Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][C:13]2[C:12]([Cl:11])=[CH:30][C:16]3[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=3[CH:14]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6 /300 MHz) 8.16 (d, 2H, J=8.9 Hz), 7.96 (s, 1H), 7.79 (s, 1H), 7.20 (d, 2H, J=8.9 Hz), 6.87 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). ESHRMS m/z 413.0006 (M-H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6 : C, 52.13; H, 2.43. Found: C, 51.81; H, 2.31.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][NH:10]1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.[Cu]I>[O:8]=[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3cccnc3)c(=O)c2)CC1
Temperature: 125 °C
Yield: 63.7 %

Procedure:
A mixture of 3-iodopyridine (287 mg, 1.400 mmol, TCI), tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (206 mg, 0.7 mmol), quinolin-8-ol (40.6 mg, 0.280 mmol, Alfa Aesar), copper(I) iodide (9.49 μL, 0.280 mmol, Aldrich) and cesium carbonate (296 mg, 0.910 mmol, Aldrich) in DMSO (0.8 mL) was heated at 125° C. for 3 hrs. The reaction mixture was diluted with EtOAC and water and filtrated. The filtrate was separated and the aqueous layer was extracted further with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH/CH2Cl2) to give the title compound (165.7 mg, 64%) as a yellow solid. MS (ESI) 372 (M+H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:11]=[CH:10][N:9]=1.O>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:8]1[N:13]=[C:12]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(-c3ccnc(OCCF)n3)sc2c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
2-Fluoroethanol (32 μL, 0.54 mmol) and sodium hydride (NaH, 22 mg, 0.54 mmol) were dissolved in a solvent of anhydrous tetrahydrofuran (4 mL) under nitrogen, and the mixture was added to a solution of anhydrous tetrahydrofuran (3 mL) containing 2-(2-chloropyrimidine-4-yl)-6-methoxybenzothiophene (105a, 100 mg, 0.36 mmol) obtained in Preparation Example 19 dissolved therein at room temperature, heated at 60° C. for 10 hours, cooled to room temperature, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-[2-(2-fluoroethoxy)pyrimidine-4-yl]-6-methoxybenzothiophene (1-31, 79 mg, 72%) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]Br>ClCCl>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: BrBr
Solvent: ClCCl
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (32 g, 212 mmol) in dichloromethane (1 litre) was treated with a solution of bromine (10.8 mL, 212 mmol) in dichloromethane (100 mL) at 0° C. After the addition the mixture was stirred at room temperature for 1 hour then washed with saturated aqueous sodium bicarbonate solution containing a small amount of sodium sulphite. The organic extract was dried and evaporated to an oil that was chromatographed on silica gel eluting with dichloromethane to afford an oil (14.8 g, 30%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:13][C:14]#[N:15]>COCCOC>[CH2:3]([O:11][CH2:13][C:14]#[N:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCO
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCOCC#N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 15.60 g sodium hydride (60%) in 200 ml of 1,2-dimethoxyethane, 50.79 g of 1-octanol was dropped in. The mixture was stirred for 45 minutes at room temperature. Then, 46.76 g of bromoacetonitrile was dropped in. The reaction mixture was refluxed for 2 hours, quenched with water, filtered, and diluted with brine. After extraction with ether, the organic layer was washed with brine and water, dried, filtered, and evaporated to dryness. The resulting dark oil was purified by distillation to yield a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)([CH3:3])[CH3:2].[BH4-].[Na+].C([OH:15])C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCCCC1=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a cold (0° C.) solution of 1-isopropylpiperidone (purchased at Chemie Brunschwig AG, 100 g, 1.0 eq.) in ethanol (500 mL) was added sodium borohydride (19.3 g, 0.7 eq.) in small portions. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. After concentration in vacuo, ice water (1 kg), sodium hydroxide aqueous solution (28% in mass, 0.5 L) and dichloromethane (1 L) were added. The mixture was stirred vigorously for 4 h and the aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and purified by fractionated vacuum distillation (20 mBar). One fraction (95° C. at 20 mBar) was isolated to yield 61.3 g (60%) of the title product as colorless oil. MS (m/e): 144.5 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.300 g, 0.77 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.219 g, 1.0 mmol) according to the general procedure VI. Obtained as a white foam (0.15 g, 48%). MS (ISP) 406.2 [(M+H)+]; mp 68-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Cl.Br[C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(O)C>[NH:32]1[CH2:33][CH2:34][CH:31]1[C:28]1[CH:29]=[CH:30][C:25]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([O:13][CH3:14])=[O:12])=[CH:26][CH:27]=1
Reactant: Brc1ccc(C2CCN2)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4)cc3)cc12
Temperature: 100 °C
Yield: 379.6 %

