Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34].[OH-].[Na+]>C(Cl)Cl.O>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)=[O:9])[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc2[nH]c(S(=O)Cc3nccc(C)c3C)nc2c1C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
m-Chloroperbenzoic acid, 91% (0.53 g, 0.0028 mol) dissolved in CH2Cl2 (25 ml) and cooled to -10° C. was added under stirring to 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.91 g, 0.0028 mol) dissolved in CH2CI2 (50 ml) maintaining the temperature at -5° C. Stirring was continued at -5° C. for 5 min and then NaOH (0.34 g, 0.0085 mol) dissolved in water (25 ml) was added under vigorous stirring. The two phases were separated and the aqueous phase was washed with CH2Cl2 (10 ml). More CH2Cl2 (50 ml) was added to the aqueous phase, the pH was adjusted to 9.5 by adding 2M HCl and after stirring the phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated off giving an oil which was crystallized from CH3CN (15 ml) yielding the desired product (0.3 g, 32%), m.p. 161° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:25]([OH:34])=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[C:25]([OH:34])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: Cc1ccc(B(O)O)c(O)c1C
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 12.40,(1H, b), 8.38,(1H, d), 8.31,(1H, d), 8.28-8.20,(2H, m), 8.14,(1H, d), 8.09,(1H, d), 7.86,(1H, d), 7.66,(1H, s), 7.00,(1H, d), 6.94,(1H, d), 6.81,(1H, d), 3.82,(3H, s), 2.30,(3H, s), 2.19,(3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=C1NCCN1c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
To a solution of 150 g of 1-(3-pyridyl)-2-imidazolidinone dissolved in 1500 ml of N,N-dimethylformamide was added 40 g of sodium hydride (60% oily dispersion). After the mixture was stirred at room temperature for 10 minutes, 154 g of cinnamyl chloride (trans-form) was added dropwise under ice-cooling and the mixture was stirred for 2 hours. After addition of 10 ml of acetic acid, the solvent was distilled off under reduced pressure and to the residue was added water, followed by extraction with chloroform. After washing with saturated aqueous sodium hydrogen carbonate and saturated saline water, the extract was dried. Chloroform was distilled off, and isopropyl ester was added to the residue. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 238.1 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone as colorless prisms.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:20])[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([NH:1][CH:2]([CH:10]([OH:20])[CH:11]([NH:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of the resultant compound of Example 12 (0.049 mmol) and 0.032 ml (0.29 mmol) of 4-methylmorpholine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.008 ml (0.10 mmol) of methanesulfonyl chloride. After 0.5 h, the solution was washed with 10% aqueous citric acid, dried over Na2SO4, and concentrated. Flash chromatography using 5% methanol in chloroform gave 2.6 mg (13%) of the desired compound. 1H NMR (CDCl3) δ 2.16 (s, 3 H), 2.34 (s, 3H), 2.93 (m, 4H), 3.41 (d, J=4 Hz, 1H), 3.7-3.8 (m, 2H), 3.92 (m, 1H), 5.06 (d, J=9 Hz, 1H), 5.42 (d, J=9 Hz, 1H), 7.2-7.4 (m, 10H). Mass spectrum (M+NH4)+ =444.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[C:27]([CH3:29])([CH3:28])[N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:37])[CH2:9]2)=[CH:4][CH:3]=1.[ClH:40]>CO.CCOCC>[ClH:40].[ClH:40].[F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[C:27]([CH3:28])([CH3:29])[NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:37])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)C(C)(C)N(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)C(C)(C)NCC2
Reaction time: 18 h

