Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:7]1=[O:21].[Br:25]Br>CC(O)=O>[Br:25][C:8]1[C:7](=[O:21])[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: BrBr
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: O=c1c(Br)c(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-1H-pyridin-2-one (0.14 g, 0.43 mmol) in AcOH (2 mL) was added a solution of bromine (72 mg, 0.45 mmol) in AcOH (1 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.45-6.95 (m, 9H), 6.05 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.14 (s, 2H). ES HRMS m/z 406.0254 (M+H C19H15BrF2NO2 requires 406.0249).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH:13]=[CH2:14])=[C:8]([CH2:15][C:16]([O:18]C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.[C:24](=[O:27])([O-])[OH:25].[Na+].O.Cl[CH2:31]Cl>>[OH:18][CH2:16][CH2:15][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH2:1][C:24]([O:25][CH3:31])=[O:27])[C:11]=2[O:10][C:9]=1[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCc1oc2c(OC)cccc2c1CC(=O)OC
Reactant: ClCCl
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: O
Product: C=CCc1oc2c(OCC(=O)OC)cccc2c1CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Methyl (7-methoxy-2-(2-propenyl)benzofuran-3-yl)acetate (464 mg) was dissolved in dichloromethane (4 ml) and the solution was cooled to 0° C. To this solution, boron tribromide (1.0 M, 3.9 ml) was added and the solution was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the resulting solution was poured into water layer (50 ml), followed by extracting the resultant twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in THF (15 ml). This solution was cooled to 0° C. and lithium aluminum hydride (91 mg) was added, followed by stirring the resulting mixture at 0° C. for 30 minutes and then at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution to quench the lithium aluminum hydride, and water (0.2 ml) and acetic acid (0.5 ml) were added, followed by stirring the solution at room temperature for 30 minutes. To this solution, sodium hydrogen carbonate (600 mg) and magnesium sulfate were added and the solution was filtered through Celite. After removing the solvent under reduced pressure, the residue was dissolved in DMF (5 ml). To this solution, methyl bromoacetate (0.5 ml) and potassium carbonate (606 mg) were added and the solution was stirred at room temperature for 17 hours. The reaction solution was poured into water (80 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturate brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (450 mg, yield: 87%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: c1ccc(CNC2CCc3cc4c(cc3C2)OCC4)cc1

Procedure:
45 g of the compound of Example 2, 25.4 g of benzaldehyde and 300 ml of benzene are brought to reflux, removing the water formed. The mixture is evaporated to dryness, the residue is taken up with 300 ml of ethanol and 9 g of sodium borohydride are added portionwise, keeping the temperature at approximately 18° C. After one night at room temperature, the ethanol is removed under vacuum and the residue taken up with dilute hydrochloric acid solution. The acid phase is alkalinized and then extracted with ethyl ether. After evaporation of the solvent, the oil obtained is purified on a silica column using a mixture of methylene chloride and methanol (95:5 V/V) as elution solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[CH:22]=[CH:23][CH2:24]Br)#[N:19].CC(C)=O>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:24][CH:23]=[CH:22][C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[C:18]#[N:19])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: N#Cc1ccccc1C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#Cc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 31 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-cyano-cinnamyl bromide (melting point: 69°-71° C.) in anhydrous dimethylformamide for 15 hours at 20° C. Yield: 31% of theory, Melting point: 140°-144° C. (acetone).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH:38]5[NH:39][CH:35]([CH2:36][CH2:37]5)[CH2:34][C:20]=4[N:21]3S(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[C:11](=[O:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.C(Cl)[Cl:46]>O>[ClH:46].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH:38]5[NH:39][CH:35]([CH2:36][CH2:37]5)[CH2:34][C:20]=4[NH:21]3)=[CH:17][CH:16]=2)[C:11](=[O:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc42)C2CCC(C3)N2)cc1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CC1CCC3N1
Yield: 39 %

Procedure:
4-(Benzyloxy)-1-(5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one (130 mg, 0.24 mmol) and NaOH (594 mg, 14.8 mmol) were added to 1:1 MeOH/CH2Cl2 (20 mL) under N2, and the resulting suspension was stirred at reflux for 16 h. The reaction was cooled, H2O was added, and the resulting suspension was filtered. The obtained solid was purified by flash chromatography (silica gel, CH2Cl2/(9:1 MeOH/NH4OH), 100:0 to 80:20) afforded the free-base that was subsequently converted to the hydrochloride salt according to the procedure for Example 2 (step d) to provide the title compound (41 mg, 39%) as a white solid: mp 209-214° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.54 (br s, 1H), 9.14 (d, J=9.