Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])(O)=O>O1CCCC1>[C:20]1(=[O:21])[N:16]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: O=C(O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1NCCc1c[nH]c2ccccc12

Procedure:
As shown in reaction Scheme A, treatment of tryptamine (1) with N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20°-65° C., preferably 65° C., for a period of 12-48 hours gives the corresponding N-phthalimidotryptamine derivative (2). The N-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0°-25° C. for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3). Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986, 26, 311-314.) with palladium (0) catalysis, a weak base such as aqueous sodium carbonate or the like, and a chloride source such as lithium chloride in an inert solvent like toluene, benzene, ethanol, propanol or mixtures thereof at a temperature of 25°-100° C., preferably 80° C., for a period of 1-6 hours to give the 2-aryltryptamine derivative (4). Finally, the phthalimido group may be removed by treatment of (4) with aqueous hydrazine in an inert solvent such as methanol or ethanol at a temperature of 0°-25° C. for a period of 4-24 hours to give tryptamine (5). ##STR8##
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:14]O>>[S:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)c1ccc2sccc2n1
Agent: Cl
Product: COC(=O)c1ccc2sccc2n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of HCl (10%) in MeOH (10 mL) was added thieno[3,2-b]pyridine-5-carboxylic acid (1.0 g, 5.6 mmol, from Step 2, Example 1) and the mixture heated to reflux for 2 hr. After cooling to r.t., half the solvent was removed by evaporation and the remainder was partitioned between EtOAc and H2O. Solid NaHCO3 was added until the system remained basic. Separation, drying, and evaporation of the organic layer afforded 0.75 g (70%) of methyl thieno[3,2-b]pyridine-5-carboxylate.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C@@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:34]4[CH2:33][CH2:32][N:31]([C:35]5[CH:44]=[CH:43][C:42]6[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:36]=5)[CH2:30][C@@H:29]4[CH3:28])[O:27][C:17]3=2)[N:22]=1
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4n2)C[C@@H]1C)O3
Temperature: 50 °C
Yield: 61.9 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (0.165 g, 0.367 mmol) and (S)-2-(3-methyl-piperazin-1-yl)-quinoline (250 mg, 1.10 mmol) in anhydrous dimethylsulfoxide (4 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 100 mg (62%) of the title compound as an off-white solid: mp 141–144° C.; MS (ES) m/z 441 [M+H]+; [α]D −36.5° (c 1.0, DMSO).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[OH2:10]>O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][C:4](=[O:3])[C@@H:5]([CH3:6])[OH:10])[CH2:5][CH2:4]1
Reactant: O
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](O)C(=O)OC1CCOCC1
Reaction time: 14 h

Procedure:
4.8 g (120 mmol) of 60% sodium hydride in oil (Fluka, pract.) are added at 65° to a solution of 3.06 g (2.85 ml, d=1.074; 29.96 mmol) of tetrahydro-2H-pyran-4-ol (Fluka, pract.) in 100 ml of absolute 1,4-dioxane. The resulting grey suspension is stirred under reflux for 2 hours, is allowed to cool to 65° again and then a solution of 3.25 g (2.59 ml, d=1.25; 29.95 mmol) of S(-)-2-chloropropionic acid (Fluka, puriss.) in 60 ml of absolute 1,4-dioxane is added dropwise over a period of 8 minutes. The resulting brown suspension is diluted with 100 ml of absolute 1,4-dioxane and the batch is heated under reflux for 3 hours, with stirring. Stirring is then continued for a further 14 hours at room temperature. 40 ml of water are then added dropwise to the resulting brown suspension over a period of 2 minutes and the yellow solution obtained is concentrated to dryness by evaporation under a high vacuum. The residue is taken up in 200 ml of water and the aqueous solution is extracted once with 250 ml and once with 150 ml of ethyl acetate. The ethyl acetate extracts are then washed once with 100 ml of water. All the aqueous phases are combined and then acidified with 4N hydrochloric acid (pH 1). The resulting solution is saturated with sodium chloride and extracted twice with 300 ml of ethyl acetate each time. The organic phases are then washed three times with 150 ml of saturated sodium chloride solution each time. All the ethyl acetate extracts are then combined, dried over magnesium sulfate, filtered and concentrated to dryness by evaporation under a high vacuum at 30°. The residue (yellow oil) is purified by bulb tube distillation (b.p. approximately 160° at 0.6 mm Hg). O-(tetrahydropyran-4-yl)-D-lactic acid is obtained in the form of a slightly yellowish oil; [α]D20 =+46.7±0.9° (c=1.058; chloroform). The oil crystallises from ethyl acetate/hexane 1:1 in the form of colourless crystals having a melting point of 68.7°-69.5°; [α]D20 =+48.8±0.8° (c=1; chloroform)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][CH2:57][C:58]([NH:60][CH3:61])=[O:59]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][CH2:57][C:58](=[O:59])[NH:60][CH3:61])=[CH:15][CH:16]=1
