Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:16]([F:25])[C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:25][C:16]1[C:15]2[O:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][N:2]=3)=[N:13][C:14]=2[CH:19]=[CH:18][C:17]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: O=Cc1nccc2ccccc12
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
In ethanol (13 ml), isoquinoline-1-carbaldehyde (500 mg, 3.18 mmol) and methyl 4-amino-2-fluoro-3-hydroxyphenylacetate (632 mg, 3.17 mmol) were stirred at room temperature for 2 days. Iodobenzene diacetate (1.23 g, 3.82 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3:1, v/v) eluate fractions, methyl (7-fluoro-2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (155 mg, 14%) was obtained as a red brown solid.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CN)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3cccc(Cl)c3)cc2)n1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 1-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)phenyl]methanamine and 3-chlorobenzaldehyde gave the title compound as a colorless oil (86%). 1H NMR (DMSO-d6, 300 MHz) δ 8.03 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (s, 1H), 7.65-7.23 (m, 3H), 3.77 (s, 2H), 3.70 (s, 2H), 3.30 (s, 1H), 2.75 (t, J=7.2 Hz, 2H), 1.79-1.65 (m, 2H), 1.41-1.16 (m, 16H), 0.84 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 5.19 min (HPLC purity: 98.4%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[NH:11]1.O>C(O)(=O)C>[Br:1][C:13]1[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:9])[NH:11][C:12]=1[C:20]([F:21])([F:23])[F:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 0.36 g (2.04 mmol) of N-bromosuccinimide was added to a suspension of 0.3 g (1.36 mmol) of methyl 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate in 10 ml of glacial acetic acid, and the mixture was then heated under reflux for 2 days. The reaction mixture was then added to water and extracted with dichloromethane. The extract was concentrated, and the residue was purified further by preparative HPLC. This gave 227 mg (56% of theory) of a colorless powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].[N:15]1[O:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O1CCCC1>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C@:19]12[CH2:20][O:21][CH2:22][CH2:23][C@H:18]1[CH2:17][O:16][NH:15]2
Reactant: Fc1ccc(Br)c(F)c1
Reactant: C1C[C@H]2CON=C2CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc([C@]23COCC[C@H]2CON3)c(F)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 3.95 mL, 9.88 mmol) was added to a solution of 1-bromo-2,4-difluorobenzene (0.558 mL, 4.94 mmol) in a 1:3 mixture of tetrahydrofuran and toluene (25 mL) at −78° C., and the reaction mixture was stirred at this temperature for 1 hour. In a separate flask, a solution of (3aR)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C9) (628 mg, 4.94 mmol) in toluene (15 mL) was cooled to −78° C. and treated with boron trifluoride diethyl etherate (1.22 mL, 9.88 mmol); this mixture was also allowed to stir at −78° C. for 1 hour, and then added via cannula to the aryllithium solution. The reaction mixture was stirred for 1 hour and was then quenched with saturated aqueous ammonium chloride solution. After dilution with ethyl acetate, the layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 40% ethyl acetate in heptane) provided the product. Yield: 610 mg, 2.53 mmol, 51%. The cis ring fusion was assigned on the basis of analogy with compound C17, whose stereochemistry was confirmed via single crystal X-ray analysis (vide infra). LCMS m/z 242.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.75-1.93 (m, 2H), 3.03-3.10 (m, 1H), 3.53-3.76 (m, 4H), 3.95-4.02 (br m, 1H), 4.03 (dd, J=12.5, 1.8 Hz, 1H), 6.93-7.00 (m, 2H), 7.84-7.92 (m, 1H).
