Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1C
Yield: 44.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (212 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 126 mg (44.3%) of the desired product as a solid.
Reaction SMILES: O=[C:2]1[N:8]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=O)[C:7]2[CH:30]=[CH:31][CH:32]=[N:33][C:6]=2[NH:5][C:4]2[CH:34]=[CH:35][CH:36]=[CH:37][C:3]1=2.C([O-])(=O)C.[NH4+:42].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N:42]1[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:19][CH2:20][CH2:21]3)=[CH:16][CH:17]=2)=[CH:9][N:8]2[C:2]=1[C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[NH:5][C:6]1[N:33]=[CH:32][CH:31]=[CH:30][C:7]2=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CN3C(=O)c4ccccc4Nc4ncccc43)cc2)CCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3cn4c(n3)-c3ccccc3Nc3ncccc3-4)cc2)CCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl (1-(4-(2-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)acetyl)phenyl)cyclobutyl)carbamate (0.3 g, 1 eq.) in acetic acid (5 mL) was added ammonium acetate (1.5 g, 20 eq.). The reaction was stirred at 120° C. for 2 hours. The reaction was carefully poured onto a saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (3×25 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (25-100% ethyl acetate in hexanes), giving tert-butyl (1-(4-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.21 g, 73%). LCMS: 480 [M+H].
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([I:9])=[CH:3]1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][C:5]2([O:13][CH2:12][CH2:11][O:8]2)[C:4]([I:9])=[CH:3]1
Reactant: OCCO
Reactant: O=C1CCC(F)(F)C=C1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: FC1(F)C=C(I)C2(CC1)OCCO2

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67a by using the 4,4-difluoro-2-iodocyclohex-2-en-1-one (1.46 g, 5.66 mmol) prepared in Example 88c, ethylene glycol (750 mg, 12.1 mmol), p-toluenesulfonic acid hydrate (60 mg, 0.31 mmol) and benzene (30 mL), to yield a mixture of the title compound and a by-product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[C:10]=1[F:16])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCN1CCC(c2cccc(O)c2F)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1
Reaction time: 20 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorophenol (0.44 g, 1.97 mmol)) in methylene chloride (20 ml) was added triethylamine (4 ml) and methanesulfonyl chloride (0.56 ml, 3.67 mmol). The mixture was stirred for 20 h and water (50 ml) and methylene chloride (50 ml) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.39 g (66%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 161.5-163.2. MS m/z (relative intensity, 70 eV) 301 (M+, 15), 287 (15), 286 (bp), 222 (23), 207 (38).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:16]=[C:17]([C:21]4[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:23][N:22]=4)[CH:18]=[CH:19][CH:20]=3)[N:8]=2)[CH:4]=[N:3]1.C[NH2:33].O.O1[CH2:39][CH2:38]CC1>>[CH2:38]([NH:33][C:29](=[O:30])[CH2:28][O:27][C:24]1[CH:25]=[N:26][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:9]3[C:10](=[O:13])[CH:11]=[CH:12][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:8]3)[CH:16]=2)=[N:22][CH:23]=1)[CH3:39]
Reactant: CN
Reactant: C1CCOC1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC(=O)Cl)cn4)c3)n2)cn1
Solvent: O
Product: CCNC(=O)COc1cnc(-c2cccc(Cn3nc(-c4cnn(C)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
128 mg (0.27 mmol) of (2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetyl chloride are dissolved in 10 ml of tetrahydrofuran, 1.35 ml of 2 Methylamine in tetrahydrofuran are added, and the mixture is stirred at room temperature for 1 h in a sealed vessel at room temperature. Water is added to the reaction mixture, which is then filtered off with suction. The precipitate is washed with water, with methanol and with ether and dried.
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:10][C@@:2]12[CH2:1][C@@H:6]([O:13][C:11]1=[O:12])[C@H:5]1[C@H:4]([O:9][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:8]1)[CH2:3]2
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1O[C@@H]2C[C@@]1(O)C[C@H]1OC(c3ccccc3)O[C@@H]21
Temperature: -20 °C
Yield: 39.6 %

