Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([O:16][CH3:17])[CH:15]=1)=[O:5])C.CS(O)(=O)=O>C(O)C.O.[OH-].[K+].C(OC(C)C)(C)C>[F:22][C:20]1[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[CH:18][C:11]2=[N:12][C:13]3[N:14]([O:16][CH3:17])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:30])[C:8]=3[CH:9]=[C:10]2[CH:21]=1
Reactant: CCOC(=O)c1cn(OC)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Yield: 32.8 %

Procedure:
A suspension of 0.98 g of 3-ethoxycarbonyl-7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 15 cm3 of ethanol, 9 cm3 water and 6 cm3 of 2 N aqueous potassium hydroxide solution is stirred at a temperature close to 20° C. for 1 hour 6 cm3 of 2 N methanesulphonic acid are added to the solution obtained and the mixture is extracted with 3 times 10 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 5 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The dry extract obtained is taken up in 5 cm3 of diisopropyl ether, drained and washed with twice 2 cm3 of the same solvent. After recrystallizing once from 30 cm3 of dimethylformamide containing 30% of ethanol, 0.3 g of 7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]-naphthyridine-3-carboxylic acid is obtained in the form of a brown solid melting at 270° C.
Reaction SMILES: [Li]CCCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[CH2:13]([O:15][C:16](=[O:20])C(C)C)[CH3:14].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:13]([O:15][C:16](=[O:20])[C:10]([CH3:11])([CH3:12])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[CH3:14]
Reactant: C=CCCCCCBr
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCCCCCC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
A solution of n-BuLi 2.5 M in hexanes (3.79 mL, 9.48 mmol) was added at −78° C. under nitrogen to a solution of diisopropylamine (1.33 mL, 9.46 mmol) in dry THF (10 mL). After 15 min, a solution of ethylisobutyrate (1.0 g, 8.61 mmol) in dry THF (5.0 mL) was slowly added. After 30 min at −78° C., a solution of 7-bromohept-1-ene (1.68 g, 9.47 mmol) in HMPA (2.0 mL) was added drop wise and the reaction mixture was allowed to warm up to room temperature. After 16 h, the reaction mixture was quenched with diluted HCl, extracted with AcOEt, washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (DCM/heptane, 2:8) afforded 800 mg (44%) of the title product (51) as a colorless oil. TLC (DCM/hexanes 1/1): Rf=0.7.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:17])[C:15]#[N:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)=[O:7])[CH2:9][CH2:10]1)[CH3:17]
Reactant: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 32 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia is hydrogenated in the Parr-apparatus at 25° C. with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again. The residue is dissolved in 2,2'-oxybispropane and the solution is filtered till clear. The solvent is evaporated, yielding 32 parts (100%) of [1-(2-amino-1-methylethyl)-4-piperidinyl] (4-fluorophenyl)methanone as an oily residue.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][C:34]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[C:34]([C:42]([F:43])([F:45])[F:44])[CH:35]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1ccc(N=C=O)cc1C(F)(F)F
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 46.4 mg (0.21 mmol) of 4-methoxy-3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 15 mg (25.3% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24][CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24]([CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[O:44])=[CH:21][CH:20]=3)[N:16]=2)=[CH:8][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(CSCCn4ccnn4)cc3)co2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added dropwise during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 77 mg (74%) title compound as off-white solid.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:18]1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH:27]([CH3:28])[CH2:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (760 μl, 6.03 mmole) and pyridine (510 μl, 6.31 mmole) were added to a solution of 2-(1H-indol-3-yl)-1-methyl-ethylamine (1.0 g, 5.74 mmole) in abs. DCM (20 ml). Stirring was then performed for 24 h at RT. Working up was performed by extracting the batch with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml). The organic phase was dried with Na2SO4 and evaporated. [2-(1H-Indol-3-yl)-1-methylethyl]carbamic acid phenyl ester was obtained as a colorless solid in a yield of 1.35 g (80%).
Reaction SMILES: Cl[CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]([OH:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>C1C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:25]([CH:24]([O:32][CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC=CCC(O)CCCCCCC
Reactant: CCOC(=O)C(Cl)Sc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCC=CCC(CCCCCCC)OC(Sc1ccccc1)C(=O)OCC

