Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[N:1]1([C:2]2[N:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=2)[CH:14]=[N:26][N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)Cc1cnc(N)cn1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cnc(-n2cnnn2)cn1
Temperature: 100 °C

Procedure:
A solution of the ethyl (5-aminopyrazin-2-yl)acetate (2.0 g, 11.0 mmol) and triethyl orthoformate (4.9 g, 33.1 mmol) in 60 mL of HOAc was added sodium azide (0.9 g, 13.8 mmol) and heated to 100° C. for 1 hour. The reaction was completed which was checked by TLC. The reaction mixture was cooled to r.t. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatograph to afford the product ethyl [5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.50 (s, 1H), 9.35 (s, 1H), 8.54 (s, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.98 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)ccc2c1SCC[C@@H]2NC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1c(C(=O)Nc2ccncc2)ccc2c1SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (2.00 g), 4-aminopyridine (582 mg) and 2-chloro-1-methylpyridinium iodide (2.37 g), the objective (S)-4-(tert-butoxycarbonylamino)-8-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.86 g) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1(O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:23]1([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid (2.53 g, 7.6 mmol) in DCM (50 ml) at 0° C. was added cyclopentanol (1.39 ml, 15.3 ml), EDC (1.61 g, 8.4 mmol) and DMAP (0.093 g, 0.76 mmol). The reaction mixture was stirred for 16 hours at room temperature before evaporation under reduced pressure. The crude residue was dissolved in ethyl acetate (100 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 2.24 g, 73% yield of title compound. LCMS purity 100%, m/z 402.5 [M++H], 1H NMR (300 MHz, CDCl3), δ: 5.20 (1H, d, J=6.3 Hz), 5.15 (1H, m), 4.20 (1H, m), 3.6 (2H, m), 2.00 (1H, m), 1.95-1.55 (9H, bm), 1.40 (9H,s), 0.85 (9H,s), 0.10 (6H,s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20].N1CCCCC1>C(O)C>[NH2:22][C:21]1[O:1][C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[CH:17]([C:16]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:18]=1[C:19]#[N:20]
Reactant: COc1ccc(C=C(C#N)C#N)cc1OC
Reactant: Oc1cccc2cccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2ccc2cccnc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 8-hydroxyquinoline (2.90 g) and 3,4-dimethoxy benzylidenemalononitrile(4.28 g) in ethanol (15 ml) was treated with piperidine (1.70 g) and the suspension stirred at room temperature for one hour. This mixture was then heated at reflux for 90 minutes. The red solution was then allowed to cool to room temperature overnight. The precipitated orange solid was filtered off and washed with ethanol and ether and dried in vacuo at 60° C., yielding 2-amino-4-(3,4-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile as a tan solid, m.p. 118°-120° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:11]([O:10][C:2]([CH:3]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCCCCOc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCOc1ccccc1)C(=O)OCC
Yield: 63 %

Procedure:
Sodium (0.22 g, 9.6 mmol) was dissolved in EtOH (20 mL). Diethyl malonate (1.53 g, 9.6 mmol) in EtOH (5 mL) and 7-phenoxyheptyl bromide (2.36 g, 8.7 mmol) in EtOH (5 mL) were subsequently added at room temperature. The reaction mixture was refluxed for 8 h. After evaporation of the solvent, the residue was taken up in ethyl acetate (150 mL). The organic phase was washed with water (2×50 mL), and brine (50 mL), and dried over Na2SO4. The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.92 g, 63%), bp 150°-154° C./0.1 torr, 1H-NMR: 1.24 (t, 6H), 1.1-1.8 (m, 12H), 3.30 (t, 1H), 3.91 (t, 2H), 4.18 (q, 4H), 6.7-7.2 (m, 5H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19].C(O)(=O)C.N1CCCCC1>ClCCl>[C:18]([C:17]([C:16](=[O:21])[CH3:15])=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)(=[O:20])[CH3:19]
Reactant: N#Cc1ccc(C=O)c2ccccc12
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(C#N)c2ccccc12)C(C)=O