Reactant: CNC(=O)CCCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: CNC(=O)CCCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.40 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.23 g of 4-(2-hydroxyphenyl)-N-methylbutyramide are reacted. The title compound is obtained as a colourless resin. Rf=025 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.73.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[CH2:19]([SH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([S:21][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1)[CH3:20]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.5 %

Procedure:
0.8 Gram (2.6 mmol) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman was dissolved in 5 ml of N,N-dimethylformamide, and 0.15 ml (3.1 mmol) of ethanethiol and 0.43 g (3.1 mmol) of potassium carbonate were added. The mixture was stirred at room temperature for 2 days. After the completion of the reaction, 20 ml of water was added, and the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.2 g (yield 100%) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [Cl-].[NH2:2][C:3]1([CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]2[CH2:19][CH2:18][C@@:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]2)=[O:13])=[O:9])[CH2:4]1.[C:36](C1NC=CN=1)(C1NC=CN=1)=[O:37].C(N(CC)CC)C>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:8]([C@@H:5]3[CH2:6][CH2:7][C:3]4([CH2:33][CH2:34][O:35][C:36](=[O:37])[NH:2]4)[CH2:4]3)=[O:9])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:29])[CH3:28])=[CH:22][CH:23]=1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(N)(CCO)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC2(CCOC(=O)N2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.33 %

Procedure:
To a solution of (1R)-3-amino-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(2-hydroxyethyl)cyclopentanecarboxamide (from step F, 30 mg, 0.061 mmol) in THF (1 mL) was added carbonyl diimidazole (14.77 mg, 0.091 mmol) and triethylamine (0.021 mL, 0.152 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and subjected preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM) to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC (Column: ChiralPak ASH, 250×3 cm, 5 μm; Flow rate: 120 mL/min; Mobile Phase: CO2/MeOH=80/20; Inj. Vol.=2.0 mL, Wavelength=220 nM; isomer 1, retention time=5.75 min; isomer 2, retention time=9.10 min) to yield the individual diasteromers (2 mg for each isomer, 3.85 μmol, 6.33% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.[H-].[Na+].[CH3:34]I>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][O:23][CH3:34])=[CH:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(CO)cn3)CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)pyrimidin-5-yl)methanol (Step F product, 198 mg, 0.44 mmol) was dissolved in Acetonitrile (6 mL) at room temperature under N2 and sodium hydride (26 mg of a 60% dispersion in oil, 0.66 mmol) was added followed by CH3I (313 mg, 2.2 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by column chromatography (SNAP, 10 g, 70% EtOAc in hexane) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.78 (dd, 1H), 7.73 (m, 1H), 7.67 (dd, 1H), 4.80-4.64 (m, 4H), 4.28 (s, 2H), 3.71 (dd, 1H), 3.61-3.54 (m, 1H), 3.37 (s, 3H), 3.08 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43-1.22 (m, 3H), 1.15-1.04 (m, 1H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.6 nM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a suspension of 7-bromoquinoxalin-2(1H)-one (224 g, 1 mol, 1.0 eq.) in POCl3 (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). The resulting mixture was stirred at 120° C. for 2 h, then cooled to rt and slowly poured into ice-water with vigorous stirring. The precipitate was collected by filtration and dried to afford 7-bromo-2-chloroquinoxaline as brown solid (180 g, 75%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:32][CH2:31]1)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
Starting materials: (a) 3-acetylaminobenzoic acid is converted by means of thionyl chloride into the acid chloride [m.p. 101°-102°], and the latter is then condensed with 1-[2-(4-chlorophenyl)ethyl]piperazine, yielding 1-(3-acetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine in the form of a foam. The latter is reacted with (BOC)2O to form 1-{3-[(N-acetyl-N-tert-butyloxycarbonyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 113°-114°. The subsequent cleavage with dimethylaminoethylamine results in a foam, which corresponds to 1-[3-(N-tert-butyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine.
