Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Product: CCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.021 ml butyryl chloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 88 mg of light yellow solid (97%). MS (ISP) 571.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:53])([F:55])[F:54])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([O:44][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:43])[CH2:37][CH2:36]4)[CH2:33][CH2:34]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1
Reactant: COCCOCCO
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol were added to a mixture of 75 mg (0.10 mmol) of (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4.1), 35 mg (0.11 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 1 h at RT. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].N[CH2:22][CH2:23][SH:24].C(O)C>O>[S:24]1[CH2:23][CH2:22][N:2]=[C:1]1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: NCCS
Solvent: CCO
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(C3=NCCS3)[nH]c12)c1cccs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.54 g), 2-aminoethanethiol (0.14 g) and ethanol (20 mL) was stirred at 60° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.19 g, yield 29%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 189-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Fc1cccc(OC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOC4)n3)cc2N1

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (66 mg, 51%). LCMS 485.09 (M+H), HPLC purity 99%. 1H-NMR (CDCl3, 400 MHz) δ 11.99 (s, 1H), 7.92 (s, 1H), 7.52-7.49 (m, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 7.11-7.06 (m, 2H), 7.01 (s, 1H), 6.93 (dd, J=9.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.96 (s, 1H), 3.90-3.86 m, 4H), 2.74-2.70 (m, 4H), 2.35-2.29 (m, 3H), 2.28-2.21 (m, 3H), 2.09-2.06 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:18]=[C:19]([CH2:21][N:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=3)=[CH:11][CH:10]=2)[S:3]1.[H][H]>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:18]=[C:19]([CH2:21][N:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: [H][H]
Reactant: CCCCCCCC(=O)N(C)Cc1cc(-c2ccccc2)cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CCCCCCCC(=O)N(C)Cc1cc(-c2ccccc2)cc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 1(g), starting with 370 mg (7 mmol) of N-[4″-(2,4-dioxothiazolidin-5-ylidene-methyl)[1,1′;3′,1″]terphenyl-5′-ylmethyl]-N-methyl-octanamide in 5 ml of dioxane and under 3 atm of hydrogen, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (6/4), 170 mg (47%) of N-[4″-(2,4-dioxo-thiazolidin-5-ylmethyl)[1,1′;3′,1″]terphenyl-5′-yl-methyl]-N-methyloctanamide are obtained in the form of a pale yellow foam.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O>C(O)C>[F:4][C:5]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1cccc(I)c1F
Agent: Cl
Solvent: CCO
Product: ON=Cc1cccc(I)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
A 50% aqueous solution of hydroxylamine hydrochloride (9 mL, 64.8 mmol) was added to a stirred suspension of 2-fluoro-3-iodobenzaldehyde (preparation 22d, 2.10 g, 8.4 mmol) in ethanol (10 mL) and the mixture was warmed slightly until a solution was formed. After stirring for 3 days at room temperature, the mixture was concentrated in vacuo and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (2.15 g, 97%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[O:23][C:24]=1[CH3:25].COC1C=C(C=C(OC)C=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Agent: COc1cc(C=O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3cc(OC)cc(OC)c3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 1 d]) was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole (prepared from 3,5-dimethoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19](I)=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:17][C:18]1[C:19]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1cc(F)c(I)c(C(=O)O)c1
Product: Cc1cc(F)c(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([OH:31])[C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>CO.CCOC(C)=O>[OH:31][CH:11]([C:12]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][C:7]=2[N:8]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1nc2cc(C#N)ccc2o1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.10 g, 2.54 mmol) and Cs2CO3 (1.65 g, 5.08 mmol) in MeOH (25 mL) was allowed to stir at 60° C. for 4 h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL). The mixture was concentrated to half of the initial volume. The mixture was then diluted with brine and 1M aq. NaHSO4. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 30:70) to give the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (t, J=1.07 Hz, 1H), 7.68 (s, 2H), 7.17 (d, J=3.15 Hz, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 6.53 (d, J=3.15 Hz, 1H), 3.81 (s, 3H), 2.50 (s, 3H). HRMS calcd. for C19H15N3O3 (M+H)+ 334.1192. found 334.1191.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].Cl.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2>CO>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[C:15](=[N:1][OH:2])[CH2:14]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Product: O=C1C(=NO)Cc2cc(F)ccc21

