Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 438.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.Br.Br.Br.[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][NH:40][CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]>>[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][N:40]([CH2:11][C:3]6[CH:2]=[N:1][C:10]7[C:5]([CH:4]=6)=[CH:6][CH:7]=[CH:8][CH:9]=7)[CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1cnc2ccccc2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cnc5ccccc5c3)C4)n[nH]c2c1
Yield: 20.9 %

Procedure:
The title compound was prepared from quinoline-3-carbaldehyde (31 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method B to afford 14.3 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([F:22])[F:21])[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[F:22][CH:20]([F:21])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:25][N:26]([CH3:28])[CH3:27])=[N:5]1
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(C)=O)c1=O
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 3-acetyl-1-[2-(difluoromethoxy)phenyl]-5-methoxypyridazin-4(1H)-one (3.70 g, 11.93 mmol) and N,N-dimethylformamide dimethyl acetal (50 mL) was refluxed for 5 h and stirred overnight at room temperature. The precipitate was collected by filtration and washed with AcOEt to give the title compound (4.07 g, 93% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.90 (3H, s), 3.12 (3H, br s), 3.87 (3H, s), 5.87 (1H, br s), 6.31-6.82 (2H, m), 7.30-7.41 (2H, m), 7.43-7.50 (1H, m), 7.63 (1H, dd, J=7.8, 1.8 Hz), 7.74 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29](O)[CH3:30]>C(O)C>[CH3:23][CH:24]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCC[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(C=O)cc1

Procedure:
p-Hydroxy-benzaldehyde (15 g), ethanol (200 ml) and 50% NaOH (12 g) were mixed with stirring, followed by pouring in the mixture, a tosylate (26 g) derived from S-(+)-2-octanol, heating the resulting mixture under reflux for 6 hours, distilling off most of ethanol, adding 6N-HCl (100 ml), extracting with toluene, washing the toluene layer with acid, washing with alkali, washing with water to make it neutral, drying, concentrating, and further concentrating the resulting concentrate according to column chromatography with Al2O3 (40 g) to obtain oily p-(1-methylheptyloxy)benzaldehyde (13.0 g). Next, sodium boron hydride (1.0 g) was suspended in isopropyl alcohol (50 ml), followed by dropwise adding to the suspension, a solution of p-(1-methylheptyloxy)benzaldehyde obtained above in isopropyl alcohol (100 ml) so that the liquid temperature might not exceed 40° C., stirring the mixture at 60° C. for 4 hours, adding 6N-HCl (30 ml) and water (20 ml), further heating with stirring at 60° C., distilling off the solvent, extracting the residue with toluene, washing the toluene layer with acid, washing with alkali, washing with water to make it neutral, drying and concentrating to obtain raw p-(1-methylheptyloxy)benzyl alcohol (13 g), which was then heated together with thionyl chloride for 6 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain raw p-(1-methylheptyloxy)benzyl chloride (IIIb-2) (13 g), which was used, as it was, in the following reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([C:38]#[C:39][Si](C)(C)C)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>[Cl-].[NH4+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:33]=[CH:34][C:35]([C:38]#[CH:39])=[CH:36][N:37]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C#C[Si](C)(C)C)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(5-trimethylsilylethynylpyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (667 mg), potassium carbonate (299 mg) and dry methanol (13 ml) is stirred at 0° C. for two hours, and diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=30:1) to give 4-tert-butyl-N-{6-[2-(5-ethynylpyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (502 mg) as colorless crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[CH:13][CH:14]=2)=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of tert-butyl (3′-bromo-4′-hydroxy[1,1′-biphenyl]-4-yl)methylcarbamate (1.50 g, 3.97 mmol), prepared in the previous step, methyl bromoacetate (376 μL, 3.97 mmol) and potassium carbonate (2.74 g, 19.86 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between methylene chloride and water. The organic layer was separated, extracted five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(3-bromo-4′-{[(tert-butoxycarbonyl)amino]methyl}[1,1′-biphenyl]-4-yl)oxy]acetate (1.67 g, 93%) as a white solid, mp 96-98° C. Elemental Analysis for C21H24BrNO5. Calc'd: C, 56.01; H, 5.37; N, 3.11. Found: C, 55.47; H, 5.40; N, 3.00
