Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:15])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: [O-][n+]1cc(Br)cc2c1CCC2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: OC1CCc2cc(Br)cnc21
Reaction time: 6 h
Yield: 77.1 %

Procedure:
3-Bromo-6,7-dihydro-5H-[1]pyrindine 1-oxide (6.97 g, 32.6 mmol) was dissolved in CH2Cl2 (150 ml); then, trifluoroacetic anhydride (20.5 g, 13.6 ml, 97.7 mmol) was added drop by drop below 25° C. with intense stirring and stirring was continued for 6 hours at RT. The mixture was then quenched with aqueous 1M NaOH solution. The aqueous mixture was stirred for two hours and extracted three times with CH2Cl2/2-propanol 4:1. The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (6.279 g) which was purified by flash chromatography (silica gel, 50 g, 20% to 100% EtOAc in heptane) to yield the title compound (5.38 g, 77%) as light brown solid. MS: 214.0 (MH+, 1Br).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][C:32]([CH:34]=O)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C>CO.ClCCl.[Cl-].[NH4+]>[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][C:32]([CH:34]=[C:6]4[S:5][C:4](=[S:7])[N:3]([CH:8]5[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]5)[C:2]4=[O:1])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Reactant: O=Cc1ccc(-c2ccc(C3CCCCC3)cc2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4ccc(C5CCCCC5)cc4)o3)SC2=S)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.1 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-cyclohexyl-phenyl)-furan-2-carbaldehyde (84 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6 N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5, 30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-cyclohexyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 65%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.49 (7H, m), 1.67-1.92 (10H, m), 2.35-2.45 (2H, m), 2.56 (1H, m), 4.97 (1H, m), 7.26 (1H, d, J=3.6 Hz), 7.36 (1H, d, J=3.6 Hz), 7.42 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.77 (1H, d, J=8.4 Hz), 12.18 (1H, s); APCI-MS: 495.37; HPLC: 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)ccc1N
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CNC(=O)c1cc(C#N)ccc1N
Yield: 48 %

Procedure:
A mixture of 2-Amino-5-bromo-N-methylbenzamide (100.0 mg, 0.4365 mmol), zinc cyanide (51.26 mg, 0.4365 mmol), Pd(PPh3)4 (75.67 mg, 0.06548 mmol) in DMF (1.5 mL) was flushed with nitrogen and irradiated in a microwave reactor at 150° C. for 5 minutes. The reaction mixture was poured into water and extracted by ethyl acetate. The combined organic layers were washed with water and brine, concentrated in vacuo and purified on an ISCO Combiflash unit to isolate the desired product (37.0 mg, 48% yield).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:12])([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])C.CO.[BH4-].[Li+]>C1COCC1>[CH3:6][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:12])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(C)N1CCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO)N1CCCC1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
2-Methyl-2-pyrrolidin-1-yl-propionic acid ethyl ester (2.00 g, 10.8 mmol, 1 eq) was suspended in dry THF (20 mL) under Ar. Methanol (2.0 mL, 50 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (25 mL of 2M, 50 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature. After 18 hours, the reaction was quenched with methanol, then aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the crude residue was used in the next step.
Reaction SMILES: OCCC1N[C:6]2[C:11](C=1)=[CH:10][C:9](CC(OC)=O)=[CH:8][CH:7]=2.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27](CCC)[CH:26]=1)[C:19]1C=CC=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N1C2C(=CC=CC=2)C=C1>C1COCC1>[CH2:19]([O:18][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:27][CH:26]=1)[CH:20]=[CH2:21]
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: C=CCOc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of methyl 2-(2-hydroxyethyl)indole-5-acetate, from Example 1, Step E (7.6 g), 4-phenoxy-2-propylphenol (8.28 g), triphenylphosphine (11.2 g), DIAD (8.5 mL) and THF (125 mL) was stirred under nitrogen at room temperature. After stirring overnight none of the starting indole remained as determined by TLC and the reaction was concentrated to a yellow oil. The oil was purified by silca gel chromatography (10%-20% ethyl acetate in hexanes) to give the desired product (9.0 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)(C(F)(F)F)[C:4]([OH:6])=[O:5].FC(F)(F)C(C1C=CC=CC=1)(C(F)(F)F)C(O)=O>>[F:1][C:2]([F:21])([F:22])[CH:3]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)Cc1ccc(C(C(=O)O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C(O)C(c1ccccc1)(C(F)(F)F)C(F)(F)F
Product: CC(C)Cc1ccc(C(C(=O)O)C(F)(F)F)cc1
Yield: 43 %

