Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:18](=[O:19])[C:13]3[NH:14][CH2:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:20]=1)(=[O:4])=[O:3].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25](Cl)[CH2:24][CH2:23]1.[Mg].C1COCC1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:18]([CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)([OH:19])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]=2[CH:20]=1)(=[O:4])=[O:3]
Reactant: CN1CCC(Cl)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCC1=C(NCC=C1)C2=O
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(S(C)(=O)=O)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
8-Methylsulfonyl-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (1 g) was dissolved in 30 ml of methylene chloride, followed by the dropwise gradual addition of a Grignard reagent under ice cooling. The Grignard reagent had been prepared from 0.07 g of N-methyl-4-chloropiperidine, 0.012 g of magnesium and 10 ml of THF. After the resultant mixture was stirred for 1 hour at the same temperature, it was stirred for additional 1 hour at room temperature. The reaction mixture was then treated in a similar manner to Referential Example 2, whereby 0.82 g of the target compound, 8-methylsulfonyl-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol was obtained (yield: 61%).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:11])[CH3:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([S:29]([O-:31])=[O:30])[CH:23]=[CH:22]3)=[CH:15][CH:14]=1.[Na+]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([S:29]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[C@@H:9]([OH:11])[CH3:10])(=[O:31])=[O:30])[CH:23]=[CH:22]3)=[CH:15][CH:14]=1
Reactant: Cc1cccc([C@H](C)O)c1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: Cc1cccc([C@H](C)O)c1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6 Step 4 using (1S)-1-(2-iodo-3-methylphenyl)ethanol and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate to give the title compound as a white solid (58 mg). SFC (10% MeOH, chiralpak AD-H) e.e. >99%; 1H NMR (400 MHz, d6-DMSO): δ 8.6 (1H, s), 8.35 (1H, s), 8.31 (1H, d, J=8.7 Hz), 8.17 (1H, d, J=8.7 Hz), 8.03 (1H, d, J=9.4 Hz), 7.93-7.89 (2H, m), 7.85 (1H, d, J=7.7 Hz), 7.75 (1H, m) 7.6 (1H, t, J=8.7 Hz), 7.4-7.35 (2H, t, J=7.5 Hz), 7.3 (1H, d, J=7.4 Hz) 5.9 (1H, m), 5.35 (1H, d, J=7.3 Hz), 2.5 (3H, s) 1.3 (3H, d, J=6.3 Hz); m/z (ES+) 403 [(M-OH)+].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][S@](C(C)(C)C)=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[ClH:21]>CO>[ClH:21].[F:1][C:2]([F:19])([F:20])[O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)c1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: C[C@H](N)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 25 ml round-bottomed flask, (S)-2-methyl-propane-2-sulfinic acid [(S)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide (157 mg, 0.51 mmol) was dissolved in methanol (1 ml) and hydrogen chloride (4.0 M in 1,4-dioxane, 0.26 ml, 1.04 mmol) was added dropwise. The reaction was stirred at room temperature for 20 min then concentrated to give (S)-1-(3-trifluoromethoxy-phenyl)-ethylamine hydrochloride as an off-white waxy solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([CH3:10])=[CH:4][N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][O:8][C:7]1[C:2]([NH:1][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])(=[O:20])=[O:19])=[N:3][CH:4]=[C:5]([CH3:10])[N:6]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1Br

Procedure:
2-amino-3-methoxy-5-methylpyrazine (1.50 g, 10.8 mmol; synthesized according to Bradbury, R. H., et. al. J. Med. Chem. 1997, 40, 996-1004) and 2-bromobenzenesulfonyl chloride (2.80 g, 11.0 mmol) were reacted according to the procedure of Example 25, Step A. 44A was a pink solid, 2.0 g (52%).
Reaction SMILES: [CH:1]([C:3]1[S:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[S:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)#[N:15]
Reactant: NO
Reactant: O=Cc1cc2[nH]c(C(=O)O)cc2s1
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)O)cc2s1

Procedure:
2-Formyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid was treated with hydroxylamine hydrochloride according to Procedure G.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH3:27])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)=[O:4].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>C(=O)(O)[O-].[Na+]>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH:32][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH3:27])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)=[O:4]
Reactant: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CCl)ccc3n1)CC2
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CNCCN(C)C)ccc3n1)CC2
Reaction time: 0.07 h
Yield: 88.1 %

