Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[I:11].[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C>[I:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:14][CH:16]1[CH2:17][O:18]1)[C:6]([NH2:8])=[O:7]
Reactant: ClCC1CO1
Reactant: NC(=O)c1ccc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCC2CO2)c(I)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
A solution of 10.0 g (0.038 mole) of 4-hydroxy-3-iodobenzamide in 40 ml of dry DMF was added to a suspension of 0.04 mole of sodium hydride (from 1.9 g of 50% sodium hydride which had been washed free of oil with hexane) in 60 ml of dry DMF at 25° under N2. When bubbling ceased, 30 ml (0.38 mole) of epichlorohydrin was added dropwise. The mixture was heated at 70° C. for 90 min and allowed to stand at 25° C. for 16 hr. The mixture was filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in CH2Cl3. The solution was washed with water and brine, dried (MgSO4) and the solvent evaporated in vacuo. The residue was recrystallized from CH2Cl2 /hexane to give 5.4 g (50% yield) of 3-iodo-4-(oxiranylmethoxy)benzamide, mp 149°-151° C.
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.Cl.[NH2:9][C:10]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([CH3:14])[C:11](O)=[O:12]>C1COCC1>[NH2:9][C:10]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([CH3:14])[CH2:11][OH:12]
Reactant: CC(N)(C(=O)O)c1ccc(F)cc1F
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(N)(CO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
To a stirred 2 M LiBH4 solution (16.22 ml) at r.t. in THF under an argon atmosphere was added chlorotrimethylsilane (5.47 ml) over 2 min. The white suspension was cooled to 0° C. and (RS)-(2-amino-2-(2,4-difluoro-phenyl)-propionic acid hydrochloride (2.57 g) was added portionwise over 5 min. The ice bath was removed and the compact off-white suspension was stirred at r.t. for 20 h. The mixture was cooled again to 0° C. and treated carefully with methanol (15 ml). The mixture was stirred at r.t. for 30 min, filtered and the cake was washed with MeOH. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-2-amino-2-(2,4-difluoro-phenyl)-propan-1-ol (1.47 g, 73%) as colorless viscous oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([OH:26])=O)[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Reactant: C1COCCN1
Product: O=C(Nc1nccs1)Nc1ccc(CC(=O)N2CCOCC2)cc1C(=O)C1CCCC1
Yield: 68.2 %

Procedure:
1-[2-Cyclopentanecarbonyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenyl]-3-thiazol-2-yl-urea (151 mg, 68%) was prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]-acetic acid (186 mg, 0.5 mmol) and morpholine (44 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.CCOC(C)=O>CN(C=O)C.O>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[N:27][CH:28]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 eq) in DMF was added potassium bis-trimethylsilylamide (1.5 eq, 1M solution in tetrahydrofuran). The solution was stirred at room temperature for 10 minutes, and 2-chloro-5-nitropyridine (1.2 eq) was added. The reaction mixture was submitted to microwave irradiation for 600 seconds at 145° C. EtOAc and water were added to the reaction and the layers separated. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated to give brown crude material. Purification by silica gel column chromatography using 10% EtOAc/hexane afforded the product as a light yellow solid. LC/MS (m/z): 324.3 (MH+) Rt 3.33 minutes
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccccc2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and phenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-phenoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH:14]=[C:9]1[CH2:8]2)(=O)C.O.C.[ClH:21]>>[ClH:21].[NH2:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH:14]=[C:9]1[CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)Cc1cc(=O)[nH]nc1-2
Agent: Cl
Solvent: O
Product: Nc1ccc2c(c1)Cc1cc(=O)[nH]nc1-2