Procedure:
240 mg (1.33 mmol) of 4-formyl-1-naphthonitrile, 132.6 mg (1.33 mmol) of 2,4-pentanedione, 119.3 mg (1.99 mmol) of acetic acid and 22.6 mg (0.27 mmol) of piperidine are dissolved in 20 ml of dichloromethane and heated under reflux with an inverse water trap overnight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator and the residue is purified by column chromatography (silica gel, mobile phase: initially dichloromethane, then isohexane/ethyl acetate 3:1). The residue after concentration of the product fractions is crystallized from diethyl ether and dried under high vacuum. 340 mg (97.5% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.O>[C:31]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(C)=O)C4)cc2)C(=O)O1
Yield: 51.1 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (80 mg, 0.23 mmol) in DCM (2 mL) were added triethylamine (0.13 mL, 0.92 mmol) and acetyl chloride (0.02 mL, 0.34 mmol) at 0° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.83:9.17 MeOH:CHCl3) to provide the title compound (42 mg, 51%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.N[CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].O[N:39]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[C:7]([CH2:18][N:19]([CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])[C:20](=[O:21])[C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH2:39])=[O:28])=[CH:29][CH:30]=3)=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CC(C)(O)CN
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CN(Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)C(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of 4-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamoyl)benzoic acid (25.3 mg, 0.058 mmol), 1-amino-2-methylpropan-2-ol (5.21 mg, 0.058 mmol), 1-hydroxybenzotriazole (HOBT) (12.9 mg, 0.094 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (18.1 mg, 0.094 mmol) in methylene chloride at 25° C. was treated with N,N-diisopropylethylamine (76.3 mg, 103 μL, 0.584 mmol). The reaction was stirred at 25° C. overnight. The reaction was diluted with methylene chloride (20 mL) and was washed with a saturated aqueous ammonium chloride solution (1×50 mL) and a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (2% methanol/methylene chloride ramped to 6% methanol/methylene chloride) provided N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-N-(2-hydroxy-2-methyl-propyl)-terephthalamide (14.3 mg, 49%) 1H NMR (300 MHz, DMSO-d6) δ ppm 8.85 (t, J=5.27 Hz, 1H) 8.33 (t, J=6.12 Hz, 1H) 8.28 (d, J=8.67 Hz, 1H) 7.91 (s, 4H) 7.99 (s, 1H) 7.54-7.74 (m, 5H) 7.46 (dd, J=8.67, 1.88 Hz, 1H) 6.91 (d, J=1.70 Hz, 1H) 4.54 (s, 1H) 4.40 (d, J=5.46 Hz, 2H) 3.25 (d, J=6.03 Hz, 2H) 1.08-1.14 (m, 6H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-chloro-benzylamine (0.158 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.115 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.74 (s, 2H) 7.22-7.38 (m, 5H), 7.92 (s, 1H). GC-MS: m/z 417 (M−1)+, 382 (M−36)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)([CH3:3])[CH3:2].N1C=CC=CC=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:29]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[O:35])=[CH:11]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1-n1ccc2ccccc21
Reactant: Cc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cn(-c3ccccc3C(C)C)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1-(2-isopropylphenyl)-1H-indole (117 mg, 0.50 mmol) and pyridine (42.5 μL, 0.0524 mmol) in dichloromethane (anhydrous) (3.0 mL) under a nitrogen atmosphere is added triphosgene (146 mg, 0.50 mmol) and the reaction allowed to stir with warming to ambient temperature for overnight. An aliquot of the reaction solution (600 μL, 0.1 mmol) is removed and added to a solution of triethylamine (28 μL, 0.1 mmol), N,N-dimethylaminopyridine (2.4 mg, 0.2 mmol), and p-toluidine (12 mg, 0.11 mmol) in dichloromethane (anhydrous) (1.0 mL) and stirred at ambient temperature for 14 hours). The reaction mixture was concentrated and the residue purified by RP HPLC to give Example 51. LC/MS (ESI+) 369.5 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])[CH:7]=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([O:38]C(OC(C)(C)C)=O)[C:28]([C:46]([F:49])([F:48])[F:47])=[CH:27][CH:26]=1>>[C:34]([O:33][C:31]([C:30]1[C:29]([OH:38])=[C:28]([C:46]([F:48])([F:47])[F:49])[CH:27]=[CH:26][C:25]=1[CH2:24][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:1]2[CH2:2][CH2:3]2)=[CH:21][CH:20]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C2CC2)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C(=O)O)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c(C2CC2)c1
Yield: 45 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(2-cyclopropyl-4′-hydroxy-1,1′-biphenyl-4-yl)propanoate (135 mg, 0.46 mmol) obtained in Example (112-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (249 mg, 0.55 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (115 mg, three-step total yield: 45%).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish solid.
Reaction SMILES: [C:1]1([C:7]([S:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NC2C=CC(NC3C=CC=CC=3)=CC=2)C=CC=CC=1.[C:34](OCC)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([O:13][CH2:12][CH2:11][S:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(SCCO)c1ccccc1
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)OCCSC(C)(C)c1ccccc1
Temperature: 120 °C

