Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[F:20][C:17]([F:18])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 3a (20 g, 70 mmol) in a 1:4 mixture of ethyl acetate and methanol (250 mL) was added palladium on charcoal (10% wt, 1.0 g, 0.90 mmol), and the mixture was stirred under an atmosphere of hydrogen. After 3 h, the solution was filtered over Celite® and the resulting solution was concentrated. 3b was recrystallized from ethyl acetate to afford 17.5 g of white crystals (97% yield). [M+H]+=255.20.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:27]1[CH2:33][C:31](=[O:32])[N:30]([CH2:34][C:35]([OH:37])=[O:36])[C:28]1=[S:29].[Cl-].[NH4+].N>C(O)C>[OH2:8].[CH2:22]([O:21][C:19]([C:18](=[C:33]1[S:27][C:28](=[S:29])[N:30]([CH2:34][C:35]([OH:37])=[O:36])[C:31]1=[O:32])[C:16]1[N:17]=[C:13]([NH:12][C:11]([NH:10][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:26])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[O:25])[S:14][CH:15]=1)=[O:20])[CH3:23]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 4 g of ethyl 2-(3-p-toluenesulfonylureido)thiazol-4-ylglyoxylate, 2 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])(O)[CH3:12])[CH:3]=1.OS(O)(=O)=O>>[CH3:12][C:11]1([CH3:14])[CH2:10][C:9]([CH3:16])([CH3:15])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[S:8]1
Reactant: CC(C)(O)CC(C)(C)c1cc(Br)ccc1S
Agent: O=S(=O)(O)O
Product: CC1(C)CC(C)(C)c2cc(Br)ccc2S1

Procedure:
A mixture of 500 mg (1.49 mmol) of 4-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 32) and 8 ml of 20 percent aqueous H2SO4 was heated at reflux for 24 h. The mixture was extracted with hexanes, the organic extracts were combined and washed successively with water, saturated NaHCO3, water again, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 1.35 (6H, s), 1.40 (6H, s), 1.93 (2H, s), 7.17 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.23 (1H, d, J~8.4 Hz), 7.26 (1H, d, J~2.1 Hz). MS exact mass, m/e 284.0221 (calcd. for C13H17S Br, 284.0234).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:23])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1)=[O:5].[C:24](OCC)(OCC)(OCC)[CH3:25]>>[F:20][C:19]([F:22])([F:21])[C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:23])[N:1]=[C:24]2[CH3:25])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(C(F)(F)F)c2)c(C)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of (Z)-3-amino-N-(3-trifluoromethyl-4-morpholinophenyl)but-2-enamide (4.0 g, 12.1 mmol) and triethyl orthoacetate (10 mL) was stirred at 150° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (3.00 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5](Br)[C:6](=O)[CH2:7][CH2:8][CH3:9])[CH3:2].C(N(CC)CC)C.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:22][C:21]([NH2:23])=[N:20][C:6]=1[CH2:7][CH2:8][CH3:9])=[O:12])[CH3:2]
Reactant: NC(N)=S
Reactant: CCCC(=O)C(Br)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCc1nc(N)sc1C(=O)OCC
Reaction time: 16 h
Yield: 33.6 %

Procedure:
2-Bromo-3-oxo-hexanoic acid ethyl ester (5.9 g, 25 mmol), was dissolved in 60 mL of ethanol containing triethylamine (4.2 mL, 30 mmol) and thiourea (1.9 g, 25 mmol). The colorless solution was protected from light and allowed to stir for 16 hours. The resulting red suspension was evaporated to dryness and dissolved in a minimum of dichloromethane. This solution was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was separated and filtered to remove a fine red precipitate which remained suspended in the organic phase. The solvent was removed and then the solid was dissolved in a minimum of 50/50 (v/v) ethyl acetate and 1 N aqueous solution of hydrochloric acid. The layers were separated and the aqueous layer was washed with an equal volume of ethyl acetate. After discarding the organic layers, the aqueous layer was then placed in an ice bath with an equal volume of ethyl acetate. Sodium hydroxide (1N) was then slowly added with vigorous swirling until the aqueous phase was basic. The layers were separated and the aqueous layer was washed two additional times with ethyl acetate. The combined organic layers were washed three times with an equal volume of a solution of saturated aqueous sodium bicarbonate followed by a solution of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield a pale yellow solid (1.8 g, 8.4 mmol, 34%) ESI-MS m/z calc. 214.1. found 215.3 (M+1)+ Retention time 1.90 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(CO)c1F
