Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH:45]([CH3:47])[CH3:46])[CH:38]=1)[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:44]([O:43][C:39]1[CH:38]=[C:37]([O:36][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:42]=[CH:41][C:40]=1[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]2)=[O:17])[CH:45]([CH3:47])[CH3:46]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1CC(C)C
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cc(C(=O)c3ccc(OCC(C)C)cc3OCC(C)C)ccc2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In 3 ml of methylene chloride is dissolved 0.12 g of 2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid, to which are successively added 50 μl of oxalyl chloride and 20 μl of N,N-dimethylformamide at ambient temperature. The mixture is stirred at ambient temperature for one hour. Then, at 5-10° C., 0.12 g of aluminum chloride and 0.13 g of 1,3-diisobutoxybenzene are successively added and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to obtain 0.18 g of ethyl 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylate as a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:10][S-:11].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:11][CH3:10])[CH:7]=1
Reactant: C[S-]
Reactant: BrCc1cncc(Br)c1
Agent: [Na+]
Solvent: CCO
Product: CSCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
3-Bromo-5-bromomethyl-pyridine (7.5 g, 30 mmol) is dissolved in EtOH (200 mL). The solution is cooled down to 0° C. Sodium thiomethoxide (3.1 g, 45 mmol) is added slowly and the reaction mixture is stirred for 16 hrs. Then the solvent is removed, water and EtOAc are added. The aqueous layer is separated and extracted with EtOAc. Organic layers are combined and concentrated to give 6.0 g of the 3-bromo-5-methylsulfanylmethyl-pyridine.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](OC)=O)=[C:6]([CH3:12])[CH:5]=[C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]=1[C:34](OC)=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.C1C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:3]([CH3:34])[C:2]=1[OH:1]
Reactant: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C)c(O)c1C
Yield: 99.9 %

Procedure:
To a solution of the dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate (5.17 g) in xylene (25 ml) at 10° was added sodium dihydrobis(2-methoxyethoxy) aluminate (20 ml of a 70% by weight solution in benzene) over 20 min with occasional cooling to keep the temperature at 10°. After 10 min the solution was heated to reflux for 1.5 hr, cooled to 10° and was poured cautiously into cold 20% by weight aqueous sulfuric acid (200 ml). The mixture was extracted with ether (3×100 ml) and the combined extracts were washed with aqueous sodium bicarbonate and brine and dried (Na2SO4) and concentrated on a rotary evaporator to give 4.29 g of crude 2,3,6-trimethyl-5-(3-hydroxy-3,7,11,15-tetramethylhexadecanyl)-phenol as a light yellow oil. Chromatography on silica gel eluting with ether in petroleum ether gave 3.19 g of pure 2,3,6-trimethyl-5-(3-hydroxy-3,7,11,15-tetramethylhexadecanyl)-phenol.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=O)[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(NCC)C.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[N:5]2[CH:4]=[N:3][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]2[CH2:7]1
Reactant: C#Cc1ccccc1
Reactant: CN1CC2=C(n3cnc(I)c3C1)S(=O)C=C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN1Cc2ccsc2-n2cnc(C#Cc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of 5,6-dihydro-7-iodo-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one (prepared in accordance with Example 73) was dissolved in 47 ml of diethylamine and 20 ml of dimethylformamide. 1.75 ml of phenylacetylene, 105 mg of bis-(triphenylphosphine)-palladium(II) chloride and 17 mg of copper(I) iodide were then added. The mixture was stirred at room temperature for 2 hours and then concentrated in a vacuum. The residue was diluted with 200 ml of dichloromethane and washed twice with water. The aqueous washings were extracted twice with dichloromethane. The combined dichloromethane solutions were dried over sodium sulphate and chromatographed through 300 g of silica gel. Elution was carried out first with trichloromethane and trichloromethane/ethanol mixtures 199:1 and 99:1. There was then eluted with a trichloromethane/ethanol mixture 97:3 an oily substance which can be crystallized from isopropanol/water. After repeated recrystallizations from isopropanol/water there was obtained 5,6-dihydro-5-methyl-7-(phenylethynyl)-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine one of melting point 143°-144°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28][OH:29])(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH:28]=[O:29])(=[O:21])=[O:20]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Oxalyl chloride (3.3 mmol, 2 eq.) was dissolved in methylene chloride and DMSO (4 eq) was added under argon at −78° C. and the reaction mixture was then stirred at this temperature for 15 min. (1-(2-Chloro-6-methylphenylsulfonyl)-piperidin-2-yl)methanol (1.65 mmol) was dissolved in methylene chloride (15 ml) and the solution was added dropwise to the reaction solution at −78° C. The resulting mixture was stirred for 1 h. Triethylamine (8.25 mmol, 5 eq) was then added and the reaction solution was warmed to room temperature and stirred for 1 h. It was then diluted with methylene chloride (10 ml) and washed with saturated ammonium chloride solution (10 ml), water (2×20 ml) and saturated sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and the filtrate was concentrated to dryness under reduced pressure. The crude product was employed in the next stage without further purification. Yield: 80%
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccccc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 88 from 6-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=O)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:24])=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (1.1 eq) was suspended in an. THF and cooled to 0° C. under nitrogen. 1.6M nButyllithium in hexanes (1.1 eq) was added drop wise, and stirred for 30 minutes. 1-(2,4-Bis-benzyloxy-phenyl)-ethanone (1 eq) was dissolved in an. THF and added drop wise to the suspension. When addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature under nitrogen overnight. Methanol was added to the reaction mixture and the resulting solution was evaporated in vacuo. Hexane was added to the resulting oil and heated to reflux for 30 minutes, then filtered through Celite. The liquor was evaporated in vacuo to give an oil which was purified by column chromatography, eluting with 30% EtOAc in hexane, to give 2,4-Bis-benzyloxy-1-isopropenyl-benzene. Rf retention time 0.722, 3:1 Hexane: EtOAc.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:4]=2[O:5]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)OCO2
Yield: 57 %

