Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])[C:2]([CH3:4])=[O:3].[H][H]>C(O)C>[C:2]([NH:1][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:4]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 58 %

Procedure:
With the catalyst prepared as in example 7 there have been reduced 0.725 g of 3-acetoxy, 4-methoxy, alpha-acetaminocinnamic acid dissolved in 25 mls of anhydrous ethanol. The reaction has been carried out in an autoclave (glass) with a hydrogen pressure of 2 atm at room temperature. There has been obtained 3-acetoxy, 4-methoxy, N-acetylphenylalanine with an optical yield of 58%. [α]D22 =+12.8 (c=1, acetone) the [α]D22 (c=1, acetone) of enantiomerically pure 3-acetoxy, 4-methoxy N-acetylphenylalanine=22.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:10]=1)[C:7](O)=O.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH2:34][O:35][C:36]1[C:44]([Cl:45])=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([F:46])[CH:37]=1)[CH2:31]2>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH2:34][O:35][C:36]1[C:44]([Cl:45])=[CH:43][C:39]([C:40]([O:42][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:41])=[C:38]([F:46])[CH:37]=1)[CH2:31]2
Reactant: O=C(O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 2, and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoic acid with 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoic acid, the title compound was obtained as a colorless oil (2.13. g, 48%): MS (ES−) m/z 393.2 (M−1).
Reaction SMILES: [CH2:1]1[CH:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[CH:3]=[N:2]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH2:1]1[CH:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[CH:3]=[N+:2]1[O-:27]
Reactant: C1=NCC2c3ccccc3CCc3cccc1c32
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][N+]1=Cc2cccc3c2C(C1)c1ccccc1CC3

Procedure:
To a cold solution (5° - 15° C) of 1,7,8,12b-tetrahydrobenzo[1,2]-cyclohepta[3,4,5-de]isoquinoline (2.7 g) in chloroform (30 ml), a solution of m-chloroperbenzoic acid (2.3 g) in 20 ml of chloroform is added dropwise. The reaction mixture is allowed to stand at room temperature (i.e., 20° - 25° C) for 30 minutes. The reaction mixture is then washed with 15% ammonium hydroxide and water. The reaction mixture is dried (MgSO4) and concentrated to yield an oily residue. The oily residue is crystallized from benzene/hexane to give the title compound, mp 156° - 158° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>CC(C)=O>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)Oc1ccc(CO)cc1
Yield: 91 %

Procedure:
To a solution of 5 g (40.3 mmol) of 4-(hydroxymethyl)phenol in 500 mL of acetone was added finely powdered K2CO3 (27.83 g, 0.2 mol) and 3.71 mL (40.3 mmol) of N,N-dimethylcarbamoyl chloride. This mixture was heated under reflux overnight and then filtered. After evaporation of the solvent, a purification by column chromatography on silica gel with cyclohexane/iPrOH (9/1) and as eluent gave 7.16 g (yield: 91%) of compound of molecular formula C10H13NO3. Aspect: white powder.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:18]=[CH:17][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:19]=[C:20]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=5)[N:21]=[C:11]4[C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[O:31]CCOC.Cl>>[CH:27]([N:26]1[C:22]([C:20]2[N:21]=[C:11]3[C:10]4[CH:9]=[C:8]([C:7]5[C:2](=[O:31])[NH:3][CH:4]=[CH:5][CH:6]=5)[N:18]=[CH:17][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:19]=2)=[N:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: COCCOC
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ncc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc[nH]c3=O)ncc1OCC2
Temperature: 80 °C