Procedure:
rac-2-Chloro-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-acetamide (150 mg, 0.39 mmol) was suspended N,N-dimethylethylendiamine (693 mg, 7.9 mmol) and placed in an ultrasound bath for 4 min. The mixture was diluted with 5 mL saturated sodium bicarbonate solution and was extracted three times with ethyl acetate and combined organic layers were dried over sodium sulfate. Removal of the solvent in vacuum left a yellow residue which was purified by silica gel column chromatography with dichloromethane/methanol to give the title compound as a white foam (149 mg, 87%). MS (ISN) m/e=432.5 [(M−H)−].
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]1[CH2:37][CH:36]([OH:38])[CH2:35][CH:34]1[CH:39]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[O:40][CH:41]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)=[O:32]>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:41]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[O:40][CH:39]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:34]2[CH2:35][CH:36]([OH:38])[CH2:37][N:33]2[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:43][CH:44]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 41 %

Procedure:
Using the above described procedure, docosanoic acid 101h (3.41 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as a foam (3.5 g, 41%). 1H NMR (DMSO-d6, 400 MHz) δ=7.69 (m, 1H), 7.32-6.80 (m, 13H), 4.98 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.10-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.08 (m, 44H), 0.81 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.78, 170.89, 170.79, 162.30, 162.25, 158.09, 157.97, 145.08, 144.73, 135.86, 135.70, 135.45, 135.40, 129.59, 129.53, 127.82, 127.72, 127.56, 126.69, 126.52, 113.14, 113.05, 85.78, 85.10, 68.58, 67.44, 65.19, 63.32, 55.60, 55.05, 54.96, 54.93, 38.22, 38.01, 36.30, 35.76, 35.43, 34.16, 32.53, 31.35, 30.74, 29.09, 28.87, 28.78, 28.73, 26.20, 25.35, 24.13, 22.13, 13.88.
Reaction SMILES: [OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[C:26]([F:29])([F:28])[F:27])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:16].Cl.O>CC(C)=O>[OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[C:26]([F:27])([F:28])[F:29])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:14])([CH3:15])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:16]
Reactant: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Ethyl (2E,4E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)penta-2,4-dienoate (150 mg, 0.36 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 10% strength hydrochloric acid was added. The resulting reaction solution was stirred at room temperature for 40 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E,4E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)penta-2,4-dienoate (80 mg, 61% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.55 (d, 1H), 6.37 (d, 1H), 6.33 (s, 1H), 5.97 (s, 1H), 4.25 (q, 2H), 2.47 (d, 1H), 2.34 (d, 1H), 1.92 (s, 3H), 1.90 (br. s, 1H, OH), 1.33 (t, 3H), 1.11 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:24]([OH:26])=[O:25])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: COc1cc(Br)c2[nH]ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(=O)O)c2[nH]ccc2c1
Temperature: -78 °C
Yield: 59.1 %

Procedure:
A mixture of 7-bromo-5-methoxy-1H-indole (1.2 g) and THF (12 mL) was stirred at −78° C. under an argon atmosphere. To the reaction mixture was added dropwise an n-butyllithium n-hexane solution (1.65 M, 9.6 mL) at −50° C. or lower. The reaction mixture was stirred for 0.5 hour under ice-cooling. The reaction mixture was cooled to −78° C., and dry ice (10 g) was added thereto, followed by slowly warming to room temperature. The reaction mixture was poured into a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (THF/hexane=20→60%) to obtain 5-methoxy-1H-indole-7-carboxylic acid (0.60 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:31][C:23]1=2>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:30]=[CH:31][C:23]4[N:22]([CH3:21])[CH2:27][CH2:26][O:25][C:24]=4[CH:28]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)OCCN3C)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (22.1 mg, 0.075 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (25 mg, 0.091 mmol) (R)-4-((R)-1-(3-methyl-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.06 was synthesized.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1([F:26])[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22](B(O)O)[C:16]=2[O:15]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[F:26][C:14]1([F:13])[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([C:2]3[N:10]4[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]4)=[CH:4][CH:3]=3)[C:17]=2[O:18]1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.531 g, 2.18 mmol), 2,2-Difluorobenzo[1,3]dioxole-4-boronic acid (0.624 g, 3.09 mmol), Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.108 mmol), 2.00 M of Sodium carbonate in Water (2.70 mL), and 1,4-Dioxane (6.6 mL) were combined in a vial, degassed (freeze-pump-thaw) and was heated under an atmosphere of Nitrogen at 80° C. overnight. Conversion was ˜75%. Further heating for a second night lead to little additional product relative to bromide. The mixture was diluted with water (20 mL) then extracted with EtOAc (3×30 mL). The org. was washed with brine, dried, filtered through 7 mL silica gel, washing with EtOAc, then conc. in vacuo onto 7 g silica gel. Purification on an ISCO (80 g, 0-10% EtOAc:Hex) afforded first an impurity, then the product 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.440 g; Yield=63.0%). LCMS (HPLC): 1.46 min, 322 (M+H); 1H-NMR (DMSO-d6): 9.12 (s, 1H), 8.16 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=7.9 Hz), 7.40 (m, 1H), 7.33 (d, 1H, J=4.8 Hz), 7.16 (d, 1H, J=4.8 Hz), 2.55 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:27]([Mg]Cl)[CH:28]=[CH2:29]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:29][CH:28]=[CH2:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Cl
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Solvent: C1CCOC1
Product: C=CCC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
To a solution of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (430 mg) in dry THF (7 ml) at 0° under nitrogen, allylmagnesium chloride (2M in THF, 0.86 ml) was added. The mixture was stirred for 2.5 h at 0° and then quenched with saturated aqueous ammonium chloride. Extraction with ether (4×) gave, after drying and rotary-evaporation, the crude product (466 mg). FCC eluting with 20% then 30% System A afforded the title product (331.9 mg) as a white solid. Rf 0.41 (System A 1:1); νmax (CHBr3) 3587 cm-1 (OH).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[Cl-].[NH4+:17].[OH-].[Na+]>CC(C)=O>[F:1][C:2]1[C:7]([S:8]([NH2:17])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 36 %