Procedure:
The procedure in J. Org. Chem. 1995, 50, 888-890 was followed. Briefly, a solution of quinic acid (20.0 g, 0.104 mol), benzaldehyde (16.6 g, 156 mmol) and para-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol) in toluene (350 mL) was refluxed for 10 hours in a flask equipped with a Dean-Stark trap. The reaction mixture was cooled, washed with saturated NaHCO3 solution and brine, dried (MgSO4). Filtered and concentrated. The concentrate was dissolved in 1:1 hexanes/ethyl acetate (100 mL) and cooled to −20° C. for 2 hours to provide 10.8 g (40%) of the desired product.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[NH:9][N:8]=[CH:7][C:6]=1[C:10]#[N:11].C(N(CC)CC)C.Br[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:4][C:5]1[C:6]([C:10]#[N:11])=[CH:7][NH:8][N:9]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cn[nH]c1N
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]nc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
To a solution of dry acetonitrile (10 mL) and dry tetrahydrofuran (30 mL) was added 5-amino-1H-pyrazole-4-carbonitrile (1.0 g, 9.25 mmol) followed by triethylamine (1.08 mL, 1.74 mmol). The resulting suspension was allowed to stir at room temperature for five minutes and then cooled to 0° C. A solution of (bromomethanetriyl)tribenzene (1.89 g, 5.84 mmol) in dry tetrahydrofuran (10 mL) was added drop-wise via an addition funnel equipped with a nitrogen inlet, at such a rate that the temperature did not rise above 5° C. The addition funnel was then rinsed with dry tetrahydrofuran (5 mL) and the reaction mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. The volatiles were removed in vacuo and residue was dissolved in EtOAc (150 mL) and washed once water (100 mL), once with saturated aqueous sodium chloride, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was applied to an 80 g silica gel cartridge using methylene chloride, and the column was eluted with a 10-30% EtOAc/hexanes gradient. The product containing fractions were combined to give 3-(Trityl-amino)-1H-pyrazole-4-carbonitrile (1.3 g, 41%) as an off-white semi-crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C

Procedure:
4-bromo-2-methylbenzoic acid (100.04 g, 465 mmol), 500 mL of anhydrous methanol, and 5 mL of concentrated sulfuric acid were stirred at reflux under nitrogen for 24 hr. Cooled to room temperature and concentrated in vacuo. Diluted the residue with 500 mL EtOAc and washed with 200 mL 1 M aqueous NaOH, 200 mL water, and 200 mL brine. Dried the solution over MgSO4 and concentrated in vacuo to obtain methyl 4-bromo-2-methylbenzoate as a clear colorless liquid (100.06 g, 437 mmol). 1H NMR (300 MHz, chloroform-d) ppm 2.59 (s, 3 H) 3.89 (s, 3 H) 7.39 (d, J=8.29 Hz, 1 H) 7.42 (s, 1 H) 7.79 (d, J=8.67 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([NH:1][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])=[CH:3][CH:4]=2)[C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1)C1CC1

Procedure:
N-(4-Amino-benzyl)-4-chloro-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.024 g, 0.06 mmol) was dissolved in CH2Cl2 (1 ml) and Hünig's base (0.01 ml, 0.07 mmol) and cyclopropanecarbonyl chloride (0.007 ml, 0.07 mmol) were added. After 30 min at r.t. the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4, brine, dried (Na2SO4), filtered and concentrated. The crude was purified using preparative RP(C18) chromatography: lyophilisate 9 mg; MS: m/e=493.4 (MNH4+).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:17]C)(=O)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[Na]>CO>[C:12]([O:14][CH2:15][C:5]1[O:6][CH:2]=[CH:3][CH:4]=1)(=[O:13])[CH2:11][CH2:10][CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: OCc1ccco1
Reactant: COC(=O)CCCC(=O)OC
Agent: [Na]
Solvent: CO
Product: O=C(CCCC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
196 parts by wt. of furfuryl alcohol and 160 parts by wt. dimethyl glutarate (stoichiometric proportions) were mixed and 0.5-0.75% wt. sodium metal added. The mixture was heated to a temperature in the range from 214°-240° F. under a nitrogen atmoshpere. Methanol was evolved and removed as the reaction progressed. After a period of 4 hours, a waxy solid was obtained. After washing the product with water, the residure was a liquid which was identified as difurfuryl glutarate by gas chromatography and mass spectrometric analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]=[C:39](B(O)O)[CH3:40]>CN(C=O)C.O>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[CH:3][C:2]([C:39]([CH3:40])=[CH2:38])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Reactant: C=C(C)B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
A mixture of 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (103 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol, EMD) and prop-1-en-2-ylboronic acid (52.4 mg, 0.610 mmol) in DMF (1.8 mL) and Water (0.2 mL) was degassed by vacuum and purged with Argon. To the resulting mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (16.72 mg, 0.020 mmol, Aldrich) and then heated under microwave conditions at 120° C. for 20 min. The reaction mixture was concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in hexanes) to yield 25 mg of desired product as a light yellow solid. MS (ESI) 467 (M+H).
Reaction SMILES: O1CCCC1.[CH2:6]([Mg]Cl)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1.CN1CCCC1=O>[C:16]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: CCCCCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCc1ccccc1

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 1.090 g (8 mmol) of zinc chloride and 4 ml of N-methylpyrrolidinone were weighed in the flask. The flask was purged with argon, followed by stirring. 3.5 ml (7 mmol) of 2M tetrahydrofuran solution of n-heptylmagnesium chloride was added dropwise at 25° C. over a period of 30 minutes, followed by stirring at 25° C. for 30 minutes. The reaction liquid previously obtained was added, followed by stirring at 25° C. for 30 minutes. Further, 0.558 g (5 mmol) of chlorobenzene was added, followed by stirring at 120° C. for 16 hours. After the completion of the reaction, 10 ml of toluene and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.688 g of 1-phenylheptane (yield: 78 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy.
Reaction SMILES: C1(OC)C=CC=CC=1.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].C(OC([N:23]1[CH2:35][CH2:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:36])[C:25]=2[CH2:24]1)=O)(C)(C)C>ClCCl>[CH3:36][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH2:34][CH2:35][NH:23][CH2:24][C:25]1=2.[F:9][C:10]([F:15])([F:14])[C:11]([O-:13])=[O:12]
Reactant: Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cn1c2c(c3ccccc31)CCNC2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1 ml portion of anisole and 0.7 ml of trifluoroacetic acid were added to 7 ml of dichloromethane solution containing 200 mg (0.70 mmol) portion of 2-t-butoxycarbonyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and stirred at room temperature for 4 hours. The solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from acetone-diisopropyl ether to obtain 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole quantitatively as trifluoroacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28]Cl)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN1CCCC1=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: CCCN(Cc1nc2cc(CCl)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCN(Cc1nc2cc(CN3CCOCC3)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 70 %