Procedure:
The mixture of sesamol (13.8 g, 100 mmol, methyl bromoacetate (15.3 g, 100 mmol) and potassium carbonate in acetone (200 ml) was refluxed for 24 h with stirring. Acetone was removed under reduced pressure. The residue was dissolved in water (200 ml) and was extracted with ether (2×100 ml). the combined organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give methyl 2-[3,4-(methylenedioxy)phenoxy]acetate as an oil (12 g, 57% yield). The aqueous phase was neutralized to pH 2-3 with concentrated HCl and the precipitated solid was filtered to get 2-[3,4-(methylenedioxy)phenoxy]acetic acid as a solid (6 g, 31% yield).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(#N)C.C1(C)C=CC=CC=1>O>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 37.4 %

Procedure:
Into a 50 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 5.2 g (0.02 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine, 2.4 g (0.06 mol) of NaOH powder and 50 ml of acetonitrile were charged, and the mixture was reacted at room temperature for 5 hours. After the reaction, toluene and water were added to the reaction mixture, followed by liquid separation. The toluene layer was washed with water. The toluene layer was concentrated and subjected to column chromatography to obtain 1.67 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 36%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:15](=[O:17])[CH3:16])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2cc[nH]c2n1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1c[nH]c2nc(C)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg) in dichloroethane (6 mL) were added aluminum chloride (1.09 g) and acetyl chloride (0.40 mL), and then the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into aqueous saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether to 1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone [REx(8-1)] (481 mg) as a yellow powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[Cl:23][C:24]1[C:25]([C:33]([F:36])([F:35])[F:34])=[C:26]([CH2:30][CH2:31][NH2:32])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[C:25]([C:33]([F:34])([F:35])[F:36])=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][CH2:31][NH:32][C:11]1[N:10]=[C:9]([NH:8][C@@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]2)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1
Reactant: NCCc1cccc(Cl)c1C(F)(F)F
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCc3cccc(Cl)c3C(F)(F)F)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.1 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (75 mg, 0.23 mmol), 2-(3-chloro-2-(trifluoromethyl)phenyl)ethanamine (100 mg, crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (42.2 mg, 0.090 mmol, 39% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.10-8.03 (m, 1H), 7.48-4.41 (m, 2H), 7.30 (m, 1H), 4.31-4.28 (m, 1H), 3.73-3.69 (m, 1H), 3.63-3.56 (m, 1H), 3.39-3.37 (m, 1H), 3.17-3.14 (m, 2H), 1.88-1.44 (m, 6H), 0.97 (s, 3H), 0.96 (s, 3H). MS (ESI) m/z 468.1 [M+H]+.
Reaction SMILES: C([NH:8][C@H:9]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Br:21])=[CH:20][C:14]=2[N:13]=1)[CH2:10][OH:11])(OC(C)(C)C)=O.Cl>C(OCC)(=O)C.O1CCOCC1>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([C@@H:9]([NH2:8])[CH2:10][OH:11])=[N:13][C:14]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.00 g (5.62 mmol) (1R)-N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16 hours at ambient temperature. The reaction mixture is evaporated down and the resulting precipitate is filtered off.
Reaction SMILES: C(=[N:14][NH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([NH:15][NH2:14])=[N:17][CH:18]=1
Reactant: Cc1cc(F)cnc1NN=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(F)cnc1NN
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of Intermediate 105a (194 mg, 0.635 mmol) in toluene (13 mL) was treated with HCl (37%, 3.5 mL) and heated at 110° C. for 1.5 h. After cooling to RT, the reaction mixture was diluted with water and extracted with toluene (×3). The aqueous layer was cooled to 0° C., neutralised with 5N NaOH and extracted with DCM (×3). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (78 mg, 86%) as a silver/green solid. LCMS (Method 4): Rt 0.29 min, m/z 142 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1)[CH3:2].O[Li].O>C1COCC1.CO.O>[CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OC)c(C)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of methyl ((1S)-5-{3-[(6-ethyl-2-methyl-3-pyridinyl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 246) in a mixture of THF (3 mL) and MeOH (˜0.2 mL), was added LiOH.H2O (15 mg, 0.36 mmol) in water (1 mL). The mixture was stirred for 12 h at rt, the solvents were evaporated, and the residue was suspended in a small volume of water. The aqueous solution was acidified to pH<3 using HCl (1 N aqueous solution), and then it was extracted with excess EtOAc. The organic layer was dried, concentrated and purified by preparative HPLC to give 18 mg (16%) of the product as a solid. 1H NMR (400 MHz, CDCl3): δ 7.16-6.88 (m, 3H), 6.71 (s, 1H), 6.62 (dd, 1H), 4.12-4.0 (m, 4H), 3.52-3.40 (m, 1H), 2.90-2.62 (m, 6H), 2.52-2.26 (m, 4H), 2.23-2.12 (m, 2H), 1.78-1.64 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: COC(OC)C1C=CC(I)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1CCOCC1.C[O:26][CH:27](OC)[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.Cl.CCOCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C.C1COCC1>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([CH:27]=[O:26])=[CH:33][CH:32]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: COC(OC)c1ccc(N2CCOCC2)cc1
Agent: COC(OC)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCN1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 28 h
Yield: 75 %

