to give 105 mg (25%) of 2-2 as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.34 (1H, s), 8.13 (1H, dd, J=6.9, 2.1 Hz), 7.63 (1H, dd, J=6.9, 2.1 Hz), 7.47-7.36 (4H, m), 6.44 (1H, t, J=6.9 Hz); ESI-MS m/z 284 [C13H8F3NO3+H]+.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccn(O)n2)cc1
Product: CN(C(=O)On1ccc(-c2ccc([N+](=O)[O-])cc2)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-nitrophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, yellow crystals).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].CCOC(C)=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[N:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CCCCNCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCN(CCCC)C(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
In a dry 100 mL flask equipped with an N2 inlet adapter, a rubber septum and a magnetic stirring bar, was placed phenyl N-(4-acetylphenyl)carbamate (6.38 g, 25 mmol) in DMSO (50 mL). Dibutylamine (4.42 mL, 26.25 mmol) was slowly added to the mixture. The resulting solution was stirred at room temperature for 15 min, after which time EtOAc (250 mL) was added to the reaction mixture. The latter was washed successively with H2O (2×50 mL), aqueous 1N HCl (100 mL), H2O (100 mL), aqueous 1N NaOH (100 mL) and brine (100 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude solid. The solid was triturated with Et2O/hexane to yield 6.98 g (96% yield) of the title compound as a white solid.
Reaction SMILES: [C:1](=[O:12])([O:9][CH2:10]Cl)[O:2][CH2:3][CH2:4][NH:5][C:6](=[O:8])[CH3:7].[I-:13].[Na+]>C(#N)C>[C:1](=[O:12])([O:9][CH2:10][I:13])[O:2][CH2:3][CH2:4][NH:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)NCCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NCCOC(=O)OCI
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
[2-(acetylamino)ethyl] chloromethyl carbonate (5.0 g) was dissolved in acetonitrile (15 ml), and sodium iodide (15.0 g) was added. The mixture was stirred at 60° C. for 2 hours under an argon atmosphere. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (200 ml). The extract was washed with an aqueous 5% sodium thiosulfate solution (100 ml×2), water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml) successively. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [2-(acetylamino)ethyl] iodomethyl carbonate (3.5 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-3-methylphenol (4.86 g) and imidazole (2.65 g) in DMF (100 mL) was added tert-butyldimethylchlorosilane (4.70 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g) as a colorless oil.