Reaction SMILES: [F:1][CH:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:10][O:11][CH3:12])[OH:9].[Li]CCCC.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[F:1][CH:2]1[C:7]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:10][O:11][CH3:12])[OH:9]
Reactant: C[Si](C)(C)Cl
Reactant: COCC1(O)C=CC(F)=CC1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(O)C=CC(F)=C([Si](C)(C)C)C1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
A flame-dried 3-necked flask was charged with 2,4-difluoro-1-methoxymethylphenol (26, 0.84 g, 4.8 mmol) in 30 mL of freshly distilled THF under argon and this mixture was cooled to -78° C. (FIG. 2E). nBuLi (2.5 M solution in hexane, 2.2 mL, 5.43 mmol) was added to this reaction mixture which was allowed to stir at -78° C. for 2.5 hours under argon. Chlorotrimethyl silane (1.0 M solution in THF, 5.43 mL, 5.43 mmol) was then added to the deep pink colored mixture at -78° C. and then the acetone/dry ice bath was removed and the reaction was allowed to proceed at room temperature for 14 h. Sat. NH4Cl (~20 mL) was added to the mixture which was then stirred for an additional 10 minutes and then extracted with ethyl ether (3×10 mL). The combined organic solution was washed with brine, water and then dried (MgSO4) and filtered. The solvent was removed under vacuo to afford the crude product which was purified by flash chromatography on silica gel (EtOAc:hexanes; 5:95) to yield a yellow oil (0.8 g, 79%). 1H NMR (CDCl3) δ 7.09-7.17 (m, 1H, ArH), 6.68-6.74 (m, 1H, ArH), 5.13 (s, 2H, CH2), 3.52 (s, 3H, CH3), 0.36-0.37 (t, 9H, Si(CH3)3); FAB-MS 247 (MH+, 70), 229 (40), 219 (60), 189 (58), 157 (40), 133 (60), 79 (100).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[CH:35]2>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:35]3[C:34]4[C:38](=[C:30]([CH2:29][S:28][CH3:27])[CH:31]=[CH:32][CH:33]=4)[NH:37][CH:36]=3)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCOC(=O)CC(C)(O)c1ccc2c(c1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(C)(c1ccc2c(c1)OCCO2)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.25 mmol) of the compound from Example 91A and 0.21 ml (2.70 mmol) of trifluoroacetic acid were added to 399 mg (2.25 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 576 mg (60% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:13][NH:12][CH2:11]2)[S:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:11][N:12]([C:58](=[O:59])[CH:57]=[CH:56][C:51]3[CH:50]=[C:49]4[C:54](=[N:53][CH:52]=3)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]4)[CH2:13]2)[S:6][CH:7]=1
Reactant: Cc1csc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(COC2CN(C(=O)C=Cc3cnc4c(c3)CCC(=O)N4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3-(4-methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride (128.0 mg, 0.6 mmol), EDCI (113.0 mg, 0.6 mmol), HOBt (80.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (99:1 to 95:5) as eluent. The residue was triturated with acetone to give a white solid (40 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([NH:16][NH2:17])=[O:15])=[CH:4][CH:3]=1.[C:18]1([CH2:24][C:25](Cl)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:24]([C:25]1[O:15][C:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:16][N:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NN
Product: Cc1noc(-c2ccc(Br)cc2)c1-c1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 8, Step 6, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid hydrazide and phenylacetyl chloride.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=1)=[CH2:34]>CN(C=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>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[S:10][C:9]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:8]=3[C:7]=2[O:6][C:5]2[CH:24]=[CH:25][C:2](/[CH:34]=[CH:33]/[C:35]3[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=3)=[CH:3][CH:4]=2)=[CH:13][CH:14]=1
Reactant: C=Cc1cn(C)cn1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(/C=C/c2ccc(Oc3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)c1
Temperature: 150 °C
Yield: 57.9 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (50 mg, 0.121 mmol) was dissolved in DMF (2 ml) and triethyl amine (0.506 ml, 3.63 mmol). To the solution was added the 4-vinyl-1-methyl imidazole (39.2 mg, 0.363 mmol) and Pd(PPh3)2Cl2 (8.49 mg, 0.012 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (31 mg, 0.070 mmol, 58.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.82 (s, 3H) 6.57-6.74 (m, 3H) 6.75-6.93 (m, 3H) 6.98-7.14 (m, 3H) 7.32-7.54 (m, 5H) 8.73 (s, 1H). LC/MS (m/z, MH+): 441.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[C:15]2=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:27]O>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]2[O:24][CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN1CC(C)(C)C(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CC(C)(C)C(OC)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-oxo-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.60 g) in methanol (20 ml) was added sodium borohydride (0.30 g) and the mixture was stirred for 30 minutes. Methanol was distilled off and the resulting residue was extracted with dichloromethane. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. The resulting crude 8-(t-butyldimethylsilyloxymethyl)-4-hydroxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline was dissolved in dimethyl formamide (15 ml), followed by addition of sodium hydride (60%, 0.24 g), methyl iodide (0.85 g) was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (20:1)] to give 8-(t-butyldimethylsilyloxymethyl)- 4-methoxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.40 g).