Procedure:
To a solution of 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (0.087 g, 0.22 mmol) in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol) was added 10% aqueous HCl (3 mL). The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 269, analyzed by rHPLC. MS: (ESI+)=390.2. 1H NMR (500 MHz, DMSO) δ 9.76 (s, 1H), 8.45-8.39 (m, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.47 (dd, J=6.1, 2.1 Hz, 1H), 6.37 (t, J=6.7 Hz, 1H), 5.91 (dt, J=13.3, 6.7 Hz, 2H), 5.91 (dt, J=13.3, 6.7 Hz, 1H), 4.61 (dd, J=13.1, 5.5 Hz, 4H), 1.52 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([Cl:22])[CH:18]=1)=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: Clc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.31 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in 1,2-dichlorobenzene (20 ml) under ice-cooling and the mixture was stirred at 60°-70° C. for 1.5 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.47 g of 6-bromo-1-(3,4-dichlorophenyl)-1-hexanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([Si](C)(C)C)=[CH:30][C:29]=1[F:38])=[O:4].[I:39]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([I:39])=[CH:30][C:29]=1[F:38])=[O:4]
Reactant: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (1.78 g, 3.20 mmol) in DCM (35 mL) was added iodine monochloride (1M in DCM, 6.40 mL) dropwise over 10 minutes. The mixture was stirred for 1 hour then quenched by the addition of saturated sodium thiosulphate solution. The solution was partitioned between ethyl acetate and an saturated solution of sodium hydrogencarbonate. The organic layer was separated, washed with water then brine, dried (Na2SO4), filtered and evaporated to give a residue. The residue was purified by flash chromatography (Si-PPC, cyclohexane:ethylacetate, gradient 100:0 to 0:100) to provide the title compound as a yellow oil (1.52 g, 79%). LCMS (method B): RT=3.47 min, M+H+=612.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:48])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:30]=[CH:31][C:32]=1[CH3:33]>>[CH3:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:48])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[CH:37]=2)=[CH:28][C:27]=1[NH:26][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH:16]=1
Reactant: COc1ccc(C(=O)O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 25, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide to give N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzamide in 48% yield and that product was treated with trifluoroacetic acid. The reaction mixture was evaporated, water (40 ml) was added to the residue and the mixture was basified by the addition of 1N aqueous sodium hydroxide solution. The water was decanted and the residue was titurated under diethyl ether. The resultant solid was isolated, dissolved in water (30 ml) and basified by the addition of potassium carbonate. The precipitate was isolated and dried. There was thus obtained the title compound in 26% yield; NMR Spectrum: (DMSOd6) 1.48 (m, 2H), 1.9 (m, 2H), 2.18 (s, 3H), 3.19 (m, 4H), 3.75 (m, 4H), 3.83 (s, 3H), 4.39 (m, 1H), 7.1 (m, 2H), 7.21 (d, 1H), 7.4 (m, 3H), 7.6 (m, 3H), 7.79 (s, 1H), 9.72 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 545.
Reaction SMILES: CS(C)=O.[NH2:5][C@@:6]1([C:26]#[N:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-:29].[K+].[K+].OO>O>[NH2:5][C@@:6]1([C:26]([NH2:27])=[O:29])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23]
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reaction time: 0.5 h
Yield: 324.1 %

Procedure:
To a dimethyl sulfoxide (1.2 mL) solution containing 303.0 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 35.5 mg of potassium carbonate was added under cooling in water bath (13° C. approximately). Subsequently, 0.2 mL of 30 wt % hydrogen peroxide was added thereto and stirred for 30 min. After stirring for 67.5 hrs at room temperature, 3 mL of water was added to the reaction solution and the precipitated solids were filtered and washed with 1.2 mL of water. The resulting solids were dried under reduced pressure at room temperature to obtain 313.2 mg of (1R, 2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[CH:8]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1
Reactant: FC(F)(F)c1ccc2nccn2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-trifluoromethyl-imidazo[1,2-a]pyridine (1 eq, 6.2 mmol, 1.1 g) in acetic acid (15 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 6.2 mmol, 0.313 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered to afford the title compound as a beige solid; [M+H]+=266(268)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][C:36]([F:39])([F:38])[F:37])[CH:10]=2)[CH2:4][CH2:3]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:36]([F:39])([F:37])[O:35][C:11]1[CH:10]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([C:40](=[O:42])[CH3:41])[CH2:7][CH2:6]2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][O:26][C:25]2=[O:34])[CH2:20][CH2:19]1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)-phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.45 g, 0.77 mmol) from Example 39 in CH2Cl2 (50 mL) was added acetic anhydride (0.15 mL, 1.5 mmol) and DIEA (0.26 mL, 1.5 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H2O (25 mL), and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][N:7](CC2C=CC=CC=2)[CH2:8][CH2:9][CH:10]=1.[Cl:18][CH:19]([O:21][C:22](Cl)=[O:23])[CH3:20]>ClCCCl>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][N:7]([C:22]([O:21][CH:19]([Cl:18])[CH3:20])=[O:23])[CH2:8][CH2:9][CH:10]=1
Reactant: CON=CC1=CCCN(Cc2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CON=CC1=CCCN(C(=O)OC(C)Cl)C1
Yield: 140 %

Procedure:
A solution of 13.2 g of 1-benzyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde-O-methyloxime in 120 cm3 of anhydrous 1,2-dichloroethane is cooled to 0° C., 11.7 g of alpha-chloroethyl-chloroformate is added and the whole is heated to reflux for 2 hours. After cooling, the insoluble matter is filtered off. The filtrate is evaporated to dryness, and the residue is taken up with anhydrous ether, diluted and filtered. The filtrate is evaporated and 19.8 g of product is obtained which is used immediately for the following reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=2)[N:7]=1.[CH3:14]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=2)[N:7]=1
Reactant: O=C(O)c1cc2ccc(O)nn2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2ccc(O)nn2c1
Temperature: 80 °C

Procedure:
The semi-crude material from above, 2-Hydroxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (100 mg, 0.56 mmol) was dissolved in methanol (5 mL) and concentrated sulfuric acid (2 drops). The solution was heated to 80° C. for 4 hours, and then the solvent evaporated in vacuo. The crude material was used directly in the next step. MS m/z 193.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].Cl>[OH-].[K+]>[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cc(C(=O)c3cccc(C(C)C(=O)OC)c3)sc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 72.8 %

