Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:13]>NN>[NH2:3][C@H:12]([C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=1)[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]1)[CH3:13]
Reactant: C[C@@H](c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Product: C[C@H](N)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The (S)-tert-butyl 4-(3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)benzyl)piperazine-1-carboxylate from the previous step (490 mg, 1.09 mmol) was dissolved in 5 mL hydrazine and stirred at ambient temperature for 16 h. The solvent was removed at reduced pressure and the resulting (S)-tert-butyl 4-(3-(1-aminoethyl)benzyl)piperazine-1-carboxylate was used in the next step without additional purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH3:29])[CH:24]=2)[N:19]=1)([C:5]1[N:9](COCC[Si](C)(C)C)[N:8]=[N:7][CH:6]=1)[OH:4].[F-].[Cs+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][CH:2]([CH3:30])[C:3]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH3:29])[CH:24]=2)[N:19]=1)([C:5]1[N:9]=[N:8][NH:7][CH:6]=1)[OH:4]
Reactant: CSc1ccc2nc(C(O)(c3cnnn3COCC[Si](C)(C)C)C(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc2nc(C(O)(c3c[nH]nn3)C(C)C)ccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
To a stirred solution of 2-methyl-1-(6-(methylthio)quinolin-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-yl)propan-1-ol (AL) (1 g, 2.25 mmol) in THF (20 mL) was added CsF (1.02 g, 6.75 mmol) followed by TBAF (2.24 mL, 2.25 mmol) (1M solution in THF) at RT under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using 30% EtOAc/Hexane as eluent to afford 7 (70 mg, 0.22 mmol, 9.9%). 1H NMR (500 MHz, CDCl3): δ 11.65-11.63 (br s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.80 (br s, 2H), 7.59 (dd, J=2.0, 9.0 Hz, 1H), 7.52-7.51 (m, 1H), 6.54 (s, 1H), 2.82-2.80 (m, 1H), 2.58 (s, 3H), 0.97 (d, J=6.5 Hz, 3H), 0.63 (d, f=6.5 Hz, 3H). HPLC: 95.12%. MS (ESI): m/z 315 [M++1].
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.Cl.Cl.[CH3:26][NH:27][CH2:28][CH2:29][N:30]([CH2:46][C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1)[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][CH2:39][CH2:38]2.[O:53]1[C:57]2[C:58]([C:62](O)=[O:63])=[CH:59][CH:60]=[CH:61][C:56]=2[CH2:55][CH2:54]1.C(OC(=O)C)C.Cl>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[ClH:1].[CH3:26][N:27]([CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][CH2:39][CH2:38]2)[CH2:46][C:47]1[CH:48]=[CH:49][N:50]=[CH:51][CH:52]=1)[C:62]([C:58]1[C:57]2[O:53][CH2:54][CH2:55][C:56]=2[CH:61]=[CH:60][CH:59]=1)=[O:63]
Reactant: CNCCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1)C(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(144 mg), and 1-hydroxy benzotriazole (HOBt)(115 mg) were added to a DMF solution (5 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-di hydro-2H-isoquinolin-1-one trihydrochloride (234 mg), and 2,3-dihydrobenzofuran-7-carboxylic acid (123 mg). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.19 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (164.6 mg) as a white powder.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N)C>CN(C=O)C.C(Cl)Cl>[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([NH:9][CH2:10][CH3:11])=[O:30]
Reactant: Nc1c(C(=O)O)ccc(F)c1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(F)c(Br)c1N
Temperature: 23 °C
Reaction time: 17 h