Procedure:
7-Acetamido-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (2.0 g) in 6N hydrochloric acid (20 ml ) was stirred at reflux for 3 hours. Further water (150 ml ) was then added to give a clear, hot solution which was then treated with charcoal and filtered through diatomaceous earth. Concentration of the filtrate gave a buff precipitate of 7-amino-[5H]-indeno[1,2-c]pyridazin-3[2H]-one hydrochloride (1.3 g) which was collected and recrystallised from water (1.1 g, m.p. >300°); ν(Nujol mull) 3200-2000, and 1696 cm-1 ; δ(DMSO-d6) 3.92 (2H,3,5-H2), 6.90 (1H,m,6-H), 7.21 (1H,m,8-H), 7.30 (1H,s,4-H), 7.71 (1H,d,9-H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:30][C:23]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:29][CH:21]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=3)[CH2:22]1)[CH2:24]2
Reactant: O=C(O)c1cccc(OCCc2ccccc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCCc2ccccc2)c1

Procedure:
Prepared from 3-phenethyloxy-benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.20-7.39 (m, 8H), 7.13 (dd, 0.3H), 7.02 (dd, 0.7H), 6.22-6.38 (m, 1H), 4.09-4.28 (m, 3H), 3.11 (t, 2H), 2.24 (t, 2H), 1.47-2.00 (m, 9H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][N:35]1[CH:39]=[N:38][C:37]([C:40]([OH:42])=O)=[N:36]1.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:40]([C:37]4[N:38]=[CH:39][N:35]([CH3:34])[N:36]=4)=[O:42])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cn1cnc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
HATU (248 mg) and DIPEA (0.211 ml) were added to a flask containing 1-methyl-1H-1,2,4-triazole-3-carboxylic acid (51 mg) in DMF (1 ml). The reaction was stirred for 30 min under nitrogen. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg) was added and the mixture was stirred for 3 h at RT under nitrogen. The reaction mixture was applied to an aminopropyl SPE cartridge (5 g) and left for 3 h. The column was washed with 10% methanol in DCM. The appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in methanol:DMSO (1 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[CH:46](OC)(OC)OC>>[NH:45]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=[CH:46]1
Reactant: COC(OC)OC
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]cnc12

Procedure:
A mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (90 mg) and trimethyl orthoformate (1 ml) was refluxed for 4 hours. After removing excess reagent by evaporation, the residue was dissolved in chloroform and the solution was washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (51 mg) as a powder.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[N:48]1([CH2:47][CH2:46][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to a stirred solution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine (1.1 eq), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 eq), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS m/z 268.0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[F:9][CH:10]([C:15](OC)=[O:16])[C:11](OC)=[O:12]>CO>[F:9][C:10]1[C:11]([OH:12])=[N:7][C:5]([CH3:6])=[N:8][C:15]=1[OH:16]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
A solution of 200 mL of 25% wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 mL of methanol. Acetamidine-HCl (40 g, 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of dimethyl fluoromalonate (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 mL). After cooling the aqueous solution to room temperature, concentrated HCl was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCl was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1M HCl and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100%). LCMS: (M+H)+: 145.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=4[CH:33]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:23]=4[CH:33]=3)[CH:14]=2)[C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:10][CH2:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)CNc1noc2ccc(-c3cccc(CNC4CC4)c3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNc1noc2ccc(-c3cccc(CN(C(=O)c4ccccc4)C4CC4)c3)cc12
Temperature: -70 °C
Reaction time: 15 h
Yield: 76.9 %

Procedure:
Triethylamine (0.18 mL, 1.29 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)phenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 51) (0.30 g, 0.86 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Benzoylchloride (0.12 mL, 1.03 mmol, 1.2 equiv.) was added in drops and the mixture was slowly heated to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (80 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×15 mL) and sat. aq. NaCl solution (1×15 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/hexane; 10:1), the desired product (0.30 g, 77%) is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:11]3=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]([CH:15]=1)=[C:10]23>C(Cl)Cl.N1C=CC=CC=1>[O:26]=[C:25]1[C:9]2[C:10]3[C:11](=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]=3[CH:15]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[CH:22]=[N:23][NH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
Methanesulfonyl Chloride (1.5 eq, 0.003 g) was added to a solution of the title compound of Example 7 (0.005 g, 0.018 mmol) in CH2Cl2 (0.045 M, 0.4 mL) and pyridine (0.045 M, 0.4 mL). The mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. Silica gel chromatography (triethylamine/methanol/CH2Cl2; 1:5:94) afforded the title compound (1.7 mg) in 30% yield.
Reaction SMILES: C(OC(N1CCC([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[CH:13]=2)CC1)=O)C.[OH-].[K+]>>[O:24]1[CH:25]=[CH:26][C:22]([CH2:21][N:14]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[C:12]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:15]3)=[CH:13]2)=[CH:23]1
Reactant: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccoc1
Yield: 248.8 %