Procedure:
Into a 3-neck 250 mL round-bottomed flask were weighed, in the following order: 2-(2-phenylpropan-2-ylthio)ethanol (30.0 g, 0.1528 moles), N,N′-diphenyl-1,4-phenylene diamine (0.318 g, 1.2224×10−3 moles) and ethyl acrylate (122.40 g, 1.2224 moles). The apparatus was then assembled in a reactive distillation arrangement before being purged with N2 (g). The Claisen head of the distillation apparatus was wrapped with Al-foil/glass wool. The reaction flask was then heated to 120° C., by use of a silicone heating oil bath, and once the ethyl acrylate (Bpt: 99° C.) started to distil over tetrapropoxytitanate (TPT) (1.04 mL, 0.999 g, 3.5144×10−3 moles) was added to the reaction mixture via a 2.50 mL Hamilton gastight syringe. The distillation rate immediately increased significantly and the distillation vapour temperature decreased from 98° C. to ca. 80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:17]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (134.48 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 510.2 (M+H)+; Rt: 2.03 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br>O1CCOCC1>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(F)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1cccc(F)c1
Reaction time: 0.25 h

Procedure:
A solution of 1-(3-fluorophenyl)ethanone (14.0 g, 100 mmol) (Aldrich) in dioxane (250 mL) at 12-15° C. was treated with a solution of bromine (17 g, 105 mmol) in dioxane (120 mL) drop wise over 0.5 h. This was stirred for 15 min and most of the solvent removed. The residue was taken up in hexane (200 mL), washed 2× water, and dried (MgSO4). Solvent was removed to give 2-bromo-1-(3-fluorophenyl)ethanone. 1H NMR (CDCl3), 300 MHz) δ3.71 (s, 2H, CH2), 7.30-7.77(m, 4H, Aromatic).
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=O)(OCC1C=CC=CC=1)=O.[BH4-].[Na+].[Br:21][C:22]1[CH:23]=C(N2CCC=C2)[CH:25]=[N:26][CH:27]=1>COCCOC.C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:13]([CH:12]2[CH2:16][CH2:17][CH2:18][NH:11]2)[CH:25]=[N:26][CH:27]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Brc1cncc(N2C=CCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Brc1cncc(C2CCCN2)c1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Carbobenzyloxy-L-proline (37.4 g, 150 mmol) was dissolved in DME (100 mL) and cooled to 0° C. with stirring. Sodium borohydride (1.89 g, 50 mmol) was added in portions (gas evolution) and the resulting mixture was stirred for 2 h at 25° C. affording a colorless solution. The solvents were removed in vacuo and the resulting gum dissolved in methylene chloride (50 mL). To this solution was added a mixture of 5-bromo-3-(2-pyrrolin-1-yl) pyridine (5.63 g, 25 mmol) and carbobenzyloxy-L-proline (6.23 g, 25 mmol) in methylene chloride (50 mL) and this was stirred at 25° C. for 36 h. The solvent was removed in vacuo and 6M HCl (200 mL) was added to the residue. The resulting solution was extracted with isopropyl acetate (200 mL) and the phases separated. The acidic aqueous phase was basified with solid NaOH to pH 14 and then extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine (150 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:19 to 1:9) as eluants to afford 5-bromo-3-(2-pyrrolidinyl)pyridine (4.1 g, 72%) obtained as a pale yellow oil. LRMS (EI) m/e 227 (C9H11N281 Br--H+), 225 (C9H11N279Br--H+); 1H NMR (DMSO-d6, 300 MHz) δ 8.53 (d, J=2.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17 (t, J=7.7 Hz, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s, 1H), 2.00-1.77 (m, 2H), 1.63 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Cl)=[N:6][CH:7]=1.Cl.[CH3:11][O:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:13][O:12][CH3:11])=[N:6][CH:7]=1
Reactant: ClCc1ccc(Br)cn1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CONCc1ccc(Br)cn1
Temperature: 60 °C
Yield: 28.5 %

Procedure:
To a stirred solution of 5-Bromo-2-chloromethyl-pyridine (2 g, 9.709 mmol) in dimethylformamide (30 mL) is added methoxy amine hydrochloride salt (0.973 g, 11.65 mmol) and K2CO3 (3.35 g, 24.27 mmol) at room temperature then heated to 60° C. for 16 hours. Reaction mixture diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 30% ethyl acetate in hexane as an eluent to afford the title compound (0.6 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.36 (s, 3H), 3.99 (d, J=5.88 HZ, 2H), 7.10 (t, 1H), 7.44-7.46 (dd, J1=8.32 Hz, J2=0.32 Hz, 1H), 7.99-8.02 (dd, J1=2.44 Hz, J2=8.4 Hz, 1H), 8.60-8.61 (dd, J1=2.4 Hz, J2=0.4 Hz, 1H). LC-MS (m/z): [M+H]=217.1.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]([C:32]3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH3:39][O:40]CCCl>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH2:32][O:40][CH3:39])=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COCCCl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Solvent: CN1CCCC1=O
Product: COCCSc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reaction time: 2 h

Procedure:
Prepared according to Method B of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]oxazolidine-2-one with 2-chloroethyl methyl ether (0.036 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. for 2 h. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.034 g (52%). MS (m/z): 343 [M+H]+. 1H NMR.