Procedure:
Methyl 2-{3-(5-methoxycarbonyl-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (36 g) in solution in a mixture of potassium hydroxide pellets (26.4 g), distilled water (160 cc) and ethanol (400 cc), is stirred for 17 hours at a temperature of about 20° C. The resulting suspension is diluted with distilled water (800 cc) and filtered. The filtrate is stirred with decolourizing charcoal (3 g) and filtered. The solution obtained is added dropwise to a 5N aqueous solution of hydrogen chloride (400 cc) cooled in an ice bath, the rate of addition being regulated in such a way that the temperature of the mixture remains below 10° C. The reaction mixture is stirred for a further hour in the ice bath, and then the resulting crystals are filtered off, washed three times with distilled water (total 150 cc), and dried in air. Crude 2-{3-(5-carboxy-thieno[2,3-b]thien-2-yl)carbonylphenyl}propionic acid (24.3 g), melting at 244° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][Mg]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)([OH:15])[CH3:43])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (177 mg, 0.31 mmol) in THF (3 mL) at 0° C. was added methylmagnesium bromide (130 μL, 0.37 mmol, 3M solution in Et2O) and the resulting mixture stirred for 1 h before further methylmagnesium bromide (130 μL, 0.37 mmol) was added. The resulting mixture was warmed to r.t. and stirred for 16 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a clear oil (104 mg, 57%). LCMS (method A): RT 3.09 min [M+H]+ 591.2
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].CCN(CC)CC.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:3][CH:2]([CH3:4])[C:1]#[N:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)C#N
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a flask containing DL-lactonitrile (36.3 mmol, 2.8 g) in DCM (25 ml), Et3N (54.7 mmol, 8.1 ml) and tert-butyldiphenylsilyl chloride (36.3 mmol, 10 g) were added. The resulting solution was stirred at RT for 24 h. The reaction mixture was quenched with H2O and extracted with DCM. The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash-chromatography. Yield 4.52 g. 1H-NMR (400 MHz; CDCl3): δ 1.10 (s, 9H), 1.50 (d, 3H), 4.43 (q, 1H), 7.39-7.51 (m, 6H), 7.65 (d, 2H), 7.71 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH:10]=[C:9]([O:13]CC)[CH2:8][C:7]=2[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:1][O:2][CH:3]1[C:12]2[CH:11]=[CH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:6]([O:16][CH3:17])[CH2:5][CH2:4]1
Reactant: CCOC1=CCc2c(OC)ccc(OC)c2C1
Agent: Cl
Solvent: CCO
Product: COC1CCC(OC)C2=C1C=CC(=O)C2
Temperature: 25 °C
Yield: 85.5 %

Procedure:
5,8-Dihydro-1,4-dimethoxy-6-ethoxynaphthalene (XII) (3.5 g, 15 mmole) was dissolved in 88 ml hot ethanol and then cooled to room temperature. The suspension was stirred with hydrochloric acid (2N) (17.5 ml) for fifteen minutes. The reaction mixture was poured onto ice water and filtered to give as a tan solid 1,4-dimethoxy-6-tetralone (XIII) (2.67 g, 86.5% yield). m.p. 99°-100° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH:14]=[CH2:15]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)c1ccccc1F
Solvent: C1CCOC1
Product: C=CC(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
A solution of 2-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) in THF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120 mmol) was slowly added, and the mixture stirred at −78° C. for 10 min, slowly warmed to rt, and stirred for another 3 h. The reaction mixture was quenched with 1 N aq HCl (100 mL) at 0° C. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to afford 1-(2-fluorophenyl)-prop-2-en-1-one (7.6 g, yield: 58.4%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: COc1cccc(C(=O)O)c1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(OC)c1Br
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2-bromo-3-methoxybenzoic acid (718 mg, 3.11 mmol) in methanol (20 mL) was added a catalytic amount of concentrated sulfuric acid and the mixture was brought to reflux for 20 h. On cooling to room temperature, the solution was concentrated and the residue was taken into ethyl acetate and washed with water, saturated aqueous sodium bicarbonate (2×) and brine then dried over sodium sulfate. The solution was then filtered and concentrated to give methyl 2-bromo-3-methoxybenzoate (610 mg, 80%). MS (EI) for C9H9BrO3: 245 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C@@H:33](O)[CH2:32]2>CC#N.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:33]1[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (2 g, 7.96 mmol) was dissolved in CH3CN (20 ml). Di(1H-imidazol-1-yl)methanone (1.936 g, 11.94 mmol) was added, and the reaction was stirred at RT for 1 hour. (R)-quinuclidin-3-ol (1.518 g, 11.94 mmol) was added, and the reaction was stirred at RT for 3 hours to achieve completion. The solvent was removed under vacuum to give a solid that was dissolved in ethyl acetate (300 ml). The precipitate was filtered, and the organic solution was washed with 60 ml of K2CO3 30%, dried over Na2SO4 and evaporated under vacuum to give a crude, that was crystallized in ethyl acetate to give (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (1.67 g, 5.2 mmol).