Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([F:30])=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CC(O)C>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.O.C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([F:30])=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26]
Reactant: CCCC1CC=C(c2ccc(Br)cc2)CC1
Reactant: CCOc1ccc(B(O)O)c(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CC=C(c2ccc(-c3ccc(OCC)c(Cl)c3F)cc2)CC1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
6.0 g of the compound (16), 5.5 g of the compound (12), 5.9 g of potassium carbonate and 0.13 g of Pd(PPh3)2Cl2 were added to a reactor having 60 mL of IPA placed therein under nitrogen atmosphere. The mixture was stirred under refluxing and heating for 3 hours. After cooling the reaction mixture to 25° C., 200 mL of toluene and 200 mL of water were added thereto, and the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water. Thereafter, the solvent was removed by distillation to obtain a residue. The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume). The resulting crystals were purified by silica gel column chromatography using toluene as eluent, and then further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume) to obtain 5.9 g of 3-chloro-4-ethoxy-2-fluoro-4′-(4-propylcyclohexa-1-enyl)biphenyl (No. 130). The resulting compound (No. 130) was colorless crystals. The yield based on the compound (13) was 45.0%.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[F:36][C:35]([F:37])([F:38])[C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
3-{4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxymethyl)-heptyl]-benzoylamino}-propionic acid methyl ester (50 mg, 0.09 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) is added. The reaction may be monitored by HPLC. After 3 h the reaction is neutralized with 5N HCl (1 mL) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound. MS (ES): 540.3 [M+H]−.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:1](=[O:3])[CH3:2])[CH2:15]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: Fc1cccc(C=C2CCCNC2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (0.515 mL) was added to a mixture of 3-[1-(3-fluorophenyl)methylidene]-piperidine hydrochloride (Intermediate 226, 1.5 g) and N,N-di-isopropyl-N-ethylamine (2.52 mL) in anhydrous THF (50 mL) at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was diluted with water (100 mL) and extracted with ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 75-100% to give 1-{3-[1-(3-fluorophenyl)-methylidene]piperidin-1-yl}ethanone (1.38 g).
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])[NH2:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[N:23][C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])=[CH:18][CH:17]=1.[OH-].[Na+]>O.CO>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[N:23][C:24]([NH:26][C@H:27]([C:35]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])=[O:36])[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Reactant: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Reaction time: 1 h

Procedure:
Operating mode: 1 equivalent of N-(4-methoxyphenylazoformyl)L-phenylalanine arginine methyl ester was taken up in a water/methanol mixture (ratio: 1/2; 3 ml/mmol). 3 equivalent of 1 N sodium hydroxide was added. After 1 h, the reactional medium was acidified, concentrated then extracted with water/dichloromethane. The dichioromethane phase was evaporated then dried. N-(4-methoxyphenylazoformyl)-L-phenylalanyl arginine was obtained as an orange powder.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OCCCC(C)(OC([NH:19][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]C)=[O:22])=O)C)=CC=1.O1CCCC1.[OH-].[Na+].Cl>CO>[NH2:19][C@H:20]([C:21]([OH:23])=[O:22])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)CCCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of Example 2 (625 mg, 1 mmol), tetrahydrofuran (7 mL) and methanol (3 mL) was treated with 1N sodium hydroxide (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 6 hours then treated with 1N hydrogen chloride (1 mL, 1 mmol). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over ahydrous magnesium sulfate, and filtered. Evaporation of solvent afforded Cmoc-protected phenylalanine of sufficient purity for use in solid-supported peptide synthesis. MS (EI−): 610 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 3 h

Procedure:
Methyl 6-hydroxy-2-naphthoate (50 g), benzyl chloride (31.3 g), anhydrous potassium carbonate (100 g) and 2-butanone (350 ml) were stirred and refluxed together for 17 hours. Tlc showed the presence of some unreacted starting material and so a further 5 g benzyl chloride was added and refluxing continued for 3 hours. The product was isolated by pouring into water (1 liter), extracting the aqueous layer with 3×600 ml and 2×350 ml 2-butanone, followed by evaporation to dryness. The residue (65.7 g brown solid) was chromatographed over alumina (330 g) and silica gel (130 g) in dichloromethane, and the product was recrystallised from ethyl acetate (350 ml). Yield 37.3 g (51.6% theory) mpt 148.4°-149.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#N)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-:22].[Na+].[OH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:24])=[O:22])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CCCCCCCCCNS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCCCCCCNS(=O)(=O)c1cccc(Cl)c1