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PCl5 (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:7])([OH:6])[OH:5].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([NH:1][CH2:2][CH2:3][P:4](=[O:6])([OH:5])[OH:7])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCP(=O)(O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To a solution of 2-aminoethylphosphonic acid (1.26 g, 10.1 mmol) in 2N NaOH (10.1 mL, 20.2 mmol) was added benzyl chloroformate (1.7 mL, 12.1 mmol). After the reaction mixture was stirred for 2 d at room temperature, the mixture was partitioned between Et2O and water. The aqueous phase was acidified with 6N HCl until pH=2. The resulting colorless solid was dissolved in MeOH (75 mL) and treated with Dowex 50WX8-200 (7 g). After the mixture was stirred for 30 minutes, it was filtered and evaporated under reduced pressure to give carbobenzoxyaminoethyl phosphonic acid (2.37 g, 91%) as a colorless solid.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]([OH:17])=O)=[O:11])[CH3:8].[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C1COCC1.O.CO>[Si:22]([O:17][CH2:15][C@@H:13]1[CH2:14][C@H:12]1[C:10]([O:9][CH2:7][CH3:8])=[O:11])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: B
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
1M Borane-THF complex THF solution (85 mL, 84.98 mmol) was added to a solution of trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (11.2 g, 70.82 mmol) in THF (100 mL) at 0° C., and the mixture was stirred overnight at room temperature. MeOH was added thereto, and then the gas was not generated. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (50 mL), tert-butylchlorodiphenylsilane (20.10 mL, 84.98 mmol) and imidazole (5.79 g, 84.98 mmol) were added thereto, and the mixture was stirred for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 2→35% ethyl acetate/hexane) to give ethyl trans-2-((tert-butyldiphenylsilyloxy)methyl)cyclopropanecarboxylate (21.40 g, 55.9 mmol, 79%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:36]1[CH2:41][CH2:40][N:39]([C:18](=[O:20])[CH2:17][N:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.26 g, 0.014 mole) and dry tetrahydrofuran (80 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. A solution of 1-acetylpiperazine (4.49 g, 0.035 mole) in tetrahydrofuran (10 ml) was added and the resulting suspension was heated at 60° C. overnight. The solvent was evaporated under reduced pressure and the residue was triturated in water (100 ml), filtered, and the filter cake rinsed with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and allowed to cool to room temperature. The resulting solid was collected by filtration and dried under high vacuum at 50° C. to yield 3.18 g (57%) of title compound, mp 217°-219° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](C(OCC)=O)C(OCC)=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-:21].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:29]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:29])=[O:21])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Diethyl 2-(5-nitropyridin-2-yl)malonate (67.47 g) was stirred in water and aqueous sodium hydroxide solution (2N) was added followed by potassium permanganate (42 g) causing the reaction temperature to rise to 60° C. Further portions of aqueous sodium hydroxide solution and potassium permanganate were added maintaining the reaction temperature at 60°-70° C. After the final addition, the suspension was stirred at 60° C. for 1.5 hours. The hot suspension was then filtered through `Hyflo Supercel`. The filter cake was washed with aqueous sodium hydroxide solution (2N). On cooling to room temperature, the filtrate was carefully acidified to pH 1-2 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried to yield 5-nitropyridine-2-carboxylic acid (26.17 g) as a fawn solid, m.p. 210°-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.BrC1C=C(C(F)(F)F)C=CC=1N1CCOC2C=C(S(Cl)(=O)=O)C=CC1=2.ClC1C=C(C(F)(F)F)C=CC=1F.[F:63][C:64]1[C:69]([F:70])=[C:68]([F:71])[C:67]([F:72])=[C:66]([F:73])[C:65]=1[OH:74].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:74][C:65]3[C:64]([F:63])=[C:69]([F:70])[C:68]([F:71])=[C:67]([F:72])[C:66]=3[F:73])(=[O:23])=[O:24])[CH:20]=[CH:21][C:13]1=2
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Agent: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
INTERMEDIATE F was prepared from 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (INTERMEDIATE E), which was prepared in an analogous fashion to INTERMEDIATE C, except using 2-chloro-1-fluoro-4-(trifluoromethyl)benzene instead of 2-bromo-1-fluoro-4-(trifluoromethyl)benzene in STEP 1. A 25 mL septa/cap vial under Argon was charged with INTERMEDIATE E (0.400 g, 0.970 mmol), and dissolved in DCM (3.6 mL). 2,3,4,5,6-Pentafluorophenol (PFP) (0.268 g, 1.456 mmol) was added, followed by dropwise addition of triethylamine (0.202 mL, 1.46 mmol). The reaction was stirred for 1 hour at room temperature. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 40% EtOAc:Heptane; product eluted at 30%) to afford perfluorophenyl 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (0.543 g, 0.970 mmol) as a clear colorless oil. m/z (ESI) 391.8 (M-PFP)−.
