Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C@@H:30]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH3:31])[CH2:25][CH2:24]1>>[OH:38][CH:35]1[CH2:34][CH2:33][N:32]([C@@H:30]([CH3:31])[CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:28][CH2:27]2)[CH2:37][CH2:36]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCC4CCC4)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) and amine 50.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Si:14]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.CCCCCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:24][CH2:23][CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:31][CH:30]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(OCc2ccc(COCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (212 mg, 1.047 mmol) in THF (15 mL) was added the product of Example 8C (475 mg, 1.570 mmol), triphenylphosphine (412 mg, 1.570 mmol), and then diisopropyl azodicarboxylate (DIAD, 304 μL, 1.570 mmol). The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Thin layer chromatography (1:1 hexane:ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated in vacuo. The crude material was purified by flash column chromatography (90:10 pentane:ethyl acetate) to obtain a clear oil (336 mg, 66% yield). 1H NMR (600 MHz, CDCl3): 7.70 (s, 1H), 7.39 (m, 4H), 4.58 (s, 2H), 1.63 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H); HRMS calcd for C24H31D6ClN2O4Si: 509.24738, found 509.2480.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.Cl>O.CO>[C:17]1([C:15]2[N:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])[O:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCc1nc(-c2ccccc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCc1nc(-c2ccccc2)co1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
Add solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (30 mL) to a solution of 7-(4-phenyloxazol-2-yl)heptanoic acid methyl ester (5.75 g, 20.0 mmol) in methanol (40 mL) at room temperature and heat the mixture at 40° C. for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (600 mL). Wash the organic extract with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by filtration to provide 7-(4-phenyloxazol-2-yl)heptanoic acid (5.01 g, 91%): APCI mass spectrum m/z 272 [C16H19NO3−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Temperature: 7.5 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (0.85 mmol, 349 mg) and carbon tetrabromide (1.26 mmol, 423 mg) in dichloromethane (10 mL) was added triphenylphosphine (1.07 mmol, 281 mg) at ˜0° C. The resulting colorless solution was stirred for 3 h at 5-10° C. Then, the solvent was removed under vacuum and the crude was tried to dissolve in a mixture of ethyl acetate and hexanes (1:3, 50 mL). As a result, a cloudy solution containing some precipitate was formed and the cloudy solution was transferred into a separatory funnel and was washed with a mixture of methanol and water (2:1, 150 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (100 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a colorless oil which was purified by using a Biotage (40M) column chromatography eluting with 10% ethyl acetate in hexanes to obtain the desired 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (350 mg, 87.5%) as a colorless oil: ES(+)-HRMS m/e calculated for C23H35BrO5 (M+Na)+ 493.1560, found 493.1560.
Reaction SMILES: Cl[C:2]1C(Cl)=CC(C(Cl)(Cl)Cl)=C[N:3]=1.[Cl:13][C:14]1[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.[C-]#N.[K+]>CS(C)=O>[Cl:13][C:14]1[C:19]([C:2]#[N:3])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3Chloro-2-fluoro-5-(trifluoromethyl)pyridine (obtained as a by-product from the fluorine exchange reaction when converting 2,3-dichloro-5-trichloromethyl pyridine to 2,3-dichloro-5-(trifluoromethyl)pyridine) (40.0 g, 0.2 mole) was put into 270 ml of dimethyl sulfoxide and stirred while potassium cyanide (14.4 g, 0.221 mole) was spooned in over a 20-minute period. The mixture was then stirred for another 20 minutes. The temperature was held between 23° C. and 28° C. throughout the reaction. The mixture was poured into 600 ml of ice water and the product was extracted into hexane. The hexane was removed on a rotary evaporator. The product was treated with activated charcoal and distilled on a Vigreaux-Claisen still at 108°-110° C. at 30 mm Hg to yield 31.45 g of colorless oil with an analysis of, in percent by weight:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CS(C)=O.C(Cl)Cl.CC(=O)OCC>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at 65° C. overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried under vacuum. It was then purified by flash column eluting with PE:EA (20:1) and then DCM to give 17 gm of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate as a yellow solid (37% yield). MS: [M+H]+ 309
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=O)[C:5](F)=[N:6][CH:7]=1.O.[NH2:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:21][NH:20][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)c1cc(Br)cnc1F
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of (5-bromo-2-fluoro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (1.9 g, 6.1 mmol) in ethanol (125 ml), hydrazine monohydrate (691 μl, 12.2 mmol) was added and the resulting solution was allowed to stir at room temperature overnight. Solvent was removed under reduced pressure and the product was precipitated out by addition of water to afford 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (1.1 g, 58% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.07 (m, 1H), 7.20 (d, 1H), 7.45 (m, 1H), 7.62 9d, 1H), 8.34 (s, 1H), 8.60 (s, 1H). MS: m/z 304+306 (M+H+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:37][CH3:38])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([N+:21]([O-:36])([CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:17][CH2:16]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:37]([N:9]([CH2:8][CH2:7][OH:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([N+:21]([O-:36])([CH3:35])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)(=[O:23])=[O:24])[CH2:17][CH2:16]1)[CH3:38]
Reactant: CCN(CCCCC[C@H]1CC[C@H]([N+](C)([O-])S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CCO)CCCCC[C@H]1CC[C@H]([N+](C)([O-])S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 335 mg (5.5 mmol) trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide N-oxide in 8 ml THF were added 0.83 ml 1M TBAF at 0° C. The solution was stirred at RT for 1 h, partitioned between EtOAc and an aqueous solution of Na2CO3. The organic phase was washed with brine and dried over Na2SO4. Column chromatography with CH2Cl2/MeOH 9:1 yielded 190 mg (44%,3 steps) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide N-oxide as colorless oil, MS: 495 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CC(O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Yield: 45 %

