Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH2:14]([O:16][C:17]([C:19]#[C:20][C:21](OCC)=[O:22])=[O:18])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:19]1[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[S:3][C:2]2=[N:1][C:21](=[O:22])[CH:20]=1)=[O:18])[CH3:15]
Reactant: Nc1nnc(-c2ccc(Cl)cc2)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(-c3ccc(Cl)cc3)nn12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 5.5 g of 2-amino-5-(p-chlorophenyl)-1,3,4-thiadiazole, 100 ml of absolute ethanol and 4.5 g of acetylene dicarboxylic acid diethyl ester is heated to about 50° C. until a clear solution has formed and then left standing for 2 days. The product is filtered off, washed with ethanol and dried. Thus 2-(p-chlorophenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 220°-222° C. with decomposition is obtained in a yield of 3.5 g (40.2% of the theoretical).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O.[OH-].[Li+]>O1CCCC1.O>[F:22][C:20]([F:21])([F:23])[C:15]1[CH:14]=[C:13]([NH:12][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:3]([OH:24])=[O:2])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
2-(3-Trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid methyl ester (1.643 g, 4.73 mmol., 1 eq.) was dissolved in tetrahydrofuran (40 mL). A solution of lithium hydroxide monohydrate (0.596 g, 14.19 mmol., 3 eq.) in water (40 mL) was added dropwise and the reaction mixture stirred for a further 3 hours at ambient temperature by when LCMS analysis of an aliquot showed the reaction to be complete. The reaction mixture volume was reduced by half in vacuo to remove most of the tetrahydrofuran and the obtained solution was diluted with 1.5M hydrochloric acid (40 mL). The solution was extracted with dichloromethane (2×60 mL). The organic extracted were combined, dried over sodium sulfate and the solvent removed in vacuo to give 1.41 g (90%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.68 (d, J=8.54 Hz, 1 H), 6.63 (s, 1 H), 6.44 (dd, J=1.98, 10.68 Hz, 1 H), 5.72-5.85 (m, J=6.64, 6.64, 10.28, 17.03 Hz, 1 H), 5.00 (dq, J=1.66, 17.15 Hz, 1 H), 4.95 (dt, J=0.97, 10.11 Hz, 1 H), 4.07 (dd, J=5.80, 6.87 Hz, 1 H), 2.19 (s, 2 H), 2.05 (q, J=6.87 Hz, 2 H), 1.90-1.99 (m, 1 H), 1.74-1.86 (m, 1 H), 1.43-1.51 (m, 2 H), 1.32-1.43 (m, 3 H). LC-MS: purity 98% (UV), tR 2.33 min, m/z [M+H]+334.10
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a stirred solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201 mg, 1.0 mmol) in NMP (3 mL) was added powdered KOH (392 mg, 7.0 mmol). After stirring for 10 min at RT, 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added to the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 3,6-dimethyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (80 mg). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.38 (s, 1H), 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (d, 1H), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.68 (t, 2H), 2.5 (t, 2H), 2.47 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH3:21])=[O:19].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccc(C)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2cc(F)ccc2N)sc2ccc(C)cc12
Yield: 44.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using methyl 2-(5-fluoro-2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate (4.42 g), ethyl acetate (400 ml), 10% palladium-carbon and hydrogen (400 mg, 60 atm kg/cm2), methyl 2-(2-amino-5-fluoroanilino)-5-methylbenzo[b]thiophene-3-carboxylate (1.82 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)=[CH:5][C:3]=1[NH2:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:4][C:3]2[CH:5]=[C:6]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:7]=[CH:8][C:2]=2[F:1])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cc(-c2ccoc2)ccc1F
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cc(-c2ccoc2)ccc1F

Procedure:
Using the same method as in Example 15-(i), 2-fluoro-5-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([2-fluoro-5-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2nccc(CCl)n2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2nccc(CN3CCCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)n2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyrimidine (300 mg) and homopiperazine (51 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CC(=O)CC>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
253.7 g (1.27 mol) 4-hydroxybenzophenone was dissolved in 2.56 L 2-butanone. 884.5 g (6.3 mol) potassium carbonate and 201.5 g (1.27 mol) 1-bromo-3-chloro-propane were added. The mixture was refluxed for 16 hours. The mixture was allowed to cool down to room temperature and the inorganic salts were removed by filtration. The solvent was removed under reduced pressure. The residue was treated with 250 mL acetone and 600 mL isopropyl acetate. The residue partially solidified. The solvent was removed and the residue was treated with 1.5 L water. The crude 4-(3-chloropropoxy)benzophenone crystallized from the medium, was isolated by filtration and dried. 228 g of the crude 4-(3-chloropropoxy)benzophenone was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>>[Br:22][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C#N)cc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1ccc(CBr)c(OC(F)(F)F)c1

Procedure:
4-Methyl-3-Trifluoromethoxybenzonitrile is brominated with NBS according to Example 1A to give 4-bromomethyl-3-trifluoromethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 4.51 (s, 2H), 7.55 (br s, 1H), 7.59 (d, J=8.0z, 1H), 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A 5 ml NMP solution of 352 mg of 4-morpholinoaniline was mixed with 0.95 ml of 4 M hydrogen chloride/1,4-dioxane solution and 400 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, and then the precipitate was collected by filtration. The collected solid was mixed with saturated sodium bicarbonate aqueous solution and extracted with a mixed solution of THF-ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was crystallized by adding methanol and then recrystallized (methanol-THF) to obtain 264 mg of 4-benzylamino-2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidine -5-carboxamide as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]1=[O:22])[NH:8][C:7](=[O:23])[CH2:6][NH:5]2.[OH-].[Na+].O.OO>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]1=[O:21])[NH:8][C:7](=[O:23])[CH:6]=[N:5]2
Reactant: O=C1CNc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc2[nH]c(=O)cnc2cc1F
Yield: 74.9 %