Procedure:
This compound was prepared following the procedure described in example 24, part D, starting with 4.44 g (11 mmol) of 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl) piperidine-1-carboxylic acid ethyl ester and 3.6 g of potassium hydroxide. After standard work-up, 3.85 g of 1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:9]1([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[CH2:24][CH:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:27][CH2:26]3)[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCc1cccc(-c2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C1=C(c2ccccc2)CCN(Cc2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 mg of 3-chloromethylbiphenyl in 5 mL of chloroform was added 50 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 0.5 mL triethylamine. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, washed successively with 50 mL aliquots of dilute sodim hydroxide and brine. The chloroform was removed by evaporation under reduced pressure to yield 3-phenyl[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]benzene which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 3-[(4-1,2,3,6-tetrahydropyridin-1-yl)methyl]biphenyl hydrochloride (Compound 3), mp 236°-238° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:25])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:25])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(C)(CO)CCCCCC(C)(C)CO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1

Procedure:
106.2 Grams (0.6 mole) of nicotinoyl chloride hydrochloride in 300 ml of anhydrous pyridine were reacted with 21.6 grams (0.1 mole) of 2,2,8,8-tetramethyl-1,9-nonanediol according to the procedure described in the above example.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>C1COCC1>[O:1]=[C:2]1[N:6]([C:32]([O:31][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:33])[C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of 1a (2.00 g, 10.8 mmol) in 50 mL THF at −78° C., was added LiHMDS (1M THF, 11.9 mL, 11.9 mmol). The mixture was stirred at −78° C. for 20 min, then Cbz-Cl was added, dropwise over 5 min. The mixture was stirred at −78° for 20 min, then quenched with sat. NH4Cl. The mixture was diluted with H2O and extracted with EtOAc (3×). The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (30 to 35 to 40% EtOAc/hexanes) to afford 3.12 g (90%) of 8a as a colorless solid.
Reaction SMILES: CC[O-].[Na+].[SH:5][C:6]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].CS(O[CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH3:38])(=O)=O.[NH4+].[Cl-].Cl>CCO>[CH2:10]([C:6]([S:5][CH2:38][CH2:37][CH2:36][CH2:35]/[CH:34]=[CH:33]\[CH2:32]/[CH:31]=[CH:30]\[CH2:29]/[CH:28]=[CH:27]\[CH2:26]/[CH:25]=[CH:24]\[CH2:23]/[CH:22]=[CH:21]\[CH2:20][CH3:19])([CH2:12][CH3:13])[C:7]([OH:9])=[O:8])[CH3:11]
Reactant: CCC(S)(CC)C(=O)O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)(CC)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
NaOEt (21 wt. % in EtOH, 0.37 mL, 0.98 mmol) was added dropwise to a solution of 2-mercapto-2-ethyl butyric acid (0.08 g, 0.49 mmol) in dry EtOH (7 mL) held at 0° C. under inert atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes before a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyl methanesulfonate (0.15 g, 0.41 mmol) in dry EtOH (3 mL) was added dropwise. The resulting turbid mixture was stirred at ambient temperature for 24 hours, poured into NH4Cl (sat.)(aq.) (15 mL), added 3M HCl to pH ˜2 before extracted twice with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), filtrated and evaporated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of 10-25% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions afforded 0.12 g (70% yield) of the title compound as oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22].ClCCl>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccc(Cl)c(Cl)c2)CS1)c1ccccc1
Yield: 29.7 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in example 1) (8.99 g, 39.8 mmol) was reacted with 8.3 g (39.6 mmol) of 3,4-dichlorobenzoylchloride in-dichloromethane (30 mL) and pyridine (9.6 mL) as described in Example 2 to yield 4.86 g of the desired compounds in 1:1 ratio.