Procedure:
To a suspension of 52 (444 mg, 0.98 mmol, crude material from the previous step) in iPrOH (10 ml) was added pyrrolidine (210 mg, 2.96 mmol) and the reaction mixture was refluxed for 4 hrs. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the resultant oil was purified by column chromatography (eluents EtOAc to 30% MeOH in EtOAc), to afford title compound 53 (200 mg, 45% yield) as an orange solid. MS (m/z): 450.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:30](N1C=C[N+](C)=C1)=[O:31]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:30]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20]3)=[O:31])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2CCc3ccccc3C2)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCc2ccccc2C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (53%). HPLC-MS m/z=415.2 (M+1), Rt: 5.3 min.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]([CH3:16])[CH3:15])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[CH:11]1[CH:12]2[CH:10]1[CH2:9][NH:8][CH2:13]2
Reactant: CN(C)C1C2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C1C2CNCC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 3-benzyl-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (1.80 g) in MeOH was added a catalytic amount of 20% Pd(OH)2/C. The reaction mixture was stirred for 3 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to afford the title compound as brown oil (0.74 g, 70.00%), HPLC: 99.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 127.5 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.25-1.28 (m, 3H), 1.72-1.76 (m, 2H), 2.31 (s, 6H), 3.19-3.29 (m, 2H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(#N)C.CO.[OH-].[Pd+2].[OH-]>[O:32]=[S:27]1(=[O:31])[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=[C:20]1[CH2:33][O:34][CH2:35][CH3:36]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 28 h
Yield: 58.1 %

Procedure:
A mixture of 7-(benzyloxy)-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (4.6 g, 9.04 mmol) and palladium hydroxide (1.5 g) in acetonitrile (50 mL) and methanol (75 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) for 28 hours. The mixture was filtered through CELITE filter agent, which was rinsed afterwards with 40% methanol in acetonitrile (600 mL). The filtrates were combined and concentrated under reduced pressure to yield a yellow solid that was triturated with acetonitrile and isolated by filtration to afford 2.2 g of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol as a pale yellow powder.
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]([CH3:15])=[O:14].N1CCCC1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:15])[CH:2]([CH3:11])[C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CC(C)=O
Reactant: CC(O)C(=O)c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1C(=O)c2ccccc2OC1(C)C

Procedure:
A solution of 2-hydroxypropiophenone (500 ml, 3.64 mol), acetone (400 ml), and pyrrolidine (150 ml, 1.8 mol) in toluene (1000 ml) was heated at 85° C. for 66 hours. The cooled solution was then washed successively with water, aqueous hydrochloric acid and aqueous sodium hydroxide solution. The toluene layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/heptane (50/50), to give 81 g of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil, a compound of Formula (3a); 1H NMR (CDCl3): δ1.3 (d,3H), 1.4 (s,3H), 1.6 (s,3H), 2.5-3.0 (q,1H), 6.8-8.1 (m,4H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]#[C:17][CH3:18].Cl>C1COCC1>[CH2:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:16]#[C:17][CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.83 h
Yield: 115.3 %

Procedure:
To a stirring mixture consisting of diethyl malonate (24.3 g, 141 mmol) in THF (140 mL) was added sodium hydride (60% dispersion in oil, 2.8 g, 70 mmol) and the resulting reaction mixture was stirred for 50 minutes. To the reaction mixture was added 1-bromobut-2-yne (GFS, 6.2 g, 47 mmol), and the mixture was stirred for two hours. The reaction mixture was treated carefully with 0.5 N HCl and extracted with ethyl acetate. The organic phase was washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (5:95 to 15:85 v/v) afforded the title intermediate (11.5 g, quantitative yield) as a clear oil.
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:8])(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:33]2[C:34]([CH:39]=O)=[N:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O.NCCCCN(CC1N=CC=CC=1C(O)=O)CC1C(C)=CC(C)=CN=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([C:33]2[C:34]([CH2:39][N:13]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][NH:7][CH3:8])=[N:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])=[CH:28][CH:29]=1
Reactant: CN(CCCCNCc1ncccc1F)C(=O)OC(C)(C)C
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cnc(CN(CCCCN)Cc2ncccc2C(=O)O)c(C)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCN(Cc1ncccc1F)Cc1ncccc1C(C)(C)c1ccc(Cl)cc1