Procedure:
2-(3,4-Dihydro-6-fluoro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.43 g) was added to a mixture of sodium hydroxide (0.16 g), water (2.1 ml) and 30% aqueous hydrogen peroxide (0.21 ml), and the resultant mixture was stirred at room temperature for 16 hours. Ether was added thereto to separate an aqueous layer, which was adjusted to pH 4 with acetic acid. The precipitated crystals were collected by filtration and washed with water to give 2-(6-fluoro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.32 g). m.p., >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (Step 9.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.72 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 521 [M+H]+ (LC-MS 2); Rf=0.16 (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:30])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-Bromo-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methylcyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (8.6 g, 17 mmol) is dissolved in tetrahydrofuran (100 mL) and treated with 3N HCl solution (50 mL). The reaction is stirred at 40° C. for 3 h. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in EtOAc and washed with aq. sat. NaHCO3 solution. The organic layer is separated, dried on Na2SO4, filtered and concentrated to give 5-bromo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid (7.4 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[C:11]#[N:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([N:16]([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[C:11]#[N:12]
Reactant: CNC
Reactant: COC(=O)c1cc(F)ccc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1C#N
Temperature: 65 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a stirred solution of 4.03 g (22.5 mmol) 21a and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 15 h at 65° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 21b was obtained in 89.0% yield (4.09 g, 20.0 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C@@H:6]([CH2:8][C:9]([OH:11])=[O:10])[NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O>[C:16]([NH:7][C@H:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(=O)O)c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
p-Bromo-β-phenylalanine (10.0 g, 41 mmol) was mixed with 40 ml of water and adjusted to pH 14 with 25% sodium hydroxide aqueous solution. After being cooled to 5° C., 8.5 ml of acetic anhydride (90 mmol) and 25% sodium hydroxide aqueous solution were simultaneously dropped into the mixture to keep it at a pH range of 11.5˜12 and the resulting mixture was stirred for 3 hours at a room temperature. After the mixture was adjusted to pH 2 with conc. HCl and stirred for one hour, the resulting precipitated crystal was filtered and dried under reduced pressure to give quantitatively 12.0 g of acetyl-p-bromo-β-phenylalanine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.CO>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7]2/[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]/2=[O:9])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(/C=C2/Oc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 41.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4dimethoxybenzaldehyde 1.23 g were dissolved in acetic acid 20 ml, concentrated hydrochloric acid 1.1 ml was added, and the mixture was stirred for 18 hours, and methanol 15 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.82 g.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>C1COCC1>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:33][C:34]([F:37])([F:36])[F:35]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N(CC(F)(F)F)CC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Tert-butyl 1-oxo-4-phenyl-2,7-diazaspiro[4.5]decane-7-carboxylate (1 g, 3.03 mmol) in THF (13 ml) cooled to 0° C. was treated with sodium hydride (60% in oil) (4.54 mmol, 0.182 g). The reaction mixture was stirred at 0° C. for 5 minutes and stirred at room temperature for 1 hour. The reaction mixture was cooled back down to 0° C. and treated dropwise with 1,1,1-trifluoroethyl trichloromethanesulfonate (0.547 ml, 3.33 mmol) in THF (2 ml). The reaction mixture was stirred at room temperature for 9 hours. The reaction was quenched with water and extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica chromatography, eluting with 0-20% ethyl acetate/iso-hexane. The relevant fractions were combined and concentrated in vacuo to give tert-butyl 1-oxo-4-phenyl-2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-7-carboxylate.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCCC3)ccc2n1CC1CCOCC1
Yield: 43.5 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), piperidine (0.2 mL, 2.0 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 31 mg (45%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40 (m, 2 H), 1.47-1.64 (m, 8 H), 1.65 (s, 9 H), 2.25-2.48 (m, 1 H), 2.92-3.05 (m, 4 H), 3.29-3.39 (m, 2 H), 3.88-3.98 (m, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 7.82 (dd, J=8.69, 1.66 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H), 8.06 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=420.0; Anal. Calcd for C22H33N3O3S+1.10 TFA+0.50H2O+0.10 CH3OH (557.23): C, 52.38; H, 6.42; N, 7.54. Found: C, 52.38; H, 6.43; N, 7.58.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC>[C:24]1([C:22]#[C:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CC2=CCCCC2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (106 mg, 85%); 1H NMR δ (CDCl3): 7.68 (s, 1H), 7.6-7.7.49 (m, 2H), 7.46-7.37 (m, 1H), 6.28 (m, 1H), 2.31-2.12 (m, 4H), 1.73-1.57 (m, 4H); LCMS m/z: 250.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O.[CH3:21]N(C=O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-benzyloxyindole (2.00 g, 8.96 mmol) was dissolved in DMF (20 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 1.2 equivalent, 10.7 mmol, 0.43 g) was added and the mixture stirred for 30 min. lodomethane (1.2 equivalent, 10.7 mmol, 0.67 mL) was added and the reaction stirred at room temperature overnight. The reaction was then poured into water (150 mL) and the precipitated solid collected by filtration. After washing with water and drying, 5-benzyloxy-1-methylindole (1.913 g, 90% yield) was obtained as a white solid.