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:27]#[N:28])=[C:18](OS(C(F)(F)F)(=O)=O)[C:13]=3[C:12]3[CH:29]=[CH:30][CH:31]=[N:32][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:27]#[N:28])=[C:18]([CH:33]=[CH2:34])[C:13]=3[C:12]3[CH:29]=[CH:30][CH:31]=[N:32][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ncc2c(c1OS(=O)(=O)C(F)(F)F)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1c(C#N)ncc2c1c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of trifluoromethanesulfonic acid 9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester (150 mg, 0.31 mmol), tributyl(vinyl)stannane (102 μL, 0.35 mmol), lithium chloride (40 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 6.0 μmol) in dioxane (1.5 mL) was degassed with argon and heated under reflux for 18 h. The reaction mixture was allowed to cool to ambient temperature then diluted with DCM (9 mL) and methanol (1 mL). The resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-2% MeOH in DCM) and triturated with pentane (2×2 mL) to afford the title compound as a white solid (60 mg, 52%). LCMS (Method B): RT=3.73 min, M+H+=361.
Reaction SMILES: C[Si](C)(C)Cl.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:7].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18].Cl>C(OCC)(=O)C.[Zn]>[OH:8][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(C)Br
Reactant: CC(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(C)(O)c1ccccc1
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 8.6 g of zinc powder (130 mmol) in 53 ml of ethyl acetate. After 2.5 ml of trimethylchlorosilane (19.5 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which 10.5 g of acetophenone (87 mmol) were added, and over the course of 6 min, 17.4 g of methyl 2-bromopropionate (104 mmol) were then added dropwise, the temperature being maintained at 65° C. by external cooling. The mixture was stirred at 60° C. for 25 min, and following cooling to 0° C., acidified with 70 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 70 ml of 0.5 N hydrochloric acid and finally washed with 30 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. Methyl 3-hydroxy-2-methyl-3-phenylbutyrate was obtained in a yield of 15.5 g (91% of theory) with a boiling point of 64° C. (0.03 mbar). The diastereomer ratio of the product was 2:1.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:9]([CH2:16][CH2:17][CH:18]([OH:44])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=4)[S:30][CH:31]=3)=[CH:23][CH:22]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[N:12]=1.[Cl-].[NH4+]>CC(C)=O>[N+:13]([C:11]1[N:12]=[C:8]2[N:9]([CH:10]=1)[CH2:16][CH2:17][CH:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=4)[S:30][CH:31]=3)=[CH:23][CH:22]=1)[O:44]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cn(CCC(O)COc2ccc(-c3csc(Cc4ccc(OC(F)(F)F)cc4)n3)cc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(-c3csc(Cc4ccc(OC(F)(F)F)cc4)n3)cc1)CC2
Temperature: 25 °C
Yield: 22.1 %

Procedure:
Sodium tert-butoxide (62 mg) was added to a dimethyl formaldehyde solution (5 ml) of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxybenzyl)thiazol-4-yl]phenoxy}butan-2-ol (334 mg), and the mixture was stirred at room temperature. While confirming the progress of the reaction, sodium tert-butoxide (62 mg) was added 3 times, and the resulting mixture was stirred overnight. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the precipitated solid was sequentially washed with water and diisopropyl ether. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→ethyl acetate) to afford the title compound as a pale brown powder (69 mg).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][C:62]=4[CH2:68][C:69](O)=[O:70])[C:56]([C:72]([F:75])([F:74])[F:73])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:7][C:69](=[O:70])[CH2:68][C:62]1[CH:63]=[CH:64][C:65]([CH3:67])=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([C:72]([F:74])([F:75])[F:73])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:48]=[CH:47][C:46]([CH:43]3[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:45][CH2:44]3)=[CH:51][CH:50]=2)[N:58]=1
