Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[N:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1)=[O:20])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:23][N:22]=1)=[O:20])[CH3:17]
Reactant: Cn1nnc(-c2ccc(F)cn2)c1CO
Reactant: CCOC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of [5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (416 mg, 2.0 mmol), 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (362 mg, 2.60 mmol) and triphenylphosphine (682 mg, 2.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (40% in toluene, 1.19 mL, 2.6 mmol) dropwise at 0° C. The reaction mixture was then stirred at room temperature for 1 h and then evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (386 mg, 77%) as a white solid after recrystallisation from ethyl acetate. MS: m/e=358.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:1]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1ccccc1C(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccccc1C(=O)C=CN(C)C
Yield: 63.6 %

Procedure:
A suspension of 48 g of N-[2-(1-oxo-1-ethanyl)phenyl]acetamide and 38 g of N,N-dimethylformamide dimethyl acetal in 150 ml of toluene was heated at reflux for about 16 hours, then concentrated in vacuo to a solid. The solid was recrystallized from 1-chlorobutane to yield 40 g of the title compound; m.p. 90°-95° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH:17]=[O:18])[N:6]=[CH:5]1)[CH2:2][CH3:3].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>>[C:11]1([C:10]#[C:9][C:8]2[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][N:6]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:34][N:35]=[N:36][N:37]=4)=[CH:23][CH:22]=3)[C:7]=2[CH:17]=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCn1cnc(C=O)c1C#Cc1ccccc1
Product: CCCN1CN(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C(C=O)=C1C#Cc1ccccc1

Procedure:
3-n-Propyl-4-(phenylethynyl)imidazole-5-carboxaldehyde was alkylated with 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl by the procedure described in example 1, parts D and I, to yield the entitled product. NMR (CDCl3) δ 9.88 (s,1H): 8.03 (m,1H); 7.57-7.27 (m,8H); 7.17 (m,2H); 7.01 (m,2H); 5.55 (s,2H); 2.61 (t,2H); 1.75 (m,2H); 0.99 (t,3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:30]3[C:22]([CH3:21])=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1OC
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1OC

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridine (29.50 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.63 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (23 mg, 57%). (HPLC (method F): 92%, RT: 3.82 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.13 (s, 1H), 8.50 (s, 1H), 7.94 (d, J=5.5, 1H), 7.52 (dd, J=8.4, 1.8, 1H), 7.38 (dd, J=10.5, 7.8, 2H), 7.31 (t, J=4.1, 2H), 7.06 (d, J=8.5, 1H), 7.01 (d, J=8.5, 1H), 6.52 (s, 1H), 6.12 (d, J=5.5, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H); MS (m/z) 400 [M+H]+, RT: 3.6 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Clc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
200.0 mg of the target compound (0.55 mmol, 67.2%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1C=C(C=CN=1)C(O)=O)([CH3:3])[CH3:2].N[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27]N=1)[C:21]([O:23]CC)=[O:22].NC1C=CC(C(OC)=O)=CC=1>>[CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)c1ccnc(N)c1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)NC(=O)Nc1ccc(C(=O)O)cc1

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl 4-aminobenzoate; [M+H]+ 237.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8].[O:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.C([O-])(O)=O.[Na+].[NH4+].[Cl-]>CC(O)(C)C.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:10](=[O:9])[NH:7][C:5]1[S:6][C:2]([I:1])=[C:3]([CH3:8])[N:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1nc(N)sc1I
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
The above prepared 5-iodo-4-methyl-thiazol-2-ylamine (2.768 g, 12 mmol) was dissolved in 30 mL of tBuOH and treated successively with BOC2O (3.02 g, 1.2 eq.), DMAP (0.141 g, 0.1 eq.), and NaHCO3 (3.39 g, 3.5 eq.). After stirring for 18 h at ambient temperature, the reaction mixture was poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Ensuing flash chromatography (SiO2, hexane/ethyl acetate=8/2), yielded finally 2.383 g of the title compound as off-white foam.
Reaction SMILES: [CH2:1]([NH:9][C:10](=O)[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:11][C:10]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][N:9]=1
Reactant: CC(=O)NCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccccc21

Procedure:
In close analogy to the procedure described above, N-phenethyl-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:23])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (500 mg) was dissolved in chloroform (20 mL), and oxalyl chloride (500 mg) and a catalytic amount of DMF were added, followed by stirring at room temperature for 3 hours. Under reduced pressure, the solvent and an excess reagent were distilled off to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride (520 mg) as an oily product.
Reaction SMILES: CI.[C:3]([C:7]1[CH:8]=[C:9]([C:25](=[O:27])[CH3:26])[CH:10]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][O:22][CH3:23])[C@H:17]([OH:24])[CH2:16]2)[C:12]=1[O:13][CH3:14])([CH3:6])([CH3:5])[CH3:4].[C:28]1(C)C=CC=CC=1.C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:3]([C:7]1[CH:8]=[C:9]([C:25](=[O:27])[CH3:26])[CH:10]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][O:22][CH3:23])[C@H:17]([O:24][CH3:28])[CH2:16]2)[C:12]=1[O:13][CH3:14])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccccc1
Reactant: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1OC
Reaction time: 64 h
Yield: 77 %