Procedure:
A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl) phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>CCOCC.CC#N>[I:46][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1
Reactant: II
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCO)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCI)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The mixture of tert-butyl 6-(2-hydroxyethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (5.6 g, 19.09 mmol), triphenylphosphine (6.51 g, 24.82 mmol), imidazole (1.82 g, 26.72 mmol), and a mixture of CH3CN and dry ether (1:1) was cooled to 0° C. Iodine (6.78 g, 26.72 mmol) was slowly added. The resulting mixture was stirred for 2 hour and then ether (150 mL) was added, washed successively with saturated aqueous Na2S2O3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 20% EtOAC/Hex) to afford a yellow solid (6.6 g, 86% yield). H NMR (CDCl3) δ 1.55 (s, 9H), 2.93 (s, 3H), 3.18 (t, 2H), 3.30 (t, 2H), 3.458(t, 2H), 3.85 (t, 2H), 6.85(q, 2H). LC-MS (M+H) 404.
Reaction SMILES: C([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH2:14]2)=[CH:9][CH:8]=1)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C@H:15]1[CH2:16][CH2:17][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:24])=[O:5])=[CH:8][CH:9]=2)[CH2:14]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(C(=O)O)cc2)C1

Procedure:
4-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-benzoic acid tert-butyl ester (0.28 g, 0.8 mmol) was treated with 5 mL of 4N HCl in dioxane at r.t. overnight. The HCl was removed by air blowing and absorbed into NaOH aq. solution. The solvent was evaporated to dryness and dried further under high vacuum to yield 0.37 g (HCl salt, ˜100%) of the title compound as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[S:18][C:19]([C:22]3([C:27]([O:29]CC)=[O:28])[CH2:26][CH:25]=[CH:24][CH2:23]3)=[CH:20][CH:21]=2)[C:8]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:10]=1[Cl:11])=[O:5])C.[OH-].[Na+]>CO>[CH2:12]([C:8]1[N:7]([CH2:16][C:17]2[S:18][C:19]([C:22]3([C:27]([OH:29])=[O:28])[CH2:26][CH:25]=[CH:24][CH2:23]3)=[CH:20][CH:21]=2)[C:6]([C:4]([OH:5])=[O:3])=[C:10]([Cl:11])[N:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(C2(C(=O)O)CC=CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step 1, above (71) (50 mg) in 2 ml of methanol was added 1 ml 2N NaOH. This mixture was stirred at ambient temperature for 2 hours, the solvent was removed and the residue taken up in water and extracted (2×EtOAc). The aqueous layer was then acidified with 10% HCl and extracted (3×EtOAc). The combined organics were dried over MgSO4, filtered and concentrated to dryness to yield the title compound (72).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: NCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: c1ccc2c(-c3ccc(OCCCNCc4ccsc4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, C-thiophene-3-yl-methylamine (Table No. 1, SM 9), potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=380.