Reactant: Cc1ccc(CC(=O)O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(N)=O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
HOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18 mL, 1.0 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-methylphenyl)acetic acid (A89) (0.12 g, 0.21 mmol) in dry THF (6 mL) and dry DMF (1 mL) under a nitrogen atmosphere. After 10 minutes ammonium carbonate (0.10 g, 1.0 mmol) was added in one portion and the resulting mixture stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue dried under high vacuum. The resulting residue was taken up in dry THF (5 mL) and dry DMF (4 mL) under a nitrogen atmosphere and HOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18 mL, 1.0 mmol) were added. After 10 minutes ammonium carbonate (0.10 g, 1.0 mmol) was added in one portion and the resulting mixture was stirred at 25° C. for 22 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHCO3 (65 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, the volatiles removed in vacuo and the residue absorbed onto silica gel and purified by column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A90 as a white solid (0.106 g, 86%); 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.08-7.01 (m, 2H), 5.78 (s, 1H), 5.47 (s, 1H), 4.39-4.15 (m, 2H), 3.66 (s, 2H), 3.04 (apparent s, 4H), 2.79 (t, J=12.2 Hz, 2H), 2.62 (tt, J=12.0, 3.3 Hz, 1H), 2.32 (s, 3H), 1.81 (d, J=12.7 Hz, 2H), 1.60 (qd, J=12.8, 4.2 Hz, 2H), 1.48 (s, 9H). LCMS-A: rt 6.63 min; m/z 598.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH3:17][CH2:18][O:19][CH2:20][CH:21](Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]1([CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][C:8]2=[O:11]
Reactant: CCOCC(Cl)Cl
Reactant: O=C1CCc2ccc(Br)cc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: O=C1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-indanone (0.50 g, 2.35 mmol) in anhydrous THF (40 mL) under N2 atmosphere at −78° C. was added a solution of NHMDS (1 M in THF, 2.5 mL, 2.5 mmol) within 30 min, followed by TMSCl (0.281 g, 0.327 mL 2.59 mmol) after stirred 30 min. To this reaction mixture was added NHMDS (1 M in THF, 6.0 mL, 6.0 mmol) within 30 min at this temperature. The temperature was allowed to warm to −30 to −20° C., after stirred another 30 min, 2,2-dichlorodiethyl ether (336 mg, 0.275 mL, 2.35 mmol) was added. Then the reaction temperature was allowed to warm to room temperature without removing cooling bath, and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, and extracted with EA two times. The combined organic phases were washed with 1 M HCl, H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black oil. It was purified by flash chromatography on silica gel yield 103 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:13])[CH2:11]Br)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[OH-].[Na+].CCOCC.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:13])[CH2:11][NH:24][CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CC(C)N
Reactant: CSc1ccc(C(O)CBr)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(C(O)CNC(C)C)cc1Cl
Reaction time: 0.17 h

Procedure:
7 g of 1-(3-chloro-4-methylthiophenyl)-2-bromoethanol (0.025 mol) in 50 cc of ethanol are treated with 1.4 g of sodium hydroxide (0.035 mol). The product is stirred for 10 minutes, then diluted with water. One extracts with ether and dries on magnesium sulfate. The solvent is evaporated under vacuum and the residual oil is treated with 100 cc of EtOH and 5.9 g of isopropylamine (0.1 mol). The product is brought to 50° overnight with stirring. The solvent and excess of isopropylamine are evaporated under vacuum. The residual oil crystallises after some time (melting point of 111°-112°C after recrystallisation from cyclohexane). The free base is dissolved in ether; by passing dry gaseous HCl, 4.88 g of 1-(3-chloro-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride are obtained which are recrystallised from a methanol-ether mixture. Melting point: 139°-141°C.