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-][CH:22]([CH3:24])[CH3:23])(C)C.[Li+].C[C@H]1C[C:43]2[CH:42]=[C:41]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[CH:40]=[CH:39][C:38]=2[C@@H:37]2[C@@H:28]1[C@H:29]1[C@@:33]([CH2:35][CH2:36]2)([CH3:34])[C:32](=O)[CH2:31][CH2:30]1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:32]1[CH2:31][CH2:30][C@H:29]2[C@H:28]3[C@H:37]([CH2:36][CH2:35][C@:33]12[CH3:34])[C:38]1[CH:43]=[CH:42][C:41]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:40][C:39]=1[CH2:24][C@@H:22]3[CH3:23]
Reactant: CC(C)[N-]C(C)C
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)C(=C(F)F)CC[C@H]3[C@@H]21
Reaction time: 1 h

Procedure:
A solution of 2 g of difluoromethyldiphenylphosphine oxide in 55 ml of tetrahydrofuran is slowly mixed with 3.9 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C, and it is stirred for 1 hour. Then, a solution of 1.15 g of 7β-methyl-3-tetrahydropyranyloxy-estra-1,3,5(10)-trien-17-one in 20 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 1.3 g is obtained as colorless crystals with a melting point of 85-86° C., [α]D22 =-59-4° (c=0.535% in pyridine).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=2)[O:21][C:20]([CH3:29])([CH3:28])[CH2:19][C:18]3([CH3:31])[CH3:30])[CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:25]([C:23]1[CH:24]=[C:15]([C:14]#[C:13][C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:28])([CH3:29])[CH2:19][C:18]2([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#Cc2cccc(C=CC(=O)O)c2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 3-[3-(8-isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-acrylic acid ethyl ester (Intermediate 33, 0.058 g, 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 5N solution of potassium hydroxide (2 mL, 10 mmol) and the reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound (0.036 g, 66%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([O:13][CH3:18])=[O:12])[NH:2]1
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H]1Cc2ccccc2CN1
Product: Cl
Reaction time: 0.17 h

Procedure:
In succession 5 g of tetrahydroisoquinoline 3-carboxylic acid and 30 ml of methanol are introduced into a three-necked flask. 6 g of thionyl chloride are added to this suspension by pouring carefully, taking care that the temperature does not exceed 0, +5°. The addition takes approximately 10 minutes. After the addition is completed, stirring is continued for 2 hours at room temperature, and then the mixture is heated to reflux for 11/2 hours. Once the mixture has dissolved completely, heating is discontinued and the mixture is then evaporated to dryness. The residue is taken up three times in methanol and then evaporated to dryness. Finally, 8 g of colourless crystals are obtained and purified by trituration with ether. The crystals are separated off by filtration, washed with ether and dried. 6.4 g of methyl tetrahydroisoquinoline-3-carboxylate hydrochloride are thus obtained.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:34]([NH2:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:44][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCN
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
5.0 g (20 mmoles) of Z-Pro-OH are dissolved in 50 ml of DMFA, 2.8 ml (20 mmoles) of triethylamine are added to the solution, and the mixture is cooled to -10° C. The mixture is stirred at the same temperature, 2.8 ml (21.5 mmoles) of isobutyl chloroformate are added dropwise, and after 10 minutes 4.4 ml (22 mmoles) of n-decylamine are introduced dropwise. After the addition the reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The resulting suspension is filtered, the filtrate is evaporated, and the residue is dissolved in 100 ml of ethyl acetate. The solution is shaken four times with 50 ml of n hydrochloric acid, each, twice with 50 ml of n sodium hydrocarbonate solution, each, and then with 50 ml of water, dried over anhydrous sodium sulfate and evaporated. The oily residue is crystallized from n-hexane to obtain 5.43 g (70%) of Z-Pro-NH-C10H21 ; m.p.: 78°-80° C., Rf2 =0.75.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.BrC1C=CC(S(O[CH2:24][C@@H:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([CH2:6][CH2:7][NH:8][CH2:24][CH:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)=[CH:5]1
Reactant: NCCc1csc2ccccc12
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCc1csc2ccccc12)O3
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 2-benzo[b]thiophen-3yl-ethylamine (354 mg, 2.0 mmol) in 1 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromo-benzenesulfonate (300 mg, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 4 days. The reaction was diluted with H2O (10 mL), poured into saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with 1:1 H2O/brine (40 mL) and brine (40 mL), then were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography (2×20 cm SiO2, CH2Cl2 to 3% MeOH/CH2Cl2 gradient) afforded 225 mg (86%) of the (S)-enantiomer of the title compound as a thick oil. The fumarate salt was prepared by treating the amine in ethyl acetate with a solution of 66 mg (0.57 mmol) fumaric acid in methanol. The precipitated salt, a pale yellow solid, weighed 190 mg (m.p. 124-127° C.); MS (ESI) m/z 391 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](O)=O)=[CH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:27]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:18][CH:19]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccnc2ccccc12
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc3ccccc23)o1
Yield: 23 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using quinoline-4-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20, 75 mg, 23%) which was obtained as a white solid. MS: m/e=355.2 [M+H]+.