Reaction SMILES: N([CH2:5][CH2:6][OH:7])CCO.[CH3:8][CH2:9][CH2:10][CH2:11][O:12][P:13]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[CH2:25](O)[CH2:26][OH:27].C(O)C[O:31]CCO.O[Sn](=O)CCCC>OCCCC[Sn]=O.O>[CH3:19][CH2:18][CH2:17][CH2:16][O:15][P:13]([O:12][CH2:11][CH2:10][CH2:9][CH3:8])([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:14].[C:26]1(=[O:27])[O:7][C:6](=[O:31])[CH:5]=[CH:25]1
Reactant: OCCNCCO
Reactant: OCCOCCO
Reactant: OCCO
Agent: CCCCOP(=O)(OCCCC)OCCCC
Agent: CCCC[Sn](=O)O
Agent: O=[Sn]CCCCO
Solvent: O
Product: O=C1C=CC(=O)O1

Procedure:
Using a reactor setup as described in Example 1, a TBPA, glycol, maleic anhydride product was prepared using a mole ratio of anhydride to glycol of 4:5.23, a hydroxybutyltin oxide catalyst and diethanolamine (DEA) as neutralizing agent. TBPA (1.937 moles), ethylene glycol (3.377 moles), diethylene glycol (1.69 moles), hydroxy-butyltin oxide (1.49 gms), and DEA (4.41 gms) were added to the reaction at room temperature and stirred at 400 rpm. When the temperature reached 85° C., 1.937 moles of maleic; anhydride were added and the temperature was raised to 185° C. to 190° C. The reaction time was about 3 hours with 62.5 mls of water collected (86.8% of theory). The product acid number was 18.8. GPC analysis as described in Example 1 gave the following results:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30](O)=[O:31].[OH:34][N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.C(OCC)(=O)C>[OH:34][NH:35][C:30]([CH:3]1[C:2]([CH3:33])([CH3:1])[S:7][CH2:6][CH2:5][N:4]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:31]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
To a solution of 0.28 g (0.56 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane. The product was triturated with ether to provide 0.024 g (8%) of N-hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a white solid. Electrospray Mass Spec: 513.4 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>C(Cl)Cl>[N:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[NH:53][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1
Reactant: Nc1ccccn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
3-[6-(4-t-Butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (121 mg) was dissolved in methylene chloride (0.9 ml). Oxalyl chloride (27 mg) and dimethylformamide (1 droplet) were added, and the mixture was stirred for 30 minutes at room temperature. 2-Aminopyridine (38 mg) was added, and the mixture was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate was added. The organic layer was successively washed with 0.5N-HCl, sat. aq. NaHCO3, and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1), to thereby obtain 51 mg (yield: 37%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:13][C:12]1(Cl)[C:14]([Cl:18])=[C:15](Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH2:21].[CH3:22][OH:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:13][C:12]1=[C:14]([Cl:18])[C:15]([O:23][CH3:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CO
Reactant: ClC(Cl)=C(Cl)C1(Cl)CC1CCOCc1ccccc1
Agent: [Na]
Product: COC(=O)C(Cl)=C1CC1CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At 0° C., a solution of 62.9 g (185 mmol) of J, 2-(2-benzyloxyethyl)-1-chloro-1-(1,2,2-trichlorovinyl)cyclopropane, in 50 ml of anhydrous methanol is slowly added dropwise with stirring to a freshly prepared solution of 34.0 g of sodium (1.48 mol, 8 equivalents) in 250 ml of methanol. The mixture is then heated at reflux for 2 d. After cooling to room temperature, the mixture is admixed with 700 ml of water and extracted with diethyl ether. The combined organic phases are concentrated under reduced pressure and the residue is taken up in 300 ml of methanol. 25 ml of 10 per cent hydrochloric acid are added and the reaction mixture is stirred for 45 min. The mixture is then admixed with 300 ml of saturated sodium bicarbonate solution and extracted with diethyl ether. The ether extracts are dried over calcium chloride. Removal of the solvent under reduced pressure gives a dark-brown oil. Filtration through 300 g of silica gel (PE:diethyl ether 10:1) gives 24.4 g (47%) of K methyl [2-(2-benzyloxyethyl)cyclo-propylidene]chloroacetate in the form of a pale yellow liquid as a mixture of two diastereomers in the ratio of 1:1.6.