Procedure:
Part B. The method of Speckamp et al., Tetrahedron Letters, v. 32, p. 1491 (1991), is employed here. Thus, a solution of ethyl 2-chloro-2-(phenylthio)acetate [prepared according to the method of Bohme et al., Liebigs Annalen der Chemie, p. 51 (1977)], 7-heptadecen-10-ol, andcatalytic zinc acetate dihydrate in benzene is heated to reflux under a Dean-Stark trap until the formation of hydrogen chloride is complete. Workup according to the listed reference affords ethyl 2-(1-heptyl-3-decen-1-oxy)-2-(phenylthio)acetate.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10](O)[S:11][C:5]2=[N:4][CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29](CBr)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:13][O:16][C:3]3[N:4]=[C:5]4[S:11][CH:10]=[CH:9][N:6]4[C:7](=[O:8])[C:2]=3[CH3:1])=[CH:28][CH:27]=2)=[O:25])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1cnc2sc(O)cn2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2sccn2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of 6-methyl-2-hydroxy-5H-thiazolo [3,2-a]pyrimidin-5-one (365 mg) and potassium carbonate (526 mg) in DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (664 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=2:1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (400 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C1COCC1.C([Li])CCC.C([O:31][B:32](OC(C)C)[O:33]C(C)C)(C)C>CCCCCCC.O>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([B:32]([OH:33])[OH:31])[CH:7]=[CH:6][CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
50.0 g of [2-(3-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was dissolved using 500 ml of anhydrous THF and 64.6 ml of a 2.7M solution of n-butyllithium in n-heptane added dropwise at −70° C. The reaction mixture was then stirred at −70° C. for 1 h. 40.2 ml of triisopropylborate was then added dropwise at −70° C. and stirring was continued for 30 minutes at −70° C. The mixture was then allowed to warm to −20° C. and 500 ml of water added. The reaction mixture was then allowed to warm to room temperature and extracted three times using 300 ml of CH2Cl2 each. The organic layer was then dried using MgSO4 and evaporated to yield 43.6 g of the title compound, used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O.C(OCC)C>CN(C)C=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:31][CH3:32])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
5.36 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of dimethylformamide, and then 1.36 g of potassium carbonate and 3.08 g of diethyl sulfate were added. The mixture was stirred at room temperature for 3 hours. Diethyl ether was added to the reaction mixture, which was then washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed by evaporation under reduced pressure. The residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from hexane to give 4.36 g of ethyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH2:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27](=O)(O)[O-].[Na+].C=O.[P:34]([O-:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:25][CH2:27][P:34]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:49])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred mixture of (S)-2-amino-3-(biphenyl-4-yl)-propionic acid benzyl ester hydrochloride (4.7 g, 12.8 mmol) in ethyl acetate (100 mL) and water (100 mL) at 5° is added sodium bicarbonate (1.13 g, 13.5 mmol). The solution is stirred for 5 minutes, then aqueous formaldehyde (37% aq., 1.25 mL, 16.6 mmol) is added. The mixture is allowed to warm slowly to room temperature while being stirred vigorously for 18 hours. The organic layer is separated and the aqueous layer extracted with ethyl acetate (50 mL). The combined organic phases are washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude hexahydrotriazine intermediate is obtained as a white solid that is dried under high vacuum. Some of that material (0.75 g, 2.18 mmol) is dissolved in toluene (10 mL) and kept under nitrogen. Diphenyl phosphite (0.5 mL, 2.62 mmol) is added and the solution is warmed in a bath pre-heated to 70°. After 2 hours, the reaction mixture is allowed to cool to room temperature. After evaporation of the solvent under reduced pressure, the residue is purified by flash-chromatography on silica gel, eluting with a gradient of ethyl acetate (50% to 90%) in hexane. The product is recrystallized from ether/hexane, affording (S)-3-(biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester as a while solid, m.p. 85°-86°; [α]D =+8.40 (c 1.04, CHCl3).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([O:21]CC3C=CC=CC=3)[C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(Cl)Cl.CCOC(C)=O.CO.[Pd]>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(OCc2ccccc2)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 63.5 %