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.48-7.44 (m, 2H), 7.44-7.40 (m, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 6.95-6.93 (dd, J=8.3, 1.8 Hz, 1H), 6.09-6.07 (dd, J=7.6, 2.6 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 5.18 (br s, 1H), 5.14 (s, 2H), 4.40 (br m, 1H), 3.44-3.40 (dd, J=17.0, 4.0 Hz, 1H), 2.90 (d, J=17.0 Hz, 1H), 2.29-2.26 (m, 2H), 2.07-2.04 (m, 1H), 1.80-1.75 (m, 1H); ESI MS m/z 398 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.7 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred (30 min) solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (3.52 g, 14.9 mmol), 1-Boc-4-piperidone (5.96 g, 29.9 mmol), HOAc (24.0 mL, 1M in DCM, 24.0 mmol) and TEA (2.00 mL, 14.3 mmol) in 1,2-DCE was added in one portion sodium triacetoxyborohydride (4.82 g, 22.7 mmol). The reaction was stirred for 30 min at which time sodium triacetoxyborohydride (2.00 g, 9.40 mmol) and HOAc (10.0 mL, 1M in DCM, 10.0 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The organic layer was washed with H2O, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step C (6.09 g, 14.5 mmol, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.32 (m, 2H), 1.37 (s, 9H), 1.74 (d, J=10.6 Hz, 2H), 2.41 (tt, J=11.0, 3.2 Hz, 1H), 2.55-2.62 (m, 4H), 2.70 (br. s., 2H), 3.36-3.44 (m, 4H), 3.88 (s, 3H), 3.94 (d, J=13.2 Hz, 2H), 6.50 (d, J=2.6 Hz, 1H), 6.57 (dd, J=9.5, 2.6 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22](CCN)[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(CCN)c1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=S)Nc2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3-methoxyphenyl)ethyl-amine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77 g (56%) of the title product:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([C:18]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][C:25]3[NH:24][N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.O.[OH-].[Na+]>[C:30]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:26][C:25]3[N:24]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Temperature: 20 °C
Yield: 63.2 %

Procedure:
A solution of 1 g of p-toluenesulphonyl chloride in 10 cm3 of diethyl ether is added, at a temperature in the region of 20° C., to a solution of 1 g of 6,6-diphenyl-6,7-dihydro-1H-indazol-3-carboxylic acid in 10 cm3 of water and 10 cm3 of a normal aqueous sodium hydroxide solution. The reaction mixture, which sets to a solid after about ten minutes of vigorous stirring, is diluted with 10 cm3 of water. After stirring for about eighteen hours at a temperature in the region of 20° C., the reaction mixture is filtered. The solid is washed with three times 20 cm3 of water and then suspended in 20 cm3 of water. 10 cm3 of a normal aqueous hydrochloric acid solution are added. The mixture is extracted with three times 50 cm3 of ethyl acetate. The combined organic phases are successively washed with three times 70 cm3 of water and once 70 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)]. 0.94 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-carboxylic acid is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:19]1([Li])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CO>[C:19]1([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(tert-butyldimethylsilyloxy)quinoline (3.992 g, 15.39 mmol) in dry THF (35 mL), cooled by ice/water, was added phenyllithium (1.8 M in cyclohexane:ether 70:30, 10 mL, 18 mmol). The solution slowly warmed up to ambient temperature and was stirred overnight. More phenyllithium (1.0 mL, 1.8 mmol) was added, and stirring was continued for 4 h. The reaction was quenched by adding saturated NH4Cl solution and water. Most of the THF was evaporated, the residue was extracted with EtOAc (4×30 mL) and the combined EtOAc layers were washed with water (2×) and brine and dried over MgSO4. LC/MS indicated that a significant amount of the TBDMS ether had been cleaved during the workup, the ratio of quinolines to dihydroquinolines was about 1:1. Air was bubbled into the solution overnight, the MgSO4 was filtered off, the filtrate was concentrated, dissolved in MeOH, aq. HCl (2 M, 2 mL, 4 mmol) was added, and the solution was stirred at ambient temperature overnight. Sat. NaHCO3 solution was added, most of the MeOH was evaporated, water (≈100 mL) was added, and the dark brown precipitate was filtered off and washed with more water. The combined filtrate and washings were extracted with EtOAc (4×60 mL), the combined EtOAc extracts were washed with water and brine and dried over MgSO4. The dark brown precipitate was dissolved in MeOH (≈100 mL), the solution was filtered, and the filtrate was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2→5% EtOAc in CH2Cl2→10% EtOAc→15% EtOAc]. The mixed fractions were combined with the crude material from the EtOAc extracts and chromatographed on silica gel [Jones Flashmaster, material adsorbed onto Hydromatrix, 10 g/70 mL cartridge, eluting with CH2Cl2→5% EtOAc in CH2Cl2→7.5% EtOAc]. Combination of pure fractions of both columns gave the title compound as light beige solid; 1H NMR (DMSO-d6, 400 MHz) δ 7.15 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.20-8.25 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 10.19 (s, 1H); MS (ES+): m/z 222.1 (100) [MH+]; HPLC: tR=2.2 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](OC)=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1