Procedure:
9-(3-Chlorobenzenesulphonamido)nonanenitrile (4.4 g, 0.013 mol) was treated with NaOH (5 g, 0.115 mol) in 30 ml water and 50 ml ethanol by the method described in Example 6(ii). Chromatography in CHCl3 :MeOH 10:1 on silica and recrystallisation from 2-propanol/pet. ether 60°-80° gave the title compound (0.94 g, m.p. 112°-3° C.).
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:16][C@@H:15]3[C@@H:11]([CH2:12][O:13][C:14]3=[O:17])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(O)C>[CH:18]1([NH:21][C:14]([C@@H:15]2[C@H:11]([CH2:12][OH:13])[CH2:10][N:9]([C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:16]2)=[O:17])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: C[C@H](c1ccccc1)N1C[C@@H]2COC(=O)[C@@H]2C1
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO)[C@@H](C(=O)NC2CC2)C1
Temperature: 80 °C
Reaction time: 44 h

Procedure:
(1S,5R)-7-[(1R)-1-Phenylethyl]-3-oxa-7-azabicyclo[3.3.0]octane-2-one (7.73 g, 33.4 mmol) was dissolved in ethanol (92 mL). To this solution, cyclopropylamine (46.3 ml) was added and the mixture was stirred at 80° C. for 44 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diisopropylether (300 mL) was added to the residue and the solution was heated to form crystals. The solution was concentrated to approximately half the original volume and the crystals formed were filtered. The collected crystals were washed with diisopropyl ether and were dried under reduced pressure to give (3R,4S)-N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide as white crystals (4.41 g). The filtrate and the washings were then combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=1:1->ethyl acetate) to give additional (3R,4S)-N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (1.50 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]12([P:25]([C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)Cl)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.CCOCC>C1COCC1.CCCCC>[C:15]12([P:25]([C:27]34[CH2:28][CH:29]5[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]5)[CH2:34]3)[CH2:36]4)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH:17]3[CH2:23][CH:21]([CH2:20][CH:19]([CH2:18]3)[CH2:24]1)[CH2:22]2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: c1ccc(-c2ccccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.8 %

Procedure:
An oven dried Schlenk tube was charged with magnesium turnings (240 mg, 9.89 mmol), 2-bromo-biphenyl (1.55 mL, 7.5 mmol). The tube was evacuated and backfilled with argon two times. To the above mixture THF (15 mL) was added through a rubber septum and the reaction mixture was heated to a mild reflux for 3 hours. The reaction mixture was then temporarily cooled to room temperature for the addition of cuprous chloride (930 mg, 9.45 mmol) followed by a solution of the di-1-adamantylchlorophosphine in 5 mL THF. Heating was resumed for an addtional 3 hours. The reaction mixture was cooled to room temperature, and ether (50 ml,) and pentane (50 mL) were added. The resulting suspension was stirred for 10 minutes, during which time a heavy dark-brown precipitate formed. The suspension was filtered and the solid was collected on a fritted funnel. The solid was partitioned between ethyl acetate-ether (100 mL 1:1) and 38% ammonium hydroxide-water (100 ml, 1:1). The mixture was vigorously shaken several times over 30 minutes. The aqueos layer washed twice with ether-ethyl acetate (1:1, 100 ml,). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, decanted, and concentrated in vacuo. The product was crystallized from toluene/methanol to afford 450 mg (5.8%) product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:9][C:8]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OC(=O)c2ccc(-c3ccccc3)cc2)cc1O

