Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:15][C:16]1[C:21]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:9][CH:10]=2)=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(pyridin-2-ylamino)phenol (14.551 g, 78.14 mmol) and 2,3-dichloropyrazine (11.64 g, 78.14 mmol) in DMSO was added CESIUM CARBONATE (30.55 g, 93.77 mmol). The resulting mixture was heated to 60° C. overnight. Aqueous workup was carried out with DCM extraction and washing with alternating water and brine solutions. Purification by Biotage (0-2%, then 2% MeOH/DCM), followed by washing with EtOAc, produced clean product as solid. MS (ESI, pos. ion) m/z: 298.8 (M+1). IC50 (uM) 0.475.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)[CH2:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH:8]3[CH2:7][C:6]4[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[S:10][CH2:9]3)[CH2:13][CH2:14]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: OCC1CCN(CC2CSc3ccc(F)cc3C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CCN(CC2CSc3ccc(F)cc3C2)CC1)c1ccc(F)cc1

Procedure:
To a solution of 400 mg 6-fluoro-3-(4-[hydroxymethyl]-piperidinomethyl)-3,4-dihydro-2H-1-benzothiopyran and 200 mg triethylamine in 10 ml methylene chloride is added 221 mg p-fluorobenzoyl chloride. After 30 minutes at room temperature the reaction mixture is washed with 1 N sodium hydroxide, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with ether/hexane to afford the title compound, m.p. 113°-114° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]4[CH:16]=[CH:17][CH:18]=[CH:19][C:6]3=4)[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70° C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (250 mg) . 1H-NMR (CDCl3) δ: 1.65-2.11 (5H,m) , 2.32-3.10 (8H,m), 3.22-3.67(4H,m), 5.87(1H,t), 7.03-7.44(12H,m). MS m/z: 444(M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>CCCCCC.C(OCC)(=O)C.CN1C(=O)CCC1>[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][C:2]2[CH:3]=[C:4]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(Sc3ccc(N)cc3)c2)CCOCC1
Temperature: 130 °C

Procedure:
A mixture of 4-(3-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile (5.0 g, 18.79 mmol) (example 3), sodium carbonate (13.94 g, 131.58 mmol) and cesium carbonate (9.18 g, 28.19 mmol) was evacuated under vacuum for about 15 minutes. N-methyl pyrrolidinone (35 mL) and 4-aminothiophenol (2.8 g, 22.57 mmol) were added to this mixture under nitrogen atmosphere and heated at about 130° C. for about 15 hours. The reaction mixture was cooled to room temperature, poured over ice water and stirred. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated under vacuum to afford a brownish residue. Column chromatography over silica gel using ethyl acetate and hexane (3:2) yielded the title compound as a light yellow solid. Yield: 6.2 g.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]1([CH2:29][O:30][C:31]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:28][CH2:27]1>CCCCCCC.CCOC(C)=O>[CH:26]1([CH2:29][O:30][C:31]2[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:28]1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: CC1(C)OB(c2cccnc2OCC2CC2)OC1(C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC1CC1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(cyclopropylmethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN 848243-26-5) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (63%). MS (ESI): m/z=498.146 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[O:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:32]([NH:43][C:44]2[O:48][N:47]=[C:46]([CH3:49])[CH:45]=2)=[O:34])=[C:2]([F:1])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)on1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
2-Fluoro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 5-amino-3-methylisoxazole (37 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 53 mg of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][NH:41][CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][N:41]([C:5](=[O:7])[CH3:6])[CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(N3CCC(C(F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (5 μL, 0.054 mmol) was added to a solution of 2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (14.3 mg, 0.027 mmol) and pyridine (6.5 μL, 0.080 mmol) in DCM (270 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (14.3 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.23-1.31 (m, 6H), 1.45 (d, J=12.9 Hz, 1H), 1.53-1.76 (m, 2H), 1.96-2.15 (m, 2H), 2.18 (s, 1.2H), 2.21 (s, 1.8H), 2.67-2.84 (m, 4H), 3.38-3.55 (m, 2H), 3.78-3.83 (m, 1.2H), 3.83-3.87 (m, 0.8H), 4.13 (dq, J=12.6, 6.3 Hz, 1H), 4.56 (s, 0.8H), 4.59 (s, 1.2H), 5.53 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]3[N:46]=[C:47]([C:49](O)=[O:50])[CH:48]=[C:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].[CH2:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:52]([NH:59][C:49]([C:47]1[CH:48]=[C:38]2[N:37]=[C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:39]2[N:46]=1)=[O:50])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.845 g, 1.91 mmol) was added to a suspension of 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.600 g, 1.59 mmol) and benzylamine (0.209 mL, 1.91 mmol) in tetrahydrofuran (25 ml) containing triethylamine (0.665 mL, 4.77 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (25 mL) and washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.665 g, 89%).
Reaction SMILES: [H-].[Na+].[C:3]([O-])(=O)[CH2:4]C.[OH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(I)C>CN(C)C=O>[CH2:3]([O:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:4]
Reactant: CCC(=O)[O-]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl(propionate of the formula (10) (40 g) obtained according to the procedure described in step (iii) above in dimethylformamide (105 ml) at 5–10° C. over a period of 15–30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1–3 h. Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25–30° C. over a period of 2–3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47–48 g, 98–99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCC(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (2.4 g.) and glycine (525 mg.) are dissolved in 30 ml. of water, 30 ml. of acetone and 14 ml. of 1 N sodium hydroxide. After stirring at room temperature for about 25 minutes, the reaction mixture is acidified with concentrated hydrochloric acid. The precipitated material is recrystallized from acetone (25 ml.)-hexane (40 ml.) to yield the product, m.p. 189.5°-191.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Yield: 53.6 %