Reactant: COC(=O)c1cc(C)nc(OC)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(C)cc(C=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate in 15 mL of toluene and 15 mL of dichloromethane was added 6 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of water, allowed to warm to room temperature and dried with 5 g of MgSO4. Concentration of the filtrate under reduced pressure gave the product as an resin and was used without further purification: MS (m+1)=153.1 and 171.1 (hydrate).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:24][O:23][CH:22](OCC)[S:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][P:31]([O:35]CC)[O:32][CH2:33][CH3:34])[CH3:29].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])[S:21]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC1OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: CCOP(OCC)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
To a solution of 4-(t-butyldiphenylsilyloxymethyl)-2-ethoxy-1,3-oxathiolane (12.32 g, 30.6 mmol) and triethylphosphite (3.5 mL, 20.4 mmol, 0.66 eq) in dichloromethane (50 mL) were added phosphorus trichloride (890 μL, 10.2 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° C. The solution was stirred at 0° C. for 1 hr and at room temperature for 3 days. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (60:40) to give the pure compound (8.02 g) in 53% yield with a ratio of 2:1 (trans:cis).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])C.[CH:17](NC)(C)C>>[CH:15]([N:4]([CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])([CH3:16])[CH3:17]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CNC(C)C
Agent: Cl
Product: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid hydrochloride using isopropylmethylamine; LC-MS: tR=0.54 min; [M+H]+=209.09; 1H NMR δ 1.37 (d, J=6.3 Hz, 6H), 2.64 (s, 3H), 3.17 (s, 3H), 4.50-4.60 (m, 1H), 7.16 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:40]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)c2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccc(C(F)(F)F)cc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(4-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: CCCCC(=O)Cl
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 5.6 %

Procedure:
To a 0° C. suspension of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (5.27 g, 13.4 mmol) in chloroform (400 mL) was added valeryl chloride (2.1 mL, 17 mmol) and tin (IV) chloride (2.3 mL, 20 mmol). The reaction mixture was refluxed for 22.5 hours. During reflux, valeryl chloride (8.5 mL, 70 mmol) in four portions and tin (IV) chloride (8.9 mL, 76 mmol) were added in four portions. After cooling to ambient temperature, the reaction mixture was poured into ice water. The phases were separated, and the organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography using (1) 100% chloroform, (2) 20–60% methylene chloride in hexane and 100% methylene chloride and (3) HPLC in 86% acetonitrile (0.1% trifluoroacetic acid) in water. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 30 minutes yielded (0.356 g, 5.23%) of the title compound as a clear brown gum: mass spectrum (+EI, [M+H]+) m/z 478/480. 1H NMR (500 MHz, DMSO-d6): δ8.24–8.28 (m, 2H), 8.20 (d, 1H, J=1.83 Hz), 8.10 (dd, 1H, J=6.49 Hz and 1.48 Hz), 7.96–7.97 (m, 1H), 7.81 (dd, 1H, J=8.71 Hz and 1.84 Hz), 7.73 (d, 1H, J=9.15 Hz), 7.46–7.52 (m, 2H), 5.47 (s, 2H), 2.42 (t, 2H, J=7.26 Hz), 1.41–1.46 (m, 2H), 0.97–1.04 (m, 2H), 0.57 ppm (t, 3H, J=7.33 Hz). Elemental Analysis for C25H20BrNO2S+0.6 mole H2O: Calcd: C, 61.38; H, 4.37; N, 2.86; Found: C, 61.07; H, 4.21; N, 2.67.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:23])([CH3:22])[CH2:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: CC(C)(CCO)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
12 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 19 mL of dichloromethane and cooled on a dry ice/acetone bath. To this solution was added a dropwise a solution of 3.6 mL of DMSO in 16 mL of dichloromethane. After 10 minutes, a solution of 3-(4-fluorophenyl)-3-methylbutan-1-ol (3.6 g, 19.8 mmol) in 12 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 14 mL of triethylamine was then added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature and was quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-dichloromethane (9:1), gradient) to give 1.2 g of 3-(4-fluorophenyl)-3-methylbutyraldehyde as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[CH2:15]1[CH2:25][C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C([O-])(=O)C.[NH4+:30].C1(C)C=CC=CC=1>C(OCC)(=O)C>[NH2:9][C:8]1[C:5]([C:6]#[N:7])=[C:4]([C:3]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[C:25]2[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]=2[N:30]=1
Reactant: [NH4+]
Reactant: O=C1CCCc2ccccc21
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
A mixture of 2-(2,4-dichloro-benzylidene)-malononitrile (1.125 g, 5 mmol), alpha-tetralone (735 mg, 5 mmol), ammonium acetate (578 mg, 7.5 mmol), and toluene (5 ml) was stirred for 3 h at reflux. Upon cooling to room temperature, the mixture was taken up in ethyl acetate and extracted with satd. NaHCO3, water, and satd. NaCl, and dried over Na2SO4. The solvent was then evaporated and the title compound (868 mg, 47%), MS: m/e=365.9 (M+H+), was isolated from the residue by column chromatography (silica gel, hexanes, ethyl acetate).