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[CH3:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[C:26](=[O:28])=[O:27].Cl>CCCCCC.C1CCCCC1.CCOCC>[CH3:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([OH:28])=[O:27]
Reactant: COc1cccc2ccccc12
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: COc1c(C(=O)O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Reference: J. Organomet. Chem., 20 (1969) p. 251-252. n-BuLi (208.60 mmol, 83.44 ml of a 2.5 M solution in hexane, Aldrich) was stirred under argon in 42 ml of dry cyclohexane. This solution was cooled to 0° C. and treated dropwise (10 min.) with distilled tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 ml). The resulting slurry was stirred at 0° C. for 30 minutes, then treated dropwise (20 minutes) with a solution of 1-methoxynaphthalene (208.60 mmol, 33 g, 30.28 ml) (Aldrich Chem. Co., used without further purification) in 84 ml of dry cyclohexane. The resulting bright red homogeneous reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C. and added portionwise over 30 minutes via cannula to a -78° C. solution of dry Et2O (250 ml) saturated with CO2 (g) (CO2 pellets sublimed through drying tube containing SiO2, bubbled into dry Et2O at -78° C.). The resulting white slurry was warmed to ~0° over 45 minutes and then treated with 450 ml of 5% HCl (aqueous). The Et2O layer was separated and the aqueous layer extracted three times with Et2O. The organic extracts were combined and extracted with 3×150 ml saturated NaHCO3 (aqueous). The aqueous layer was filtered through a sintered glass funnel to remove insolubles and the filtrate was cooled to 0° C. and acidified slowly with concentrated HCl until pH=1. The resulting precipitate was filtered, azeotroped with 2× 150 ml of toluene, dried under high vacuum at 50° C. for 5 hours to afford 32.52 g (0.161 mol, 77% yield) of the 1-methoxy-2-naphthalene carboxylic acid as an off-white powder, m.p. 118-121.5° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)#[N:11]
Reactant: N#CCC(=O)O
Reactant: O=CC1CC2CCC1C2
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CCC=C1CC2CCC1C2
Yield: 78.7 %

Procedure:
A stirred solution of 95 g (0.77 mol) of 2-formylbicyclo[2.2.1]heptane, 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evaluation of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 88 g (79% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]heptane: b.p. 72-80° C/1 mm; ir 2960, 2870, 2260, 1685, 1450, 1420, 1305, 920; nmr 1.15-2.8 (10H, m), 2.96 (2H, m) 4.9-5.4 (1H, m); ms 147.
Reaction SMILES: O=[C:2]1[CH2:7][C@H:6]([NH:8]C(=O)OC(C)(C)C)[C@@H:5]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH2:4][CH2:3]1.Cl.[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=12.C(N(CC)CC)C.[B][B][B][B][B][B][B][B][B][B]>CO>[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][N:32]([C@@H:2]3[CH2:7][C@H:6]([NH2:8])[C@@H:5]([C:16]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=4[F:24])[CH2:4][CH2:3]3)[CH2:31][C:30]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@@H]1c1cc(F)c(F)cc1F
Reactant: c1nc2n(n1)CCNC2
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@H]1C[C@@H](N2CCn3ncnc3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl [(1S,2R)-5-oxo-2-(2,4,5-trifluorophenyl)cyclohexyl]carbamate (Intermediate 1, 200mg) in anhydrous methanol (8.0 mL) under nitrogen was added 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55 mg), triethylamine (0.081 mL) and decaborane (22 mg). After stirring at 50° C. for 24 h, the reaction mixture was concentrated and chromatographed by preparative TLC (silica gel, 1:4:95 ammonium hydroxide/methanol/dichloromethane). The slow moving desired compound was recovered, stirred in 4N hydrogen chloride in 1,4-dioxane for 50 min, and concentrated. The residue was purified by preparative TLC (silica, 1:9:90 ammonium hydroxide/methanol/dichloromethane) to afford the title compound. LC-MS 352.1 (M+1).