Procedure:
Tetra-n-butylammonium bromide (227 mg, 0.704 mmol) and methyl iodide (0.18 ml, 2.9 mmol) were added to a mixed solvent of 1-{3-(tert-butyl)-5-[(3R,4R)-3-hydroxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (496 mg, 1.41 mmol) in a toluene (3 ml) −50% aqueous NaOH (3 ml) mixed solvent in that order at room temperature and the mixture was stirred for 64 hours. It was then diluted with water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (397 mg, 77%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=O)[C:5](=[O:11])[NH:6][C:7]=1[CH:8]([F:10])[F:9].[NH2:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])=[O:14])[C:5](=[O:11])[NH:6][C:7]=1[CH:8]([F:9])[F:10]
Reactant: COCC(C)N
Reactant: COC(=O)c1cc(Br)c(C(F)F)[nH]c1=O
Agent: Cl
Product: COCC(C)NC(=O)c1cc(Br)c(C(F)F)[nH]c1=O

Procedure:
At room temperature, 334 mg (1.19 mmol) of methyl 5-bromo-6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate in 3.3 ml (41 mmol) of 2-amino-1-methoxypropane were stirred for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 360 mg (89% of theory) of the product.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH2:12][N:24]3[CH2:25][CH2:26][CH:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccn(-c2ccccc2)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CC2CCN(Cc3ccn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL of methanol was added 525 mg of 4-benzylpiperidine, 175 mg of 4-benzylpiperidine. HCl and 63 mg of sodium cyanoborohydride. The reaction mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 50 mL of ethyl acetate, then washed successively with 50 mL aliquots of 10% sodium hydroxide and water. The ethyl acetate extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 1-phenyl-3[(4-benzylpiperidin-1-yl)methyl]pyrrole, which was purified by chromatography on silica gel using 5% methanol in dichloromethane as elvent. On evaporation of the solvent, the free base was dissolved in ethanol and treated with 1 equivalent of maleic acid. The 1-phenyl-3[(4-benzyl-piperidin-1-yl)methyl]pyrrole maleate salt (compound 7) had a melting point of 159°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][O:26][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:22][CH2:23]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N2CCC(CCO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol (0.93 g), which was prepared in the similar method as shown in example 1, in CHCl3 (10 mL), was added methanesulfonyl chloride (0.47 g) and pyridine (0.64 g) and the mixture was stirred at room temperature for 3 hours. Water was added into the reaction mixture and the mixture was extracted with CHCl3. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oil. The oily product was crystallized from diisopropylether to obtain methanesulfonic acid 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl ester (1.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([N:6]1[C:10]([CH:11]([C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)O)=[C:9]([CH3:23])[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=[O:5])=[O:4].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[CH3:31][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH2:11][C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)=[C:9]([CH3:23])[N:8]=[CH:7]1)(=[O:4])=[O:5]
Reactant: Cc1nc([Si](C)(C)C(C)(C)C)n(S(=O)(=O)N(C)C)c1C(O)c1ccc2c(c1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1ncn(S(=O)(=O)N(C)C)c1Cc1ccc2c(c1)OCCO2
Temperature: -78 °C

Procedure:
A solution of the above ethyl ester 3 (1.0 g, 5.9 mmol) was dissolved in hexanes (50 mL) and cooled to −78° C. A solution of DIBAL (5.8 mL 1.0 M in cyclohexane) was added dropwise. After 15 m, diethyl ether (50 mL) was added and the mixture was stirred with Rochelle's salt solution (25 mL) for 10 m. The organic layer was separated, dried and filtered. Chromatography on SiO2 with 7% Et2O:Hx delivered the aldehyde as a clear colorless oil, 0.52 g (74%). The aldehyde 4 was subjected to the Büchi protocol as described above. The fumarate salt of the imidazole 5 (U-1) was obtained in three steps (25% overall).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.NC(N)=O.[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)Cl>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: C1=CSCC1
Reactant: O=S(=O)(O)Cl
Agent: NC(N)=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccs1
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
2-H-thiophene-urea (85 mg, 0.27 mmol), available from Step C of Preparative Example 16.3, was partially dissolved in methylene chloride (4 mL and added dropwise to a stirred solution of chlorosulfonic acid (0.09 mL, 1.35 mmol) in 4 mL of methylene chloride at room temperature. After 10 min, the mixture was poured into crushed ice and extracted with ethyl acetate several times. The extracts were washed with water and brine, dried with sodium sulfate, and concentrated to give the corresponding thiophene sulfonyl chloride as a greenish oil (45 mg) used in next step directly.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14].[OH-].[K+].OO.C(O)(=[O:23])C>O>[NH2:9][C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:5][C:6]=1[C:7]([OH:14])=[O:23]
Reactant: CC(=O)O
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed in water (35 mL) and cooled to 0° C. With vigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) was added drop-wise keeping the temperature below 10° C. After stirring 1 hour at 0° C., glacial acetic acid (22 mL) was added drop-wise, causing foaming and formation of a precipitate. The contents were stirred overnight and filtered to afford the 2-amino-5-trifluoromethoxybenzoic acid as an amber solid (12.5 g, 87%). A small amount was recrystallized from ethyl acetate-hexanes to afford amber needles for an analytical sample and the remaining compound was used without further purification: mp 142.5-144.2° C. 1H NMR (CDCl3, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J=8.0 Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C8H6NO3F3 : C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35.
Reaction SMILES: P(C#N)(=O)(OCC)OCC.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[CH2:18][C:17]([C:24]([OH:26])=O)=[CH:16]2.[ClH:27].Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.Cl>C(O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:27].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[CH2:18][C:17]([C:24]([N:38]1[CH2:37][CH2:36][N:35]([CH2:34][C:33]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:40][CH2:39]1)=[O:26])=[CH:16]2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)CC(C(=O)O)=C2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2
Temperature: 0 °C
Yield: 79 %