Procedure:
3-Hydroxy-4-nitro-benzoic acid 1a (10 g, 54.60 mmol) was dissolved in 125 mL of toluene followed by the addition of benzyl alcohol (9 g, 83.20 mmol) and p-toluenesulfonic acid (1 g, 5.30 mmol). The reaction solution was heated to reflux for 16 hours in water segregator. The resulting solution was added with 50 mL of ethyl acetate, washed with water (50 mL) and saturated sodium chloride solution (50 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 3-hydroxy-4-nitro-benzoate 29a (8 g, yield: 53.7%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (1.31 g, 4.12 mmol) in DMF (40 ml) was added N-iodosuccinimide (1.39 g, 6.17 mmol) and TFA (2.4 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 1.71 g (93%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.5 g, 1.84 mmole) in THF (20 mL) at 0° C., is added a solution of benzyl magnesium chloride in tetrahedronfuran (2.0M, 1.0 mL, 2 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 2 hrs. The reaction is quenched with NH4Cl(aq), partitioned between ethyl ether and water. Extracted the aqueous layer with ethyl ether. The combined organic is washed with brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].[CH3:22]CCCCC.C([Li])CCC.[C:33]([C:37]1[CH:38]=[CH:39][C:40](=[C:42]([CH2:45]C)[CH2:43][CH3:44])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CCOCC.O>[C:33]([C:37]1[CH:38]=[CH:39][CH:40]([CH:42]([CH:43]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)[CH2:44][CH3:22])[CH3:45])[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CCCCCC
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CCC(CC)=C1C=CC(C(C)(C)C)=C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(c1cc(C(C)(C)C)cc2c1Cc1ccc(C(C)(C)C)cc1-2)C(C)C1C=CC(C(C)(C)C)=C1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 1.99 g (7.1 mmol) of 3,6-di-tert-butylfluorene in 30 ml of THF, 4.6 ml (7.5 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.50 g (7.9 mmol) of 3-tert-butyl-6,6-diethylfulvene in 30 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.34 g (4.99 mmol) of a white solid (yield: 70%). The analyzed values are given below.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][CH2:19]4)[CH2:13][CH2:12]3)[C:8]2=[O:29])=[CH:4][CH:3]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Cl:53]CCCl>>[ClH:53].[ClH:53].[CH2:32]([N:20]1[CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]([CH2:17][N:14]2[CH2:13][CH2:12][C:9]3([C:8](=[O:29])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:31][CH:30]=4)[CH2:11][CH2:10]3)[CH2:16][CH2:15]2)[CH2:19]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClCCCl
Reactant: O=Cc1ccccc1
Reactant: O=C1N(Cc2ccc(Br)cc2)CCC12CCN(CC1CNCC1c1ccccc1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Product: Cl
Product: O=C1N(Cc2ccc(Br)cc2)CCC12CCN(CC1CN(Cc3ccccc3)CC1c1ccccc1)CC2
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of 28.9 mg (60 μmol) of 2-(4-bromobenzyl)-8-(4-(SR)-phenylpyrrolidin-3-(RS)-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one and 6.3 mg (60 μmol) of benzaldehyde in 1.5 mL of DCE was agitated for 10 minutes at room temperature before adding 20 mg (90 μmol) of triacetoxyborohydride. The reaction mixture was then stirred overnight and quenched with a saturated solution of sodium bicarbonate (1 mL). The solution was extracted with DCM (2×2 mL) and the combined organic layers were concentrated. The crude was purified by semi-preparative HPLC (method B) yielding 15.3 mg (39.5%) of Compound 98 as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](\[C:17]2[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:19][CH:18]=2)/[C:21]([OH:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: O=Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccc(Br)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
Aryl Bromide AB1 was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100 mL) was added 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) and piperidine (2 mL). After overnight refluxing, the mixture was cooled down to r.t. To the slurry thus formed, toluene was added (10 mL). Filtration gave (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid as a white solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH2:13].[CH2:18]([O:20][CH2:21][C:22]1[N:23]([CH2:35][C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:19].[H-].[Na+]>O1CCCC1.O>[CH2:18]([O:20][CH2:21][C:22]1[N:23]([CH2:35][C:36]2([O:40][CH2:13][CH2:12][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:39][CH2:38][CH2:37]2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:19]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.74 mmol) followed by methyl vinyl sulfone (1.60 g, 14.8 mmol) were added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (2.30 g, 7.39 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 1 hour and a small amount of sodium hydride (60% dispersion in mineral oil) was added. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 2.0 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-1H-imidazo[4,5-c]quinoline as an oil.