Procedure:
tert-Butyl 7-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-1,1,5-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (106 mg, 0.240 mmol) was dissolved in MeOH (5.00 mL), and 2 M HCl in Et2O (1.20 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was separated, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Purification by preparative thin layer chromatography (silica gel, 90:9:1 CH2Cl2/MeOH/NH4OH) gave the free base of the title compound (19.0 mg) as a white solid. The free base was dissolved in MeOH (2.00 mL) and treated with 1.25 M HCl in MeOH (0.108 mL). The mixture was concentrated to provide the title compound (22.0 mg, 17%) as an off-white solid. Free Base: 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=8.5 Hz, 1H), 7.21-7.17 (m, 3H), 7.02-6.94 (m, 3H), 3.75 (t, J=5.0 Hz, 2H), 3.59 (s, 3H), 3.43 (s, 2H), 3.26 (t, J=5.5 Hz, 2H), 2.90 (t, J=5.5 Hz, 2H), 2.86-2.82 (m, 2H), 2.74-2.69 (m, 4H), 1.55 (s, 6H); HPLC (Method B) 97.0% (AUC), tR=10.7 min. HCl salt: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.39-7.35 (m, 2H), 7.12-7.06 (m, 3H), 4.20-4.04 (m, 4H), 3.71-3.65 (m, 7H), 3.45-3.44 (m, 2H), 3.17-3.14 (m, 4H), 1.85 (s, 6H); ESI MS m/z 435 [M+H]+; HPLC (Method B) 95.2% (AUC), tR=10.8 min.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.Cl[C:11]1C(Cl)=CC=[CH:14][C:12]=1[NH2:13]>>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]2[C:3]=1[CH2:11][CH:12]([NH2:13])[CH2:14]2
Reactant: Nc1cccc(F)c1Cl
Reactant: Nc1cccc(Cl)c1Cl
Product: NC1Cc2ccc(F)c(Cl)c2C1

Procedure:
Substituting 2-chloro-3-fluoroaniline as a starting material for 2,3-dichloroaniline and following the procedure of Example 1 yields 4-chloro-5-fluoro-2-indanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:18]([NH:25][C@H:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:18]([NH:25][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C2CCCC(=O)C2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2CCC[C@H](NCc3ccccc3)C2)cc1OC
Product: COc1ccc([C@H]2CCC[C@H](NCc3ccccc3)C2)cc1OC
Temperature: 25 °C
Yield: 32.4 %
Yield: 33.2 %

Procedure:
3-(3,4-Dimethoxyphenyl)cyclohexanone (6.90 g) and benzylamine (3.16 g) were refluxed for 1.5 hours in benzene (150 ml) in the presence of para-toluenesulfonic acid (630 mg), using a Dean-Stark apparatus while removing the water generated. After distilling off the benzene under reduced pressure, it was dissolved in methanol (120 ml) while cooling on ice, sodium borohydride (1.12 g) was gradually added and the mixture was stirred at room temperature for an hour. After concentrating the reaction solution, water was added, extraction was performed with chloroform, and the solution was washed with saturated sodium bicarbonate water and saturated saline. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to produce a light yellow oily substance which was then separated and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1→1:2), to give 3.16 g of (trans)-N-benzyl-N-[3-(3,4-dimethoxyphenyl) cyclohexyl]amine (33.2% yield) and 3.09 g of (cis)-N-benzyl-N-[3-(3,4-dimethoxyphenyl)cyclohexyl]amine (32.4% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([O:62][Si](C(C)(C)C)(C)C)[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([OH:62])[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 56.2 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.6 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 20.8 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6' "-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][O:19][CH2:20][CH3:21])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][O:19][CH2:20][CH3:21])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylate (3.25 g, 10.8 mmol) in tetrahydrofuran (58.7 mL), methanol (58.7 mL) and water (12.6 mL) was added lithium hydroxide monohydrate (0.731 g, 17.42 mmol). The pink mixture was heated to reflux overnight. The organic solvents were removed in vacuo and the aqueous layer was washed once with ether and then acidified slowly with concentrated HCl until the pH reached 4. The resulting suspension was extracted with methylene chloride three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product as a mixture of two cis/trans isomers (2.75 g, 89%). MS calculated for C14H24NO5: (M+H) 286.2; found 186.2 (M+H-Boc).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10]1=[O:28].Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[C:42]1([CH:48]2[CH2:52][N:51]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:50](=[O:59])[NH:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10](=[O:28])[C@H:9]([NH:8][C:30]([N:56]2[CH2:55][CH2:54][CH:53]([N:51]3[CH2:52][CH:48]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:49][C:50]3=[O:59])[CH2:58][CH2:57]2)=[O:31])[CH2:15][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: O=C1NC(c2ccccc2)CN1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(N3CC(c4ccccc4)NC3=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Triethylamine (0.012 mL, 0.084 mmol) was added to a solution (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one (25 mg, 0.084 mmol) and p-nitrophenyl chloroformate (25 mg, 0.126 mmol) in tetrahydrofuran (1 mL) at 0° C. After 0.5 h, triethylamine (0.036 mL, 0.252 mmol) and 4-phenyl-1-piperidin-4-yl-imidazolidin-2-one (31 mg, 0.126 mmol) were added and the mixture was allowed to warm to ambient temperature. After 1 h, the mixture was quenched with water, extracted with dichloromethane, and washed with 1 N NaOH solution. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0.5% methanol/dichloromethane→6% methanol/dichloromethane) gave the title compound (11 mg). MS 570.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1c(Cl)cncc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2oc(-c3c(Cl)cncc3Cl)nc2c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 0.35 g of 3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide, 5 ml of carbon tetrachloride, 0.78 g of triphenylphosphine and 0.30 g of triethylamine was heated to reflux for three hours. The mixture was cooled to room temperature, and then water was added to the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 17”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37])[CH3:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:37][CH2:36][C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH2:31][CH3:32])=[O:29]
Reactant: CCOc1ccccc1CN
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: O=C(Br)CBr
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)cc(OC)c2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].Cl.[NH2:8]O.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]>CO>[Br:10][C:11]1[CH:12]=[C:13]([C:14]2[N:8]=[C:2]([CH3:1])[O:4][N:15]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cccc(Br)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1nc(-c2cccc(Br)c2)no1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Potassium tert-butoxide (7.33 g, 65.4 mmol) was added over 5 minutes to ice chilled, stirred methanol under argon. After a further 5 min hydroxylamine hydrochloride (4.9 g, 70.43 mmol) was added in one portion and the resultant mixture stirred at room temperature for 1 h. A solution of 3-bromobenzonitrile (7.93 g, 43.6 mmol) in methanol (120 ml) was added in one portion and the mixture heated at reflux for 4 h, cooled filtered, and the filtrate evaporated in vacuo. The residue was refluxed in acetic anhydride (60 ml) for 3 h, cooled to room temperature and poured into ice-water (300 ml). The precipitate was filtered, washed with water, dried in vacuo and chromatographed on silica eluting with 0-10% ethyl, acetate-hexane gradient. Fractions containing desired product were pooled and evaporated in vacuo and the residue recrystallised from hexane to afford the title compound as colourless crystals (5.2 g, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1CCO
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1CCO
Yield: 79.1 %