Procedure:
Diethyl phosphorocyanidate (0.9 g) is added dropwise to an ice-cooling mixture consisting of 5,6-dimethoxy-1H-indene-2-carboxylic acid (0.8 g), 1-(3,4,5-trimethyoxybenzyl)piperazine dihydrochloride (1.3 g), triethylamine (2 ml) and N,N-dimethylformamide (12 ml) with stirring. The whole mixture is stirred at room temperature for two hours and water is added. The mixture is extracted with ethyl acetate. The extract solution is washed with water, dried and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:hexane:acetone=12:8:5) to give an oily product. This product is converted to the hydrochloride in ethanol to afford 1-(5,6-dimethoxy-1H-inden-2-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.45 g) as colorless scales, m.p. 245°-250° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[C:13]1[CH:17]=[C:16](C)[NH:15][C:14]=1[CH:19]=O.N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:19][C:14]1[NH:15][CH:16]=[CH:17][CH:13]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc[nH]1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 5-chlorooxindole (6.98 g, 41.6 mmol), 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (5.12 g, 41.6 mmol) and piperidine (410 μL, 4.16 mmol) in 200 mL of EtOH was heated at reflux for 8 h. The reaction mixture was cooled to room temperature and filtered to give the title compound (4.50 g, 40%) as a red/orange solid.
Reaction SMILES: BrBr.C[C@@H]1C2C(=CC=CC=2)C[C@@H]1C(=O)C.[Br:16][C:17]1([C:27](=[O:29])[CH3:28])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]1[CH3:26].[Br:30]CC([C@H]1CC2C(=CC=CC=2)[C@H]1C)=O>C(Cl)Cl>[Br:30][CH2:28][C:27]([C:17]1([Br:16])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]1[CH3:26])=[O:29]
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)CBr
Reactant: CC(=O)C1(Br)Cc2ccccc2C1C
Agent: BrBr
Agent: CC(=O)[C@H]1Cc2ccccc2[C@H]1C
Solvent: ClCCl
Product: CC1c2ccccc2CC1(Br)C(=O)CBr

Procedure:
Bromine in methylene chloride is slowly added to a stirred solution of cis-1-(2,3-dihydro-1-methyl-1H-inden-2-yl)ethanone (34.8 g) in methylene chloride (835 ml), while keeping the temperature at +10° C. The reaction is followed by GLC. The first products are the isomers of 1-(2-bromo-2,3-dihydro-1-methyl-1H-inden-2-yl)ethanone and cis-2-bromo-1-(2,3-dihydro-1-methyl-1H-inden-2-yl)ethanone. When the added amount of bromine is about 0.3 mol, only the final product, 2-bromo-1-(2-bromo-2,3-dihydrol-methyl-1H-inden-2-yl)ethanone is visible in the chromatogram and the mono bromo products cannot be seen in the chromatogram any more. The methylene chloride solution is washed with water, then several times with the diluted NaHCO3 solution and finally with water. The solvent is dried with Na2SO4 and evaporated to dryness.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])=[CH:3]1.[Br-].[Li+]>C(#N)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(C2CCCCNC2=O)CCC1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: O=C1NCCCCC1c1cccc(O)c1
Yield: 57.5 %

Procedure:
A mixture of hexahydro-3-(3-oxocyclohexen-1-yl)-2H-azepin-2-one (20.73 g), cupric bromide (44.9 g) and lithium bromide (8.8 g) was refluxed in acetonitrile (1000 ml) for 1 hour. Evaporation of the solvent left a black gum which was triturated with an excess of 2 N sodium hydroxide solution. The resulting orange suspension was filtered through Kieselguhr, and the filtrate acidified (conc.HCl). The white suspension was extracted several times with chloroform, and the residue left on evaporation of the organic layers was crystallised from ethyl acetate to give 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (11.8 g) m.p. 175°-178° C.