-13C-NMR (62.9 MHz, CDCl3, additionally DEPT), isomer A: δ=11.6 (−), 20.3 (+), 31.6 (−), 52.8 (+), 68.8 (−), 72.9 (−), 115.3 (Cquart), 127.49 (+), 127.53 (+), 128.3 (+), 138.3 (Cquart), 143.8 (Cquart), 162.4 (Cquart). -isomer B: δ=15.6 (−), 16.1 (+), 31.5 (−), 52.8 (+), 69.3 (−), 73.0 (−), 114.6 (Cquart), 127.49 (+), 127.53 (+), 128.3 (+), 143.3 (Cquart), 162-7 (Cquart). MS (70 eV), m/z (%): 280 (<1) [M+], 245 (1) [M+—Cl], 189 (2) [M+—CH2Ph], 91 (100) [CH2Ph+]. —C15H17ClO3 (280.8): calc. C, 64.17 H, 6.10; found C, 63.24, H, 5.97.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>ClCCl.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:27][CH:26]=[CH2:25])(=[O:3])[CH3:2]
Reactant: C=CC[Si](C)(C)C
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.08 h

Procedure:
To a solution of 17β-acetoxy-4,6-androstadien-3-one 1 (2.0 g, 6.1 mmol) in dry dichloromethane (130 ml) was added titanium tetrachloride (5.36 g, 3.1 ml, 28 mmol) at -70° C. The reaction mixture was allowed to stir for 5 min. Then, a solution of allyltrimethylsilane (4.0 g, 5.6 ml, 35 mmol) in dry dichloromethane (10 ml) was added over a period of 10 min and the resulting solution stirred during 1 hour at -70° C. followed by 1 hour at -20° C. Afterwards, the solution was diluted with 150 ml of ether and was washed with water (6×100 ml), dried, filtrated and concentrated to yield the crude 17β-acetoxy-7α-allyl-4-androsten-3-one which was immediately hydrolyzed.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:5]2[CH:4]=1.CN(C=O)C.[NH2:22][C:23]1[CH:24]=[C:25]([C:30]2[N:34]=[C:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][CH3:42])=[O:40])[CH2:36]3)[O:32][N:31]=2)[CH:26]=[CH:27][C:28]=1[CH3:29]>ClCCl.N1C=CC=CC=1>[CH3:29][C:28]1[CH:27]=[CH:26][C:25]([C:30]2[N:34]=[C:33]([CH:35]3[CH2:36][N:37]([C:39]([O:41][CH3:42])=[O:40])[CH2:38]3)[O:32][N:31]=2)=[CH:24][C:23]=1[NH:22][C:12]([C:9]1[N:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:4][C:5]2=[N:11][CH:10]=1)=[O:14]
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)ccn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(C(F)(F)F)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24) (89 mg, 0.387 mmol) in anhydrous dichloromethane (3 mL) at 0° C. under Argon oxalyl chloride (34 uL, 0.407 mmol) was added dropwise. Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was concentrated and the crude solid was added to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (19 mg, 0.0645 mmol) in anhydrous pyridine (1.5 mL) at 0° C. The reaction was stirred at room temperature under Argon for 20 minutes. The crude product was filtered and purified by preparative HPLC to give methyl 3-(3-(4-methyl-3-(7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F57). 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 9.64-9.61 (m, 1H), 9.75 (s, 1H), 8.33-8.30 (m, 1H), 8.10 (dd, J=1.6 Hz, 1H), 7.86 (dd, J=1.6, 8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.46 (dd, J=2.0, 7.6 Hz, 1H), 4.40-4.33 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.18 (m, 2H), 3.59 (s, 3H), 2.38 (s, 3H). MS m/z 501.43 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]SNC1C=CC=CC=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(OCC)(=O)C.CCCCCC>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:19]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C#CC(=O)OCC
Reactant: Nc1ccccc1SSNc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CNc2ccccc2S1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
2-(2-Aminophenyl)disulfanylaniline (1.0 g, 4.0 mmol) and ethyl prop-2-ynoate (790 mg, 816 μL, 8.05 mmol) were combined in a microwave tube and heated at 150° C. for 30 min. The reaction was concentrated in vacuo. Silica gel chromatography (10-35% ethyl acetate/hexane) provided ethyl 4H-1,4-benzothiazine-2-carboxylate as an orange solid (200 mg, 23% yield). LC/MS m/z 222.0 [M+H]+. 1H NMR (400.0 MHz, CDCl3) δ 7.11 (d, J=6.6 Hz, 1H), 6.86-6.82 (m, 1H), 6.79-6.74 (m, 2H), 6.27 (d, J=7.9 Hz, 1H), 5.68 (br d, J=4.2 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H)
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[CH:14]1([CH:17]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)O)C[CH2:15]1.C(O)(C(F)(F)F)=[O:29]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:14]([CH:17]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)[C:5]1[C:6](=[O:7])[O:1][C:2]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]=2[C:4]=1[OH:29])[CH3:15]