Procedure:
A solution of 0.2 mL of 0.2M (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide in 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hr with 0.3 mL of 0.2M solution of morpholine in toluene. The resulting mixture is diluted with 2 mL of ethyl acetate and washed 2×2 mL of water 1×2 mL brine. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo to afford 70% of (2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N:22]1([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:39]([O:43]C(C)(C)C)(=[O:42])[CH:40]=C>>[N:22]1([C:28]2[CH:33]=[CH:32][C:31]([O:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([CH:11]4[CH2:10][CH2:9][N:8]([CH2:6][CH2:40][C:39]([OH:43])=[O:42])[CH2:13][CH2:12]4)=[CH:19][CH:18]=3)=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Oc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Product: O=C(O)CCN1CCC(c2ccc(COc3ccc(N4CCCCC4)c(C(F)(F)F)c3)cc2)CC1

Procedure:
Mitsunobu coupling of 4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 4-Piperidin-1-yl-3-trifluoromethyl-phenol, followed by: Boc deprotection, alkylation with t-butyl acrylate, t-butyl ester deprotection, and final RP LC-MS purification as described in a previous example gave 3-{4-[4-(4-piperidin-1-yl-3-trifluoromethyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.25 (bs, 1H), 7.49 (d, 1H), 7.41 (d, 2H), 7.27 (d, 2H), 7.30-7.20 (m, 2H), 5.10 (s, 2H), 3.61-3.52 (m, 2H), 3.36-3.26 (m, 2H), 3.14-3.02 (m, 2H), 2.90-2.80 (m, 3H), 2.78-2.72 (m, 4H), 2.03-1.94 (m, 4H), 1.65-1.55 (m, 4H), 1.53-1.45 (m, 2H); MS (ES+): (491.2, M+1)+.
Reaction SMILES: C([O:5][C:6](=[O:60])[C:7]([F:59])([F:58])[O:8][C:9]1[CH:57]=[CH:56][C:12]([CH2:13][C:14]([C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([P:34]([O:41]C(C)(C)C)([O:36]C(C)(C)C)=[O:35])([F:33])[F:32])=[CH:27][CH:26]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:33][C:31]([F:32])([P:34]([OH:36])([OH:41])=[O:35])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:14]([C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])[CH2:13][C:12]2[CH:56]=[CH:57][C:9]([O:8][C:7]([F:59])([F:58])[C:6]([OH:60])=[O:5])=[CH:10][CH:11]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)O)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h

Procedure:
The compound of Step 2 was treated with TFA/CH2Cl2 (1/1) at r.t. After a period of 18 h, the solvents were evaporated under reduced pressure to give the title compound (racemate).
Reaction SMILES: N[CH:2]1[N:6]2[C:7](=[O:20])[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:5]2[C:4]2[S:21][CH:22]=[CH:23][C:3]1=2.O>C(O)(=O)C.[Zn]>[O:20]=[C:7]1[N:6]2[CH2:2][C:3]3[CH:23]=[CH:22][S:21][C:4]=3[C:5]2=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=[C:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1c2ccsc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1C2
Yield: 97.3 %

Procedure:
A suspension of 45.7 g of 4-amino-4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]pyrrolo [1,2-a]pyridine-9-carboxylic acid in 915 ml of acetic acid was treated with 27.6 g of zinc powder and heated to boiling under reflux for 2 hours. The suspension was then cooled and poured into 3000 ml of water. The excess zinc was for the most part removed by decantation. The separated crystals were filtered off under suction and dried in a vacuum. There was obtained 42.4 g of 4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]-pyrrolo[1,2-a]pyridine-9-carboxylic acid with a m.p. of >300° (purity 85-90%). This material was purified further by recrystallization from methanol/N,N-dimethylformamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76 %

Procedure:
To a solution of (500 mg, 1.67 mmol) 1-[2-(2-hydroxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A) in 5.5 mL of anhydrous DMF was added 377 mg of t-butyldimethylsilyl chloride followed by addition of 113 mg of imidazole. The reaction mixture was stirred at room temperature for 30 h. To the reaction was added 6 mL of water. The mixture was extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was azeotroped with xylenes to remove any DMF present. Purification by flash chromatography (silica gel, 3% to 4% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 528 mg (1.27 mmol, 77%) of a yellow oil.