Procedure:
A mixture of methyl 6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate (50 mg, 0.16 mmol), 2-(4-bromophenyl)azetidine hydrochloride (400 mg, 1.24 mmol), 2M aqueous potassium carbonate (3.11 mL, 6.22 mmol), toluene (9 mL), and ethanol (3 mL) was sparged with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (46 mg, 0.056 mmol). The reaction mixture was heated to 100° C. and stirred. After 2 hours the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (40 g silica, 0-40% methanol/ethyl acetate (1% TEA modifier), 24 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a yellow solid (207 mg, 49% yield). MS (ES+) 341.2 (M+H)+; 1H NMR (500 MHz, CD3OD) δ 7.98 (d, J=3.90 Hz, 2 H), 7.56 (s, 1 H), 7.41 (s, 4 H), 5.02 (t, J=8.17 Hz, 1 H), 3.84 (s, 3 H), 3.68-3.79 (m, 1 H), 3.34-3.45 (m, 1 H), 2.47-2.66 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: OCCOCCN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(N2CCN(CCOCCO)CC2)cc1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
A mixture of 54.3 grams (0.61 mol) of N-[2'-(2"-hydroxyethoxy)ethyl]piperazine, 50 grams (0.40 mol) of 4-fluorobenzaldehyde, 50 grams of anhydrous potassium carbonate, and 50 mL of DMSO was heated to 120° C. for four days under nitrogen. After cooling to room temperature, the solution was diluted with one liter of water. The aqueous solution was "processed" as follows. It was extracted with dichloromethane; the separated organic layers were combined and dried over anhydrous magnesium sulfate or sodium sulfate. The organic layer was separated, and solvent was removed on a rotary evaporator under reduced pressure (hereafter these steps will be referred to as "processed" and the product was dried under vacuum overnight to afford 75.3 grams (96%) of 4-[4'-(2"-(2'"-hydroxyethoxy)ethyl)piperazino]benzaldehyde (F).
Reaction SMILES: [I-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][CH:40]=O)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.O>O1CCCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][CH:40]=[CH:6][CH2:5][CH2:4][O:3][CH3:2])[CH2:37][CH2:38]2)=[CH:31][CH:32]=1
Reactant: O=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: COCCC=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension, gassed with nitrogen, of 11.4 g of (3-methoxypropyl)triphenylphosphonium iodide in 50 ml of tetra- hydrofuran is cooled to -5° C., treated with 3.36 g of potassium tert.-butylate, stirred at -5° C. for 10 minutes and at room temperature for 1 hour. After cooling the reaction mixture to -5° C. a solution of 4.6 g of [trans-4-(4-chlorophenyl)cyclo-hexyl]acetaldehyde in 25 ml of tetrahydrofuran is added dropwise within 5 minutes, the mixture is stirred at -5° C. for 10 minutes and at room temperature for 1 hour, treated with 50 ml of water and the aqueous phase is extracted with 100 ml of ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is taken up in 50 ml of toluene and dissolved by heating to 70° C. and stirring for 30 minutes. The solution is cooled to room temperature, treated with 50 ml of hexane, stirred for 2 hours, filtered and washed with 30 ml of toluene/hexane (1:1 vol.). The filtrate is filtered over 100 g of silica gel and the silica gel is washed with 200 ml of hexane/toluene (1:1 vol.). The filtrate; is concentrated and gives 5.4 g of 1-chloro-4-[trans-4-(5-methoxy-2-pentenyl)cyclo-hexyl]benzene. The following compounds can be manufactured in an analogous manner:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1C=C2C(=CC=1)[C:44](=[O:48])NC=C2>CN(C=O)C>[CH2:6]([N:13]1[CH:22]=[C:21]([CH:44]=[O:48])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C=O)c2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
DMF (5 mL) was cooled in an ice bath and phosphorus oxychloride (0.11 mL) added. The solution was stirred for 10 minutes. 3-(2-Benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide, Example 1 (0.4 g) was then added in one portion and the mixture heated at 80° C. for 6 hours. The mixture was allowed to cool then poured onto ice and stirred for 10 minutes. This was then extracted with ethyl acetate. The organics were combined and evaporated under reduced pressure. The residue was purified (SiO2, 1:1 isohexane/ethyl acetate) to give the sub titled compound (0.15 g).
Reaction SMILES: FC(F)(F)C([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=O>CO.[OH-].[Na+]>[CH2:6]([NH:5][CH:9]1[CH2:10][C:11]2[CH:12]=[C:13]([OH:19])[CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1)[CH2:7][CH3:8]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC1CCc2ccc(O)cc2C1
Yield: 113.5 %