Procedure:
Reaction was carried out in the same manner as in Example 1, except that methyl ester of α,α-bis(trifluoromethyl)-p-isobutylphenylacetic acid obtained in Reference Example 3 was used in place of methyl ester of α,α-bis(trifluoromethyl)phenylacetic acid obtained in Reference Example 2, whereby α-(trifluoromethyl)-p-isobutylphenylacetic acid was obtained in yield of 43%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20](Br)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[C:36]([CH3:51])[N:35]=[N:34]1>[Cu]I.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.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20]([C:37]4[N:33]([CH3:32])[N:34]=[N:35][C:36]=4[CH3:51])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(Br)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)nnn1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), and 1,4-dimethyl-5-(tributylstannanyl)-1H-1,2,3-triazole (CAS: 1047637-17-1, 754 mg, 1.95 mmol) in a microwave tube was added 1,4-dioxane (10 mL), copper (I) iodide (28 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.14 mmol). The solution was degassed using a stream of argon gas and degassing was continued for 10 minutes. The microwave vial was sealed and the mixture was heated at 125° C. for 2 hours under microwave irradiation. TLC (petroleum ether/ethyl acetate=1:1, Rf: 0.5) showed about 50% of 253g remained. However, further heating did not prove fruitful. The mixture was diluted with methyl tert-butyl ether (100 mL), washed with water (3×100 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=1:1 to yield -{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (229a, 108 mg, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.76 (s, 1H), 7.44 (d, J=1.35 Hz, 2H), 7.28-7.34 (m, 3H), 6.75 (s, 1H), 5.38 (s, 2H), 4.71 (s, 2H), 3.77 (s, 3H), 3.30-3.34 (m, 2H), 2.82 (s, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.08 (s, 3H) MS: 446.1 [M+1].
Reaction SMILES: [C:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])(O)=[O:2].C(Cl)(=O)C([Cl:57])=O.CN(C)C=O>ClCCl>[Cl:57][C:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:2]
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl

Procedure:
The solution of 0.80 g of benzyl 3-[4-carboxy-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 15 ml of dichloromethane is cooled to 0° C. with stirring and admixed successively with 0.190 ml of oxalyl chloride and 0.008 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C. over 6 hours. The reaction mixture is subsequently concentrated by evaporation at room temperature to obtain the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.Cl.[C:9](=N)(OCC)[CH2:10][CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:10]([C:9]1[NH:7][C:6]2[C:2](=[CH:3][S:4][CH:5]=2)[N:1]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=N)OCC
Reactant: Nc1cscc1N
Agent: Cl
Solvent: CCO
Product: CCCCc1nc2cscc2[nH]1
Reaction time: 1.5 h

Procedure:
A mixture of 3,4-diaminothiophene (1.7 g) and ethyl valeroimidate hydrochloride (3.0 g) in ethanol (30 ml) was stirred at room temperatures for 1.5 hour. 10 The reaction mixture was concentrated and the residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether afforded colorless crystals (0.72 g, 27%), m.p. 118°-120° C. 1H-NMR(200 MHz, CDCl3)δ: 0.95(3H,t), 1.35-1.54(2H,m), 1.73-1.88(2H,m), 2.79(2H,t), 6.75(2H,br s), 8.50(1H,br s). IR(KBr)cm-1 :3200-2200, 1530, 1480, 1440, 1390, 1240, 1230, 1160, 830, 815, 760, 740.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>CCCCCC>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(OCC)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To 41.15 g (0.3 Mol) of p-phenetidine in 90 ml of hexane, 64.9 g (0.3 Mol) of diethyl ethoxymethylenemalonate was added dropwise with stirring at room temperature. After an additional hour of stirring at room temperature, the reaction mixture was cooled with an ice bath and the product crystallized spontaneously. The crude solid material was isolated by filtration and washed with hexane to give 78.3 g of the title product; white solid melting at 55-56° C. UV 329 nm (E=802).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[CH3:6])C.Cl>[OH-].[Na+]>[Cl:15][C:9]1[C:8]([O:7][CH:5]([CH3:6])[C:4]([OH:16])=[O:3])=[CH:13][CH:12]=[C:11]([Cl:14])[N:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1ccc(Cl)nc1Cl)C(=O)O
Yield: 61.8 %