Yield: 77.4 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU; Aldrich; 5.36 g, 14.10 mmol) was added to a mixture of 2-amino-3-bromo-4-fluorobenzoic acid (Example 719; 3.00 g, 12.82 mmol), ethylamine (2.0 M in MeOH; Aldrich; 7.05 mL, 14.10 mmol), and TEA (2.68 mL, 19.23 mmol) in a mixture of DMF (10 mL) and DCM (10.00 mL), and the resulting solution was stirred at 23° C. for 17 h. The reaction mixture was then diluted with DCM (100 mL), and the resulting solution was sequentially washed with water (2×80 mL), 0.5 N aqueous NaOH (50 mL), and brine (50 mL), then concentrated in vacuo. The residue was chromatographically purified (silica gel, 0-60% EtOAc/hexanes) to yield 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (2.59 g, 9.92 mmol, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, t, J=4.5 Hz), 7.59 (1H, dd, J=8.8, 6.3 Hz), 6.86 (2H, br. s.), 6.57 (1H, t, J=8.5 Hz), 3.20-3.29 (2H, m), 1.11 (3H, t, J=7.2 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −101.26 (1F, s). m/z (ESI, +ve) 260.9/262.9 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10](=[O:11])[C:9]2([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]2)[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C@H:6]1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)([OH:3])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[C:60]2[CH2:75][C:65]3([C:73]4[C:68](=[N:69][CH:70]=[CH:71][CH:72]=4)[NH:67][C:66]3=[O:74])[CH2:64][C:61]2=[N:62][CH:63]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:27]1[CH:26]=[C:25]([C@H:6]2[N:5]([CH2:4][C:1](=[O:3])[NH:57][C:58]3[CH:59]=[C:60]4[CH2:75][C:65]5([C:73]6[C:68](=[N:69][CH:70]=[CH:71][CH:72]=6)[NH:67][C:66]5=[O:74])[CH2:64][C:61]4=[N:62][CH:63]=3)[C:10](=[O:11])[C:9]3([CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17]3)[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:7]2)[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
0.13 g (0.28 mmol) tert-butyl (R)-4-carboxymethyl-3-(3,5-difluoro-phenyl)-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate in 2 ml DMF were combined with 0.11 g (0.29 mmol) HATU and 0.08 ml (0.60 mmol) TEA and stirred for 3 min at RT. Then 72 mg (0.28 mmol) 3-amino-5,7-dihydrospiro[cyclopenta-[b]pyridin-6.3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto saturated sodium hydrogen carbonate solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[O:11][N:10]=1)=[O:14]
Reactant: CCOC(=O)c1noc(Cc2ccc(Cl)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(Cl)cc2)n1
Yield: 29.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.115 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0536 g (30%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-chlorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([CH2:15][O:16][CH3:17])[N:14]=2)=[CH:6][CH:5]=1.CS(O)(=O)=O.CC1(C)[O:28][CH:27]([CH2:29]O)[CH2:26][O:25]1.O>CN(C=O)C>[CH3:17][O:16][CH2:15][C:13]1[N:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[CH:9][CH:8]=2)[NH:11][CH:12]=1
Reactant: COCc1c[nH]c(-c2ccc(O)cc2)n1
Reactant: CC1(C)OCC(CO)O1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1c[nH]c(-c2ccc(OCC(O)CO)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
Under N2, a mixture of NaH (1.5 g, 0.037 mol), 60% oil dispersion), DMF (45 mol) and 89 (6.8 g, 0.033 mol) was heated at 80° C. for 30 minutes and then a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methansulfonate (8.4 g, 0.04 mol) in DMF (25 ml) was added dropwise. After the addition, the mixture was heated at 120° C. with stirring for 18 hours. The mixture was then poured into H2O and the solution extracted with EtOAc (4×). The combined organic extracts were backwashed with H2O, 5% NaOH, dried, filtered and concentrated to dryness. The residue was combined with acetone (75 ml) and 3N HCl (75 ml) and the solution heated on a steam bath for 30 minutes. After cooling, the solution was adjusted to pH 10 and extracted with 10% CH3OH--CHCl3. The combined extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 10% CH3OH--CHCl3 to yield 1.7 g of 90 (18%); m.p. 154°-56° C. (isoProOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](O)([CH3:11])[CH3:10])=[N+:6]([O-:8])[CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:11])=[CH2:10])=[N+:6]([O-:8])[CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)c[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)c1ccc(Br)c[n+]1[O-]
Temperature: 130 °C