Procedure:
Under room temperature, a solution of 468 g of pentafluorobenzenesulfonyl chloride in acetone was added dropwise to an aqueous solution containing 964 g of ammonium chloride, during which a pH was adjusted to 7 with an aqueous sodium hydroxide solution. The precipitated product was filtered, and recrystallized from toluene to obtain 156 g of pentafluorobenzenesulfonamide as white crystals. A structure was confirmed by 1H-NMR, 19F-NMR and IR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 7) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 2.77 min; MS: m/z (ESI) 520 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20]C1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]([C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:50])[CH3:49])[C:42]=1N)([CH3:40])[CH3:39]>>[CH:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:41]([CH:38]([CH3:40])[CH3:39])[C:42]=1[NH:20][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])([CH3:50])[CH3:49]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 2,6-diisopropylaniline, mp 202°-205° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
To a solution of 4-benzyloxy-2-chlorobenzoic acid (788 mg) in tetrahydrofuran (7.9 ml) was added dropwise borane-dimethylsulfide complex (10.0M, 0.6 ml) at room temperature under a nitrogen atmosphere and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was allowed to cool to room temperature, and 1N hydrochloric acid (1.5 ml) was carefully added dropwise. The mixture was stirred for 30 min. To the reaction mixture was added water and the resulting product was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 4-benzyloxy-2-chlorobenzyl alcohol (778 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH2:32]([N:34]([CH2:49][CH3:50])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](O)=[O:44])[CH3:38])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:49]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[N:8]=1)=[O:5])=[O:44])[CH3:38])[CH3:50]
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (74 mg, 0.28 mmol, 1.20 equiv), EDC.HCl (90 mg, 0.47 mmol, 2.01 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv). The resulting solution was stirred overnight at 30° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 1×10 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 58.5 mg (32%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.502-8.532(d, J=9.0 Hz, 1H), 8.277-8.286(m, 1H), 8.060(s, 1H), 7.851-7.966(m, 4H), 7.475-7.610(m, 5H), 6.949-6.958(m, 1H), 3.922(s, 2H), 3.450-3.485(m, 4H), 3.273-3.316(m, 2H), 3.035-3.108(m, 4H), 2.957-2.998(m, 2H), 2.449-2.475(m, 3H), 1.857-1.872(m, 4H), 1.666-1.683(m, 2H), 1.139-1.200(m, 6H). MS (ES, m/z): 676 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BrH:16].N([O-])=O.[Na+]>CC(C)=O.O>[Br:16][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Br
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in 10 ml of acetone and 1.5 ml of water, 1.80 ml of 48% hydrobromic acid was added, and then 0.23 g of sodium nitrite dissolved in 1 ml of water was added dropwise under ice-cooling, followed by a short period of stirring. Next, 0.51 g of cuprous bromide was added, and the mixture was warmed to room temperature. After completion of the reaction, insoluble matter was filtered, and the resulting residue was mixed with water, extracted with chloroform and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, methyl 5-bromo-2,4-dimethoxybenzoate was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:11][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCCBr
Reactant: C1CCNCC1
Product: C=CCCN1CCCCC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
4-Bromobut-1-ene (1.35 g) was treated with piperidine (1.7 g) and heated at reflux for 3 hours. The mixture was cooled to ambient temperature, filtered and the residue washed with ether (50 mL). The combined filtrate and washings were evaporated to give the title compound (1.3 g).