Procedure:
To a solution of 158b (0.29 g, 1.01 mmol) in CH2Cl2:EtOAc:MeOH (2:2:1, 10 mL) was added 10% Pd on carbon (15 mg). Reaction was stirred under balloon hydrogen pressure for 5 h. Reaction mixture was filtered and solvent was evaporated. Column chromatography using gradient CH2Cl2:Acetone (max 20%) gave pure 159b (0.19 g, 64%) as a slightly brownish solid. 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.62 (s, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.38 (m, 3H), 7.15 (d, J=6.6 Hz, 1H), 6.68 (d, J=6.4 Hz, 1H), 6.11 (t, J=6.7 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 3.99 (m, 2H), 2.27 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 147.49, 129.71, 128.52, 127.99, 125.29, 120.42, 107.98, 66.61, 47.10, 29.27. (expected aromatic carbons=11; quaternary carbons can't be seen even after repeated cycles) HRMS (EI) calcd for C16H16N4O2 [M]+ 296.1273. found 296.1274.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>[Zn].C(OCC)(=O)C>[F:8][CH:2]([CH:23]([OH:24])[CH:20]1[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C=O)CC1
Reactant: CCOC(=O)C(F)Br
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC1CCC(C(O)C(F)C(=O)OCC)CC1
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 1.7 g of well-dried zinc, 3.6 g of ethyl bromofluoroacetate (e-2) and 10 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 2.0 g of 4-propylcyclohexane carboaldehyde (e-8) and 10 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. Then, the resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 3.8 g of ethyl 2-fluoro-3-hydroxy-3-(4-propylcyclohexyl)propanoate (e-9) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:24](=[O:25])[O:23][CH2:22][CH2:21][Cl:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)OCCCl
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(4-benzyl-1-piperazinyl)propylamine (2.01 g/8.61 mmol) in tetrahydrofuran (15 ml) were added 2 N NaOH (6.5 ml/13.0 mmol) and 2-chloroethylchloroformate (1.38 ml/12.9 mmol), and the mixture was stirred for 1 d. Water (50 ml) was added to the mixture and the whole was extracted with ethyl acetate (50 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]([CH3:28])[CH:21]=[C:20]2[C:29]1[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C:32]2=[N:33][CH:34]=[CH:35][C:36]([CH2:37]OS(C)(=O)=O)=[C:31]2[CH:30]=1>C1COCC1.O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]([CH3:28])[CH:21]=[C:20]2[C:29]1[N:43]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)(=[O:46])=[O:45])[C:32]2=[N:33][CH:34]=[CH:35][C:36]([CH2:37][N:12]3[CH2:13][CH2:14][CH:9]([N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH2:10][CH2:11]3)=[C:31]2[CH:30]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(-c3cc4c(COS(C)(=O)=O)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
0.003 g of sodium hydride is added to a solution of 0.008 g of 4-piperidinopiperidine in 0.5 cm3 of THF, at a temperature in the region of 20° C. The reaction medium is stirred at room temperature for 20 minutes. 0.04 g of methanesulfonic acid 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl ester is added. The reaction medium is heated at 60° C. for 3 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 2 cm3 of water and 3 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 90/10 by volume as eluent), 0.026 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)=C(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O>[O:16]=[C:10]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)=C(Cl)Cl
Product: COc1ccc(Cl)cc1C(=O)CCC(=O)O

Procedure:
A mixture of 4-chloroanisole (20 g), succinic anhydride (16 g) and AlCl3 (42 g) in 1:1 tetrachloroethylene/nitrobenzene (200 ml) is stirred at -10°-0° C. for a week. The mixture is poured into a conc. HCl/crushed ice bath and the solvent is distilled under vacuo at 40° C. The resulting suspension is made basic with 10% aqueous NaHCO3. The solids are filtered and the filtrate made acidic forming a precipitate which is filtered, washed with water, taken up in ethanol and dried. The solution is filtered and evaporated affording the desired product as a white solid, M.P. 113°-115° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])C=C.F[C:13]1[CH:18]=CC=C[C:14]=1O.C(Br)C=C>CCOCC>[CH2:18]([C:10]1[C:5]([OH:4])=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccccc1F
Reactant: Oc1ccccc1F
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCc1cccc(F)c1O
Yield: 80 %

Procedure:
Other workers have prepared o-fluorophenyl allyl ether in a 90.5-93% yield from o-fluorophenol and allyl bromide. Thereafter using a thermal Claisen rearrangement of the ether gave 6-allyl-2-fluorophenol in an 80% yield. However, attempts to oxidize this last named compound to 3-fluorosalicylaldehyde using dichromate solutions gave no reproducible results, i.e., a 55% yield from the first experiment but less than 5% in subsequent runs.