Procedure:
A mixture of 5-bromo-2-(1-hydroxy-1-methylethyl) pyridine N-oxide from step 2 of example 30 (1.29 g) and 25% aqueous sulfuric acid was heated at 130° C. for 2 days. After cooling, the mixture was made slightly basic using ION aqueous sodium hydroxide and partitioned between ethyl acetate and water. The crude product from evaporation of the organic phase was used as such in step 2.
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([OH:27])[CH:20]=1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=[CH:23][C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH2:28][CH3:29])[CH2:16][CH3:17])=[CH:20][C:21]=2[OH:27])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)c1ccc(C=NN(c2ccccc2)c2ccccc2)c(O)c1

Procedure:
A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until 4-diethylamino-2-hydroxybenzaldehyde was completely reacted in about 30 minutes. The solvent (800 ml) was removed by evaporation. The residue obtained was extracted with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The ether solvent was evaporated. The residue was recrystallized from ethanol. Crystals were filtered off and washed with cold ethanol. The product was 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69.
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:40][OH:41])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].[K+].[C:44]1([CH2:50][CH2:51][CH2:52][CH2:53]I)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[C:1]([NH:20][CH:21]([CH2:40][O:41][CH2:53][CH2:52][CH2:51][CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:29][CH:30]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ICCCCc1ccccc1
Reactant: OCC(COCc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CCCCOCC(COCc2ccc(-c3nc4ccccc4o3)cc2)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-hydroxy-2-propanamine (0.4 g; 0.74 mmol) is added to a suspension of potassium hydride (0.12 g; 1. mmol; 35% suspension in oil) in dry THF (4 ml) at 0° C. The reaction is stirred for 15 minutes at 20° C. 4-Phenyl-1-butyl iodide (0.21 g; 0.81 mmol) is added and the reaction mixture stirred for 15 hours. The reaction is quenched with MeOH, diluted with CH2Cl2 and washed with water 2x. The organic phase is dried (Na2SO4), concentrated and purified by column chromatography with 80% CH2Cl2 /20% petroleum ether to yield N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-(4-phenylbutoxy)-2-propanamine as an oil which is used directly in Step F.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[H][H]>CO.[Pd]>[CH3:14][C:11]1([CH2:15][OH:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CC1(CO)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(CO)CCNCC1

Procedure:
To a solution of (1-benzyl-4-methylpiperidin-4-yl)methanol (2.7 g, 12 mmol) in methanol (34 mL) was added ammonium formate (8.6 g, 135 mmol) followed by palladium on carbon (10% w/w, 3.6 g, 1.7 mmol). The reaction mixture was stirred for 18 hours under a balloon of hydrogen, then degassed, flushed with nitrogen, and filtered over a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (1.2 g, 76%).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=1>>[C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:44]3[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH:45]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Product: COc1ccc(-c2ccnc(NC(=O)OC(C)(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (686 mg, 1.10 mmol) is coupled to pyridyl bromide 155 (300 mg, 1.10 mmol) using Method A to give the title compound.
Reaction SMILES: [N:1]([CH:4]([CH3:22])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[C:8]([O:20][CH3:21])=[N:7]1)=[N+]=[N-].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:21][O:20][C:8]1[C:9]2[C:10](=[CH:11][C:12]3[C:17]=2[CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:6]([CH2:5][C@@H:4]([NH2:1])[CH3:22])[N:7]=1
Reactant: COC1=C2C=c3c(c(OC)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: COC1=C2C=c3c(c(OC)nn3C[C@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.8 %