Procedure:
A solution of 2,4-dihydroxy benzoic acid tert-butyl ester (420 mg; 2 mmol), triethylamine (202 mg; 2 mmol) and p-phenyl benzoyl chloride (415 mg; 1.9 mmol) in dry CH2Cl2 was stirred under argon atmosphere at room temperature overnight after which time H2O was added. The organic phase was isolated, dried, evaporated to dryness and re-crystallized from 2-propanol to yield 195 mg (25%). MS (LC-MS): 389 (MH−).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([F:31])[CH:22]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[NH:3][C:4](=[O:7])[O:5][N:47]=3)=[CH:38][CH:39]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([F:31])[CH:22]=1)[CH3:14]
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)C)c(F)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)c(F)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.47 g, 79%).
Reaction SMILES: C(O)C.[OH:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]2[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@H:11]2[C@H:10]([NH2:18])[CH2:9]1.[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].C(OC(=O)C)(C)C>O>[C:19]([O-:24])(=[O:23])[C:20]([O-:22])=[O:21].[OH:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C@H:11]2[C@H:10]([NH3+:18])[CH2:9]1.[OH:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C@H:11]2[C@H:10]([NH3+:18])[CH2:9]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: O=C(O)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2[NH3+]
Product: O=C([O-])C(=O)[O-]
Temperature: 65 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To an ethanol solution of (3 aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (approximately 100 kg in approximately 320 kg of to ethanol, prepared as described in WO01/92263) water (30 kg) was charged. The mixture was heated to 65° C. and oxalic acid×2H2O (57 kg) was added. Iso-propylacetate (665 kg) was added during 2 hours and the resulting slurry was cooled to 20° C. in 2 hours. The cooled slurry was kept at this temperature for additionally 2 hours. The precipitated product was isolated, washed with iso-propylacetate (141 kg) and dried under vacuum to give the title compound as a white solid (116 kg, approximately 82%). 1H NMR (400 MHz, DMSO-d6) δ 6.51 (app br s, NH2, COOH and OH protons), 4.70 (app d, J=6 Hz, 1H), 4.61 (app d, J=6 Hz, 1H), 3.91 (app br s, 1H), 3.40-3.59 (m, 5H), 2.12-2.23 (m, 1H), 1.89-2.01 (m, 1H), 1.36 (s, 3H), 1.23 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.7, 110.8, 82.8, 82.7, 82.1, 70.5, 60.0, 55.1, 32.5, 26.1, 23.9.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.C([O-])(C)(C)C.[K+].Br[CH2:32][CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>O1CCCC1>[O:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]1[O:35][CH2:34][CH2:33][CH2:32][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[N:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccc(Cl)c2Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(CC(N=C2SCCN2CCCOC2CCCCO2)c2cccc(Cl)c2Cl)c1
Yield: 48.5 %

Procedure:
A mixture of 1-(4,5-dihydrothiazol-2-yl)amino-1-(2,3-dichlorophenyl)-2-(3,5-dimethylphenyl)-ethane (300 mg), potassium tert.-butanolate and tetrahydrofuran (THF, 10 ml) was treated at room temperature with 2-(3-bromo-propoxy)-tetrahydropyran (210 mg) for 3 days. Aqueous work-up by dilution in ethyl acetate, washing with an aqueous potassium carbonate solution (5% strength) and water and drying over sodium sulphate yielded a crude product that was purified by column chromatography over silica gel to give 200 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#CCCCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-methoxy-5-(5-phenyl-pent-1-ynyl)-2H-phthalazin-1-one (1.26 g, 3.96 mmoles), prepared as described in example 64, and POCl3 (30 ml) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was brought to dryness, the residue dissolved in CH2Cl2, washed to alkalinity with a diluted solution of K2CO3, then with water, anhydrified over Na2SO4 and brought to dryness to give 1.33 g of the title compound (quantitative yield). The compound was used as such in the subsequent step.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[CH3:28])[CH2:10][C:9]2([CH3:30])[CH3:29])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:29][C:9]1([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:28])[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.2 g, 7.8 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 3 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 80%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=381.1.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.CO.C1COCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[OH:27])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(C(C)O)ccc1OCCCN1CCC(c2nsc3cc(F)ccc23)CC1
Reaction time: 3.5 h
Yield: 91.9 %

Procedure:
To a starred solution of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]3-methoxyphenyl]ethanone (4.1g, 9.3 mmol) in 60 mi MeOH--THF (1:1) under N2 at ambient temperature, NaBH4 (0,386g, 10.2 mmol) was added portionwise. After complete addition, the reaction was stirred for 3.5 hours and was concentrated to yield a white gum. This was triturated with H2O (2×) and the aqueous fraction was decanted away. Residual water was removed under high vacuum to afford 5.0 of a white powder. The compound was taken up in boiling toluene and the insolubles were filtered away. Concentration of the toluene filtrate afforded 3.8g of a beige solid. Purification via preparative HPLC (Water's Associates prep LC/System 500, using 2 silica gel columns and 2% Et2NH--EtoAc) provided 2.7 g of a light beige solid. The product was recrystallized from EtoAc to afford 1.7g (42%) of a pure white powder, m.p.=113°-115° C.