Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([O:22][Si](C)(C)C)[C:20]#N)[CH:14]=1.[CH3:27][O:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34](CBr)=[CH:33][CH:32]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.CCCCCC>[CH3:27][O:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:20][C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:22])=[CH:33][CH:32]=1
Reactant: C[Si](C)(C)OC(C#N)c1cccnc1
Reactant: COCOc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
In argon atmosphere, 2.02 g of diisopropylamine was dissolved in 50 ml of dry tetrahydrofuran, followed by dropwise addition of the solution of 12.5 ml of 1.55M n-butyl lithium in hexane at -20° C., which was then stirred at the same temperature for five minutes and cooled subsequently. 2-(3-pyridyl)-2-(trimethylsiloxy)acetonitrile (4.13 g) dissolved in 20 ml of dry tetrahydrofuran was added dropwise. After stirring at the same temperature for one hour, the reaction mixture was dissolved in 10 ml of tetrahydrofuran. 4-Bromomethylphenyl methoxymethyl ether (4.48 g) was added dropwise, and the temperature was gradually increased from -78° C. to room temperature, followed by stirring overnight. The 20.0 ml of the solution of 1.0M tetra-n-butylammonium fluoride of tetrahydrofuran was added and stirred for 3.5 hours. To the reaction mixture was added saturated aqueous sodium chloride solution, and the organic phase was separated which was then extracted with ethyl acetate from aqueous phase. The organic phases were combined and washed in aqueous sodium Chloride, dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (2:98 v/v) was obtained 2.30 g of 2-(4-methoxymethyloxyphenyl)-1-(3-pyridyl)ethanone.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[N:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:23][C:24]1[C:25](B(O)O)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[C:25]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]([NH2:16])=[N:4][CH:3]=2)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Nc1ncc(Br)nc1NCC1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a degassed suspension of 6-bromo-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (100 mg, 0.348 mmol), Na2CO3 (96 mg, 0.905 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (92 mg, 0.522 mmol) in DME (3 ml) was added PdCl2(dppf).CH2Cl2 adduct (22.75 mg, 0.028 mmol). The reaction mixture was capped in a flask and heated to 100° C. for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with H2O, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (100% EtOAc/Hexane) to yield 6-(5-chloro-2-fluoropyridin-4-yl)-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (34 mg, 0.101 mmol, 28.9% yield).). LCMS (m/z): 338.2 (MH+), retention time=0.65 min.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Li+].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C.Br[C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:43][C:44](=[O:55])[C:45]3[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=3)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:39]([O:38][C:36](=[O:37])[C@@H:35]([NH:43][C:44](=[O:55])[C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[CH:23][C:22]([C:1]([OH:3])=[O:2])=[CH:27][N:26]=2)=[CH:29][CH:30]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=C[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C(=O)O)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Prepared using General Procedure 10. Into an oven-dried vial containing lithium formate (58 mg (1.1 mmol) in DMF (5 mL) were added DIEA (400 μL, 2.2 mmol) and acetic anhydride (210 μL, 2.2 mmol). After stirring for 1 h, the reaction mixture was degassed by N2 bubbling. A second, degassed solution containing (S)-tert-butyl 3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate, INT-14 (200 mg, 0.4 mmol) and PdCl2(dppf) (27 mg, 0.04 mmol) in DMF (5 mL) was added via cannula. The resulting mixture was heated for 1 h at 120° C. in a microwave reactor. The reaction mixture was diluted with 10% citric acid and extracted with EA. The organic extract was dried (Na2SO4), concentrated, and purified by chromatography (EA/hexane) to provide 166 mg (88%) of (S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid as a brown solid. LCMS-ESI (m/z) calculated for C29H33BN3O5: 503.6. found 504.2 [M+H]+, tR=3.87 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.75 (t, J=11.9 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.91 (t, J=11.5 Hz, 1H), 5.12 (dd, J=12.9, 5.5 Hz, 1H), 3.32 (qd, J=13.8, 5.4 Hz, 2H), 1.50 (s, 9H), 1.29 (d, J=29.8 Hz, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-n2ccc3c(O)cccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2c1ccn2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 8 mL of methylene chloride, 387 mg (1.52 mmol) of 1-(4-nitrophenyl)-1H-indole-4-ol was dissolved, and 0.186 mL (2.00 mmol) of acetic anhydride and 0.318 mL (2.28 mmol) of triethylamine were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between methylene chloride (50 mL) and a saturated ammonium chloride aqueous solution (20 mL) and washed with a saturated sodium chloride solution, and the organic layer was dried and then concentrated under reduced pressure to obtain acetic acid 1-(4-nitrophenyl)-1H-indol-4-yl ester. The product was used in the next reaction without further purification.