Procedure:
1.11 g (3.71 mmol) of (RS)-1-(2-azido-propyl)-3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 110 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 50 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 430 mg (3.71 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the beige crystals were subsequently filtered off. 0.56 g (46%) of (S)-2-(3,7-dimethoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:05) with m.p. 209° was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[N:3]=1.[Cl:13][C:14]([C:24]([F:27])([F:26])[F:25])=[CH:15][C@@H:16]1[C@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22]>>[Cl:13][C:14]([C:24]([F:25])([F:26])[F:27])=[CH:15][C@@H:16]1[C@H:18]([C:19]([O:10][CH2:9][C:6]2[C:5]([F:11])=[C:4]([F:12])[N:3]=[C:2]([Cl:1])[C:7]=2[F:8])=[O:20])[C:17]1([CH3:23])[CH3:22]
Reactant: OCc1c(F)c(F)nc(Cl)c1F
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)c(F)nc(Cl)c1F
Yield: 41.5 %

Procedure:
By the method of Example 2, 0.4 g (0.002 mole) of 2-chloro-4-hydroxymethyl-3,5,6-trifluoropyridine (from Example 7) was reacted with 0.54 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce 0.35 g of (2-chloro-3,5,6-trifluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as a light yellow oil, Compound 14 in the Tables below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.CCCCCC.[OH-].[Na+]>O1CCCC1>[OH:13][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)[C@H](O)Cc1ccc(O)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-hydroxyphenylpyruvic acid 9.01 g (50.0 mmol) in tetrahydrofuran 120 ml, triethylamine 7.0 ml (50.0 mmol) was added and the mixture was stirred at −20° C. for 0.5 hr. A solution of (−)-B-chlorodiisopinocamphenylborane in 60% hexane 41.2 ml (70.0 mmol) was added to the reaction mixture dropwisely and the mixture was warmed to room temperature and stirred for 6 hrs. 1N sodium hydroxide solution 200 ml was added to the reaction mixture and the mixture was washed with ethyl ether 200 ml. 3N hydrochloride aq. 80 ml was added to the aqueous phase and the mixture was extracted with ethyl acetate 200 ml. The organic phase was washed with brine 200 ml and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and n-hexane:ethyl acetate=60:40 50 ml was added to the residue and the precipitate was corrected by filtration to obtain (R)-2-hydroxy-3-(4-hydroxyphenyl)propanoic acid 5.53 g (yield 61%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1)(=[O:5])=[O:4].[CH2:19]([Mg]Br)[CH:20]=C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:18])([F:17])[S:3]([O:6][C:7]1[CH:12]=[C:11]2[C:10](=[C:9]([CH3:16])[CH:8]=1)[NH:13][CH:20]=[CH:19]2)(=[O:5])=[O:4]
Reactant: C=CC[Mg]Br
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2cc[nH]c12
Reaction time: 2 h

Procedure:
A solution of 3-methyl-4-nitrophenyl trifluoromethanesulfonate (8.96 g, 31.4 mmol) in THF (200 mL) at 0° C. was treated dropwise with 1M allylmagnesium bromide in THF (110 mL 110 mmol), stirred for 2 hours, transferred into saturated NH4Cl (200 mL), and extracted with ethyl acetate (200 mL). The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 9:1 hexanes/ethyl acetate to provide 3.19 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[CH3:18][NH:19][CH3:20]>C(Cl)Cl.CN(C)C=O>[CH3:18][N:19]([CH3:20])[C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)ccc1F
Reaction time: 3 h

Procedure:
A suspension of 2-fluoro-5-bromobenzoic acid (680 mg, 3.10 mmol) in methylene chloride (20 ml) was treated with oxalyl chloride (0.35 ml, 4.04 mmol), followed by four drops of N,N-dimethylformamide. The resulting clear solution was stirred for about three hours. The solvents were removed in vacuo and the residue was redissolved in methylene chloride and treated with dimethylamine (4.6 ml, 9.3 mmol). Stirring was continued for 18 hours. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraciton was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title product was further purified by liquid chromatography.