Procedure:
Using General Procedure B, {4-[(3-fluoro-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 were reacted to give a pale yellow oil. Deprotection with TFA using General Procedure F and conversion to the HBr salt using General Procedure D gave a white solid. 1H NMR (D2O) δ 1.21-1.25 (m, 2H), 1.36-1.42 (m, 2H), 1.67 (s, 6H), 2.30-2.36 (m, 2H), 2.65 (s, 3H), 2.89-2.91 (m, 2H), 3.75 (s, 2H), 4.10 (s, 2H), 7.18 (d, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.87-7.94 (m, 1H), 8.19 (t, 1H, J=8.7 Hz), 8.58 (d, 1H, J=5.1 Hz), 8.66 (dd, 1H, J=5.7, 8.7 Hz); 13C NMR (D2O) δ 21.64, 23.34, 29.58, 33.16, 42.64, 48.88, 50.52, 53.30, 54.88, 126.15, 128.30 (d, J=7 Hz), 128.50, 129.41, 131.78 (d, J=19 Hz), 132.40, 140.91, 141.13, 141.21, 141.33, 143.16, 146.54 (d, J=4 Hz), 150.78, 158.93 (d, J=256 Hz). ES-MS m/z 455 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.N#N>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].O.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>[Cl:16][C:10]1[C:9]([CH3:17])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 92 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonate (3.0 g, 8.3 mmol), (3-fluorophenyl)boronic acid (1.7 g, 12 mmol) in toluene (80 mL) and saturated sodium bicarbonate in water (80 mL) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 80° C. for 2 hours. After cooling to r.t., the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (2.35 g, 92%). LCMS calculated for C15H12ClFNO3 (M+H)+: m/z=308.0. found: 308.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21](C)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].O[NH:44]S(O)(=O)=O>C1COCC1.C([Li])CCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:44])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Reactant: O=S(=O)(O)NO
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(N)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 43.9 %

Procedure:
Under nitrogen, a solution of 4.55 g (13.2 mmol) of 1-[2-(4-fluoro phenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene (from Step 10 of Example 1) in 50 mL of THF at -78° C. was treated with 6.3 mL (0.27 mmol) of n-butyllithium (2.5M in hexane) over a period of 5 minutes. The reaction was stirred at ambient temperature for 25 minutes, cooled to -78° C., and treated with 19.8 mL (19.8 mmol ) of tributylborane (1.0M in THF). The resulting dark brown solution was stirred at ambient temperature for 30 minutes and then at reflux for 14 hours prior to the addition of 8.7 g (106 mmol) of sodium acetate, 37 mL of water, and 5.2 g (46 mmol) of hydroxyamine-O-sulfonic acid. The resulting light orange mixture was stirred at ambient temperature for 6 hours and the aqueous phase extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 2.0 g (40%) of 4-[2(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide as a colorless solid: mp 117°-118° C.; NMR (CDCl3) δ1.24 (s, 6H), 2.70 (s, 4H), 4.72 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.09 (dd, J=9 and 7 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.74 (d, J=9 Hz, 2H). HRMS. Calc'd for C19H20FNO2S: 345.1199. Found: 345.1194. Anal. Calc'd for [C19H20FNO2S+0.27 H2O]: C, 65.14; H, 5.91; N, 4.00; S, 9.11. Found: C, 65.07; H, 5.94; N, 3.86; S, 9.29.
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[O:10][C:9]([CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[CH:8]2>>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:10])[NH:1][C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8]2
Reactant: N
Reactant: CCOC(=O)Cc1cc2cc(Br)ccc2c(=O)o1
Solvent: CO
Product: COC(=O)Cc1cc2cc(Br)ccc2c(=O)[nH]1

Procedure:
A solution of 7 N ammonia in MeOH (3.14 mL, 21.95 mmol, 10.0 equiv.) and ethyl 2-(6-bromo-1-oxo-1H-isochromen-3-yl)acetate (683 mg, 2.195 mmol) was stirred at room temperature for 1 h. Upon completion of the reaction, the excess solvent was concentrated, diluted with 1 N HCl (5 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-40% EtOAc/hexanes to give 250 mg of methyl 2-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate as a white solid.