Procedure:
105 g of 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid ethyl ester is refluxed with 550 ml of 1N sodium hydroxide solution for 1 hour. The pH value of the solution is brought to 1.5 with concentrated hydrochloric acid and the solution is filtered. Recrystallisation in ethanol/water yields 58 g of the above acid; m.p. 128°-131°;
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][P:12]1([Cl:22])[N:17]=[P:16](Cl)([Cl:18])[N:15]=[P:14]([Cl:21])([Cl:20])[N:13]=1>C1COCC1>[Cl:20][P:14]1([Cl:21])[N:15]=[P:16]([Cl:18])([O:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[N:17]=[P:12]([Cl:22])([Cl:11])[N:13]=1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: O=Cc1ccc(OP2(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N2)cc1
Reaction time: 12 h
Yield: 75 %

Procedure:
500 mg of 4-hydroxybenzaldehyde sodium salt (3.47 mmol) is added at 0° C. and under an inert atmosphere to a solution containing 4.8 g of hexachlorocyclotriphosphazene (13.8 mmol) in THF (200 mL). The reaction medium is stirred for 12 hours while the temperature is left to gradually return to room temperature. The crude reaction product is evaporated to dryness then purified by “flash” chromatography on a silica column. The product is isolated in the form of a translucent oil with a yield of 75%.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-])=O)=[CH:24][CH:23]=1)([CH3:3])[CH3:2]>CCO.C1COCC1.[Pt]=O>[CH:1]([C:4]1[N:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][CH:23]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(OCc2c(C(C)C)nnn2-c2ccccc2OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(OCc2c(C(C)C)nnn2-c2ccccc2OC(F)(F)F)ccc1N
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a room temperature solution of 6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-3-nitro-pyridine (2.78 g, 6.35 mmol) in EtOH/THF (1/1, 200 mL) is added platinum (II) oxide (144 mg, 0.636 mmol, 10 mol %). The mixture is stirred under an atmosphere of hydrogen gas. After 3 h, the reaction is filtered through diatomaceous earth. The filtrate is concentrated and the residue is chromatographed (SiO2 120 g, 0% to 30% EtOAc/Hexane to yield 6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-ylamine (2.28 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.57-7.51 (m, 2H), 7.46-7.38 (m, 2H), 6.92 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.4 Hz), 5.25 (s, 2H), 3.29 (sept, 1H, J=7.0 Hz), 2.24 (s, 3H), 1.40 (d, 6H, J=7.0 Hz).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>O1CCCC1>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[S:18]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=S)Cc2ccccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
148 g (1.76 mol) of sodium bicarbonate are added in 20-gram portions with brisk stirring and at room temperature to a suspension of 130 g (0.8 mol) of 1-methyl-2-indolinone, prepared according to R. A. ABRAMOVITCH and D. H. HEY (J. Chem. Soc., 1954, 1699) and 133 g (0.3 mol) of phosphorus pentasulfide in 1.30 1 of anhydrous tetrahydrofuran. After 10 hours' stirring at room temperature, the mixture is filtered and the filtrate is concentrated on a water bath under vacuum. The residue is taken up with a water/ice mixture and the resulting mixture is extracted three times with chloroform. The organic phase is washed with water and then with saturated aqueous sodium chloride solution, dried and evaporated to dryness. The residue is recrystallized in methanol.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=2)=[N:16][C:15]([Br:26])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh].C1COCC1>[Br:26][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:23]3[CH:22]=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2cccc(C=O)c2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCCCCCCC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(C=O)cc12
Temperature: 80 °C
Yield: 58 %