Reactant: O=c1ccc2c(o1)C=CC=CC=C2
Reactant: OC(c1cc2ccccc2s1)C1CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1cc2ccccc2s1)c1c(O)c2c(oc1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a methylene chloride solution of 2H-cycloocta[b]pyran-2-one of formula II-3 (196 mg) and cyclopropyl benzothien-2-yl carbinol of Preparation 65 (204 mg) is added several drops of TFA. The reaction is stirred for 30 minutes at room temperature without reaction. Several addition drops of TFA is added and the reaction stirred an additional 30 minutes. The solvent is removed in vacuo and the resulting solid dissolved in hot 40% EtOAc/hexane and placed in the freezer over night. The solid is collected on a filter to yield 257.5 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].CCOCC>CO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCC(=O)Cl
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CO
Product: CCC(=O)N1CCCC(c2cccc(C(=O)OC)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of the HCl-salt of methyl-3-(3-pyridyl)benzoate (5.54 g, 0.022 mol) in methanol was hydrogenated (atm. pressure) at r.t. using PtO2 as catalyst. After filtration and evaporation the residue was partitioned between a saturated potassium-carbonate solution and ether. The ether layer was dried (K2CO3), cooled and treated with triethylamine (2.23 g. 0.022 mol) and propionylchloride (2.05 g, 0.033 mol). Stirring at r.t. for one hour followed by filtration and evaporation gave an oil which was eluated twice through an Al2O3 with ether. Evaporation of the ether gave 4.8 g of pure methyl-3-(1-propionylpiperdin-3-yl)benzoate as an oil, which could not be crystallized.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:3])[N:9]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: OCCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COCCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydride (74 mg, 1.87 mmol) in tetrahydrofuran (2 ml) was cooled to 0° C. 2-(6-Bromopyridin-2-yl)ethanol (Example 235, Step 3) (126 mg, 0.62 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction was allowed to warm to room temperature. After 45 minutes at room temperature, the reaction was cooled to 0° C. and ethyl bromoacetate (0.14 ml, 1.25 mmol) was added. The reaction was allowed to warm to room temperature and then heated to 50° C. Upon completion, the reaction was cooled to 0° C. and water was added dropwise. Ethyl acetate was then added and the layers were separated. The organic layer was then dried over sodium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:58][O:59][C:60]([C:62]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C>[CH3:58][O:59][C:60]([C:62]1([NH:67][C:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[O:12][CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:24])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]
Reactant: O=C(O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Reactant: COC(=O)C1(N)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCC2COc3ccccc3O2)CCCC1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 84 mg 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid in 1 ml abs. DMF under inert atmosphere 42 mg 1-hydroxybenzo-triazole and 60 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.65 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 42 mg of 1-amino-cyclopentanecarboxylic acid methyl ester hydrochloride, followed by 0.65 μl of N,N-diisopropylethylamine were added. After 48 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 96 mg of 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14][CH2:15][CH2:16]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCSCCO)c1cc(F)ccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCSCC1
Yield: 64 %

Procedure:
In toluene (50 ml) was dissolved 2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol (800 mg, 2.00 mmol), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.50 g, 6.22 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, it was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (504 mg, 1.28 mmol, 64%) was obtained as a white powder.