Procedure:
15 ml of isoamyl nitrite and then 7.5 ml of concentrated hydrochloric acid are added dropwise to a solution, heated to 40° C., of 11.2 g of 5-fluoro-1-indanone in 185 ml of methanol. After reaction for 45 minutes at 40° C., the reaction mixture is cooled with ice. A precipitate is formed, which is filtered off and then dried in vacuo, allowing the expected product to be isolated.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.C(OCC)(=O)C.[Cu]I>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cn(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Into a 500-mL round bottom flask, was placed a solution of 4-nitro-1H-imidazole (10 g, 88.50 mmol, 1.00 equiv) in DMSO (50 mL), 1-iodo-3-(trifluoromethyl)benzene (24 g, 88.24 mmol, 1.00 equiv), potassium carbonate (25 g, 181.16 mmol, 2.00 equiv), copper(I) iodide (2.5 g, 13.16 mmol, 0.15 equiv), and L-proline (1.53 g, 13.30 mmol, 0.15 equiv). The resulting solution was stirred overnight at 85° C. in an oil bath. The resulting solution was diluted with 1000 mL of ethyl acetate. The solids were filtered out. The filtrate was washed with 2×500 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3) to yield 6.7 g (28%) of 4-nitro-1-(3-(trifluoromethyl)phenyl)-1H-imidazole as a pale solid.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][CH3:13].CC(N1CCCC(C(C)=O)=C1)C>>[CH2:11]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: CC(=O)C1=CNCCC1
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CCCN1C=C(C(C)=O)CCC1

Procedure:
Methyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and 1-bromopropane according to the procedure of Part (b) of Example 1. The product distilled as a pale yellow (b.pt98-100°C./0.5 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
18.0 g (52.1 mmol) 4-[4-(1-Methoxycarbonyl-ethyl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (VII.1) in 400 mL methanol are hydrogenated for 1 h at rt using 5.55 g (5.21 mmol) Pd/C. After that time, the catalyst is filtered off (celite) and the solvent is evaporated. The residue is purified by column chromatography (silica gel; heptane:EtOAc gradient 100:0->60:40).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 10% Pd--C (5 g) in ethanol (500 ml) is added 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10% Pd--C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (46.7 g) as yellow powder, m.p. 185°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([SH:18])[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].O1CCOCC1.II.S(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][C:7]2[S:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=C(S)C(=O)O)cc1OCC
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc2cc(C(=O)O)sc2cc1OCC