Procedure:
A solution of 2,2,2-trifluoro-N-(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (340 mg, 1.03 mmol) in methanol (30 mL) and 1N NaOH (30 mL) were stirred at room temperature for 30 h. The reaction was concentrated and the residue partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer was extracted twice more with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated to afford 7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-ol (240 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].C1(=O)C=CC(=O)C=C1.CCOCC>C(O)C>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[S:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccccc1S
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Solvent: CCOCC
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccccc4s3)cc2)S1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a suspension of 5-(4-formylbenzylidene)-2,4-thiazolidinedione (50 mg, 0.21 mmol) and 2-aminothiophenol (0.025 mL, 0.23 mmol) in ethanol (7 mL) was heated to reflux for 10 h. 1,4-Benzoquinone (24 mg, 0.22 mmol) was added, and the mixture was heated additional 1 h. The mixture was cooled to room temperature, ether (3 mL) was added, and the precipitated product was collected by filtration to afford 2-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]benzothiazole (53 mg, 75%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([C@H:26]3[CH2:36][C@H:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([C@H:26]4[CH2:36][C@H:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Reactant: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@@H]2C[C@H]32)C1
Yield: 21.5 %

Procedure:
2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 222, 0.21 g) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A 0.290 g) in DCM (10 mL) and pyridine (2 mL) and the resultant mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness and the residue was partitioned between DCM and water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.071 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].N[NH:24][C:25]([NH2:27])=[S:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]2[S:26][C:25]([NH2:27])=[N:24][N:13]=2)=[CH:14][CH:15]=1
Reactant: COCCCCOc1ccc(C#N)cc1
Reactant: NNC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCCCOc1ccc(-c2nnc(N)s2)cc1

Procedure:
To a solution of 4-(4-methoxybutoxy)benzonitrile (21.8 g) and trifluoroacetic acid (109 ml) in toluene (218 ml) was added thiosemicarbazide (11.62 g). The solution was stirred for 31 hours at 60° C., during which period additional thiosemicarbazide (2.90 g) and trifluoroacetic acid was added to the mixture. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried to give 5-[4-(4-methoxybutoxy)phenyl][1,3,4]thiadiazol-2-ylamine trifluoroacetic acid salt (15.10 g).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:23])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][S:44]([C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=1)(=[O:46])=[O:45].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:23])/[C:13](/[C:50]1[CH:51]=[CH:52][C:47]([S:44]([CH3:43])(=[O:46])=[O:45])=[CH:48][CH:49]=1)=[CH:14]/[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16 g, 20 mmol) in dry tetrahydrofuran (5 mL) over 10 min. The reaction mixture was then stirred at 40–45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask; bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 mL), and the organic compound was extracted into ethyl acetate (3×150 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e calcd for C18H24O4S (M+) 336.1395, found 336.1395.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:15]=[C:16]([Cl:29])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([Cl:29])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:31]([O:33][CH3:34])=[O:32])[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc2nc(Cl)nc(Cl)c2c1-c1ccccc1
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
A solution of diisopropylamine (0.755 mL, 5.33 mmol) in dry tetrahydrofuran (10 mL) was cooled with an acetone/cardice bath to −55° C. under a nitrogen atmosphere. Butyllithium in hexanes (2.0 mL, 4.98 mmol, 2.5 M) was added and the temperature was allowed to rise to 0° C. for 10 min. The mixture was cooled to −55° C. and a solution of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1.00 g, 3.56 mmol) in dry tetrahydrofuran (10 mL) was added. The mixture was stirred for 1 hr, maintaining the temperature at −55° C. Methyl chloroformate (0.561 mL, 7.11 mmol) was added and the mixture was allowed to rise to room temperature. It was stirred for 4 hr. Water (20 mL) was added to quench the reaction. The layers were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown solid. (1.63 g). This was purified by silica chromatography (50 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 10%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the target compound as a yellow solid (1.24 g). m/z [M+H]+338.9/340.9. Retention time 4.89 min (LCMS method+ve 6 min).