Procedure:
1,2-Dichloroethane (1.7 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(3-formylphenyl)isonicotinate (903 mg, 2.50 mmol), rhodium octanoate dimer (156 mg, 0.20 mmol) and crushed 4A° molecular sieves (0.9 gm) in an flask. This was heated at 80° C. for 18 hr. The reaction was diluted THF and filtered. The collected solid was washed with multiple portions of boiling THF to complete extraction of the product. The solvent was removed from the combined filtrates, the residue was suspended in MeOH, and the product was collected by filtration. This left methyl 2-bromo-8-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (484 mg, 1.45 mmol, 58% yield) as a grey solid. MS (ESI) m/z 334.91 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (1H, s), 10.12 (1H, s), 8.80 (1H, s), 8.11 (1H, d, J=9.32 Hz), 7.98 (1H, s), 7.88(1H, d, J=8.56 Hz), 3.33 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.[C:22](Cl)(=O)[CH2:23][CH3:24]>>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:15])[C:12]#[N:13])=[CH:7][CH:6]=3)[C:22]([CH2:23][CH3:24])=[N:1][C:2]=2[CH:19]=1
Reactant: CC(C)(C#N)c1ccc(Nc2cc(Cl)c(Cl)cc2N)cc1
Reactant: CCC(=O)Cl
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)C#N)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-[4-(2-amino-4,5-dichloroanilino)phenyl]-2-methylpropanenitrile (step 2) and propionyl chloride.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CC1N(C2C=CC(C(F)(F)F)=CC=2C#N)C=NC=1>>[CH3:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:19]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Cc1c[nH]cn1
Agent: Cc1cncn1-c1ccc(C(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-5-(trifluoromethyl)-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and extraction with ethyl acetate the organic phase was dried over sodium sulfate and concentrated to afford a 3.4:1 mixture of the title compound and its regioisomer [2-(5-methyl-imidazol-1-yl)-5-trifluoromethyl-benzonitrile] as a light brown oil (yield: 85%). MS: m/e=252.3 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:37][C:38]([O:40][C@@H:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[O:39])[C:8]2[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=2)[O:11][CH2:12][C:13]2[CH:33]=[CH:32][C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]4OCC[O:28]4)[CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:37][C:38]([O:40][C@@H:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[O:39])[C:8]2[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=2)[O:11][CH2:12][C:13]2[CH:33]=[CH:32][C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)OCc3cccc(C4OCCO4)c3)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(COC(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.32 g, 0.57 mmol) in THF (8 mL) was added 2M aqueous hydrochloric acid (8 mL). The reaction mixture was stirred at RT for 1 hour. The mixture was diluted with ethyl acetate and was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine. The organic extract was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used in the next step with no further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[C:1]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:15]([OH:17])=[O:16])[NH2:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
Methacryloyl chloride (4.8 mL, 50 mmol) was slowly added, via syringe, to a cooled (0° C.) solution of lysine monohydrochloride (8.0 g, 43.6 mmol), CuSO4.5H2O (5.46 g, 21.8 mmol), NaOH (3.6 g, 90 mmol), and Na2CO3 (4.6 g, 43.6 mmol) in H2O (80 mL). The reaction was stirred at RT for 2 h. The resulting blue precipitate was filtered and washed with H2O, acetone, ether, then H2O again. After air-drying, the violet-blue solid (26) was purified by ion exchange: ca. 40 mL of DOWEX® 50WX8-400 resin was treated with 1 M NH4OH (100 mL), and the suspension was poured into a column and washed with conc. NH4OH. The copper complex (26) was dissolved in conc. NH4OH (2 mL), loaded onto the column, and eluted with ca. 500 mL of conc. NH4OH. The solution was evaporated in vacuo, and dried under high vac. to yield pure 27 as a white solid (5.5 g, 60%). 1H NMR (250 MHz, D2O) δ: 1.53 (m, 2H), 1.67 (m, 2H), 1.98 (m, 2H), 2.02 (s, 3H), 3.37 (t, J=6.5, 2H), 3.83, (t, J=6.0, 1H), 5.53, (s, 1H), 5.77 (s, 1H); 13C NMR (69.3 MHz, D2O) δ: 17.75, 21.85, 28.12, 30.14, 39.14, 54.71, 120.82, 139.22, 171.93, 174.79. See Makromol. Chem. 1980, 181, 2183-2197.