Reaction SMILES: C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[NH2:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([CH2:24][O:31][C:32]([NH:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC[C@H](N)C(=O)O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: N#CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
Bis (trimethylsilyl)trifluoroacetamide (9.4 mL, 35 mmol.) was added to a suspension of (αS)-amino-3-cyanopropanoic acid (2.0 g., 17.5 mmol.) in 10 mL of dry acetonitrile and the reaction mixture was stirred for 3 hours. Benzylchloroformate (2.5 mL, 17.5 mmol) was added, the reaction mixture was stirred overnight, concentrated in vacuo, and dissolved in ethyl acetate (200 mL). The organic solution was washed with water (2×) and brine, dried (Na2SO4), and concentrated in vacuo. Crystallization from isopropyl ether yielded 3.82 g. of the title A product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Br:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl.ClCCl>[Br:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCBr
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCBr)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 4-chloroquinolin-3-amine (3.70 g, 20.74 mmol) and 4-bromobutyryl chloride (11.54 g, 62.22 mmol) dissolved in 100 mL of 1,2-dichloroethane was heated to reflux. After 17 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. The solid was triturated with a mixture of hexane and ether, filtered and dried to give 4-bromo-N-(4-chloroquinolin-3-yl)butanamide (3.65 g) as a brown solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1([CH3:18])[CH2:13][CH2:12][CH2:11][C:10](=[CH2:14])[CH:9]1[C:15]([OH:17])=[O:16].[CH2:19](Br)[CH3:20].[OH-].[Na+]>CC(C)=O>[CH3:7][C:8]1([CH3:18])[CH2:13][CH2:12][CH2:11][C:10](=[CH2:14])[CH:9]1[C:15]([O:17][CH2:19][CH3:20])=[O:16]
Reactant: CCBr
Reactant: C=C1CCCC(C)(C)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1CCCC(C)(C)C1C(=O)OCC
Reaction time: 2 h
Yield: 92.3 %

Procedure:
In a flask maintained under nitrogen and equipped with a mechanical stirrer, a suspension of K2CO3 (29.5 g, 0.241 mole) in an acetone (200 ml) solution of 2,2-dimethyl-6-methylene-1-cyclohexanecarboxylic acid (30.0 g, 0.179 ml) and ethyl bromide (23.3 g, 0.214 mole) was warmed up to reflux. After 2 h 30, the temperature was allowed to cool to 25° and the reaction mixture was poured on 5% NaOH, extracted with ether (twice), washed with H2O and sat. NaCl, dried over Na2SO4, filtered and the solvents evaporated. Distillation of the crude product yielded, at 90°/5.3×102Pa, 32.3 g of the desired ester (yield: 92%).
Reaction SMILES: [C:1](Cl)([C:3]([CH3:6])([CH3:5])[CH3:4])=[O:2].N1C=CC=CC=1.[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>C(Cl)(Cl)Cl>[C:1]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][OH:22])(=[O:2])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCCCCCCO
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCCCCO
Reaction time: 24 h
Yield: 68 %

Procedure:
Piv-Cl (0.12 ml, 1.0 mmol) and pyridine (0.03 ml, 0.4 mmol) were added to a solution of 1,7-Heptanediol (Compound 26-1, 0.28 ml, 2.0 mmol) in CHCl3 (2 ml) at 0° C., and the mixture was stirred for one day. H2O was added to the reaction solution, the organic layer was then separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with a saturated aqueous NaCl solution, and was dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=3:1) to yield 7-hydroxyheptyl pivalate (147 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=1.Br[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[N:25][CH:24]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[N:25][CH:24]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncc2ccccc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C#N)c(-c2cncc3ccccc23)c1
Temperature: 120 °C
Yield: 59.8 %

Procedure:
The mixture of 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (100 mg, 0.348 mmole), 4-bromo-isoquinoline (80 mg, 0.383 mmole), Pd2(dba)3 (31.9 mg, 0.035 mmole), Sphos (28.6 mg, 0.070 mmole), 2 molar K3PO4 aqueous (0.4 ml, 0.8 mmole) and dioxane (5 ml) was degassed and heated to 120° C. for 40 minutes in microwave. Reaction solution was diluted with water and extracted with EtOAc. EtOAc layer was concentrated. Residue was purified by using silica gel chromatography, eluting with EtOAc/heptane to afford 4-cyano-3-isoquinolin-4-yl-benzoic acid methyl ester (60 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 3.88 (s, 3H), 7.45 (d, J=8.03 Hz, 1H), 7.65 (m, 2H), 7.90 (m, 1H), 8.06 (d, J=8.53 Hz, 1H), 8.15 (m, 2H), 8.42 (s, 1H), 9.29 (s, 1H). HR-MS m/z 289.0979 [M+1].