Procedure:
Two grams of β-(3,4-diethoxyphenyl)-α-mercaptoacrylic acid were dissolved in 68.5 ml. of dioxane. To the solution were added 2.74 g. of iodine. The solution was heated at 60°-70° C. for 22 hours. The reaction was then poured into 550 ml. of water, decolorized with 11.0 g. of sodium bisulfite, and stirred vigorously for several minutes. The crude product was collected by filtration and dissolved in approximately 15 ml. of a warm 10% sodium hydroxide solution. The alkaline solution was treated with decolorizing carbon and filtered. The solution was allowed to stand at refrigerator temperature overnight. The resulting pink crystals were collected and dissolved in water. Dilute hydrochloric acid was added and the resulting precipitate was collected to give 0.59 g. of the desired title product. Two recrystallizations from 95% ethanol gave white needles, m.p. 243°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
2-(3,4-Dichlorophenyl)ethyl bromide (5 g, 19.7 mmol) was added slowly to a suspension of magnesium turnings (0.48 g, 19.7 mmol) in ether (30 ml). After spontaneous reflux had finished the mixture was stirred under reflux for 15 minutes and allowed to cool to room temperature. The mixture was added dropwise via cannula to a stirred, cooled (-25° C.) solution of diethyl oxalate (3 g, 20.7 mmol) in THF (15 ml). The mixture was stirred at -10° C. for 30 minutes and allowed to warm to room temperature. Hydrochloric acid (2M, 15 ml) was added and the mixture was extracted with ether (2×20 ml). The combined organic fractions were washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90) to give the title compound (0.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:28](O)[CH2:29][OH:30]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH2:28][CH2:29][OH:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Product: O=C(OCCO)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
3,4-Bis(benzyloxy)benzoic acid was dispersed in ethylene glycol, and heated to 80° C. A catalytic amount of KOH was added to the solution that was left to react until all solids were dissolved. The solution was precipitated into cold water and left to stir for several hours, yielding a white solid. The solid was obtained by filtration, rinsed with water, and then freeze dried.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([N:13]2[CH2:14][CH2:15][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:9][C:8]3=[O:10])[CH2:12]2)=[N:30][CH:29]=1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Reactant: Clc1cnc(Cl)nc1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3ncc(Cl)cn3)C2)C(=O)O1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2,5-dichloropyrimidine at 150° C. for 20 min. LC-MS Method 1 tR=1.51 min, m/z=431,433(M+1); 1H NMR (CD3OD) 8.24(s, 2H), 7.41-7.27(m, 5H), 4.78(m, 1H), 3.71-3.57(m, 2H), 2.73(m, 1H), 2.52(m, 2H), 2.17(s, 2H), 1.24(s, 3H), 0.93(s, 3H).
Reaction SMILES: C([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])C1C=C(C)C=C(C(C)(C)C)C=1O.[CH2:26](C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)[C:27]1[CH:32]=C(C(C)(C)C)C(O)=C(C(C)(C)C)[CH:28]=1.C(C1C(O)=C(C2(C)CCCCC2)C=C(C)C=1)C1C(O)=C(C2(C)CCCCC2)C=C(C)C=1.C(C1C(C)=CC(O)=C(C(C)(C)C)C=1)(C1C(C)=CC(O)=C(C(C)(C)C)C=1)CCC.CC1C=C(O)C(C(C)(C)C)=CC=1C(C1C=C(C(C)(C)C)C(O)=CC=1C)CC(C1C=C(C(C)(C)C)C(O)=CC=1C)C.C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C=1C)(C)(C)C.CC(C1OCC2(COC(C(C)(C)CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)OC2)CO1)(C)CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.C(C1C=C(CCC(NC(=O)C(=O)NC(=O)CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C(C)(C)C)C=1O)(C)(C)C>>[C:27]([C:14]1[C:15]([OH:25])=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1)([CH3:32])([CH3:28])[CH3:26]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CC(C)(C)C2OCC3(CO2)COC(C(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC3)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CCC(=O)NC(=O)C(=O)NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CCCC(c1cc(C(C)(C)C)c(O)cc1C)c1cc(C(C)(C)C)c(O)cc1C
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
distearyl (4-hydroxy-3-methyl-5-t-butyl)benzylmalonate; 2,2'-methylenebis(4-methyl-6-t-butylphenol); 4,4'-methylenebis(2,6-di-t-butylphenol); 2,2'-methylenebis[6-(1-methylcyclohexyl)p-cresol]; bis[3,3-bis(4-hydroxy-3-t-butylphenyl)butyric acid]glycol ester; 4,4'-butylidenebis(6-t-butyl-m-cresol); 1,1,3-tris(2-methyl-4-hydroxy-5-t-butylphenyl)butane; 1,3,5-tris(3,5-di-t-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene; 3,9-bis[1,1-dimethyl-2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]-2,4,8,10-tetraoxaspiro-[5.5]undecane; 1,3,5-tris(3,5-di-t-butyl-4-hydroxybenzyl)isocyanurate and bis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionyl]oxamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[C:17]1([S:23]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3[nH]ccc3c2)CC1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)CC1
Reaction time: 6 h
Yield: 66 %

Procedure:
5-(4-Methylpiperazin-1-yl)-indole (215 mg, 1 mmol), benzenesulfonylchloride (265 mg, 1.5 mmol) and Aliquat 336 (10 mg) were dissolved in DCM (10 mL). Aqueous NaOH (20%, 2 mL) was added and the mixture was stirred vigorously for 6 h. The organic layer was separated, dried and concentrated to give the crude as an oil that was purified on a silica column using DCM and MeOH as eluent. The pure fractions were concentrated to give an oil (260 mg, 0.66 mmol) 1H NMR (CDCl3) δ 2.35 (3 H, s), 2.59 (4 H, t, J=5), 3.18 (4 H, t, J=5), 6.57 (1 H, d, J=4), 6.98–7.03 (2 H, m), 7.38–7.54 (4 H, m), 7.82–7.90 (3 H, m); MS (posES-FIA) 355.1345 M+; Purity (HPLC chromsil C18) >98%.