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:7]1)[CH3:27]
Reactant: CCOC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C3CCCCC3)ccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 32.7 g of 3 -carboethoxy-4-hydroxy-7-cyclohexyl-quinoline and 7.1 g of sodium hydride (50% strength in mineral oil) in 400 ml of absolute dimethylformamide is stirred for 45 minutes at room temperature with exclusion of water. In the course thereof, the temperature of the reaction mixture rises to 35°C and a homogeneous solution is produced. 39 g of ethyl iodide are added dropwise to this solution over the course of 10 minutes whilst stirring and the mixture is stirred for a further 21/2hours at 55°C. It is then cooled to room temperature and 500 ml of water are added slowly, whilst stirring. The resulting precipitate is filtered off, well washed with water and recrystallised from ethanol-ether. 1-Ethyl-3-carboethoxy-4-oxo-7-cyclohexyl-1,4 -dihydroquinoline, thus obtained, melts at 176°-178°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([O:35]CC)=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([OH:35])=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A solution of 41 mg of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (see example 160, step a)) in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 ml of water and washed with ethyl acetate. It was treated with 2 M hydrochloric acid to adjust the pH to 5-6 and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 12 mg of 4-[2-(1-carboxy-1-methyl-propylcarbamoyl)-4-chloro-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(O)(c1cccs1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCCC1
Yield: 40.1 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 16.2 g (0.064 mol) of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester (Intermediate I-12), dissolved in 400 ml of toluene, 9.5 g (0.074 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.51 g (0.038 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.97 g) was purified by chromatography on silica gel, eluting with chloroform/methanol/ammonia 95:5:0.5, to obtain 8.97 g of a pure product as a mixture of diastereomers, structure confirmed by 1H-RMN. Three crystallisations of this mixture from ethyl ether yield 1.68 g (15.2%) of a pure diastereomer (Intermediate I-6a). The mother liquors of the crystallisations were enriched with the other diastereomer (Intermediate I-6b).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=3[CH:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO.C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:16][C:15]=2[CH:17]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(F)ccc3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(C3CCNCC3)cc2c1

Procedure:
5.9 g (about 0.02 mole) of 4-(5-fluoro-2-benzofuranyl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 65 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the cloudy solution formed is heated, with vigorous stirring, for 18 hours at 160°. The reaction solution is thereupon cooled to 100°, diluted with 65 ml of toluene and then cooled to 20°. The organic phases are firstly extracted twice with one liter of water each time, then four times with 200 ml of a 10% solution of methane sulphonic acid in water. The methanesulphonic acid solution is thereupon brought to the pH-value of 12 by the addition of 30% sodium hydroxide solution, and is subsequently extracted with one liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered and concentrated by evaporation to thus obtain crude 4-(5-fluoro-2-benzofuranyl)-piperidine. The base is distilled by molecular distillation in high vacuum. The fraction distilling at 190°-200° and 0.05 Torr is 4-(5-fluoro-2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallised from ethyl acetate, whereupon it melts at 235°-237°.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-(N-benzyl-butylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
134 mg [(3-chloro-5-trimethylsilylethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetic acid are dissolved in 2 ml of methanol, combined with 50 mg potassium carbonate and stirred for 2 hours at ambient temperature. Then the mixture is diluted with dichloromethane and washed with 4 M hydrochloric acid. The organic phase is dried on magnesium sulphate and the solvent is then eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:20]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23])(Cl)[CH3:18])(=O)C>CO>[C:22]([N:21]=[N:20][C:17]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:18])[CH2:16][CH2:15][CH2:14][OH:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1ccccc1
Reactant: CC(=O)OCCCC(C)(Cl)N=NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N=NC(C)(CCCO)Oc1ccccc1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of 1.72 grams (0.026 moles) of 85% KOH in 20 mls. of methanol in a 100 ml. 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added 2.44 grams (0.026 moles) of phenol. The reaction was stirred for 15 minutes at 15° C and then 6.25 grams (0.025 moles) of the chloro compound prepared in step B was added dropwise over 20 minutes. The reaction was stirred an additional 30 minutes at room temperature. A sample was withdrawn and checked by infrared analysis which indicated the acetate was partially saponified to the alcohol. An additional 1.5 grams of KOH was added to the reaction mixture and the reaction stirred another 15 minutes. Infrared analysis indicated the saponification was complete so the reaction mixture was diluted with 200 mls. water and extracted with pentane. The pentane solution was washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 5.2 grams (80% yield) of the desired alcohol.