Procedure:
A solution of 2-(3-nitropyridin-4-yl)ethanol (24) (WO 2006136562) (2.00 g, 11.89 mmol) in MeOH (150 mL) was passed through a Thales H-cube (2.0 mL·min−1, 30° C., 30 bar, Pd/C Cat-Cart, 55 mm, controlled mode). Analysis by LC-MS showed a significant amount of starting material was still present and the solution was passed through the H-cube twice more (2.0 mL·min−1, full hydrogen mode, RT, and 2.0 mL·min−1, full hydrogen mode, 40° C.). Evaporation of the volatiles gave the title compound (25) as a purple oil (1.30 g, 81%): m/z 139 (M+H)+ (ES+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>CN1CCN(C)C1=O.O1CCCC1>[CH2:26]([S:29]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:31])=[O:30])[CH2:27][CH3:28]
Reactant: CCCS(=O)(=O)Cl
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
5.53 g of triethylamine was added to 6.03 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of 1,3-dimethyl-2-imidazolidinone, and then 5.10 g of propanesulfonyl chloride dissolved in 20 ml of tetrahydrofuran was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The precipitated crystals were recrystallized from methanol-acetonitrile to obtain 5.34 g of 2-(propylsulfonylaminomethyl)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane
Reaction SMILES: [CH2:1]([OH:6])[C:2]([Br:5])([Br:4])[Br:3].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].O>C(OCC)C>[Br:3][C:2]([Br:5])([Br:4])[CH2:1][O:6][C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: OCC(Br)(Br)Br
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)OCC(Br)(Br)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A first solution including tribromoethanol (50 g, 177 mmol) and triethylamine (19.73 g, 195 mmol) dissolved in 50 g of diethylether was prepared. A second solution comprising acryloyl chloride (17.65 g, 195 mmol) dissolved in 50 g of diethylether was added dropwise to the first solution followed by stirring for four hours at room temperature. The resulting solution was then added to water, and the organic phase was extracted. The organic phase was distilled to yield 48.38 g of TBEA (72.5% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.4 %

Procedure:
To a 0° C. solution of a solution of COMPOUND 249 (150 mg, 0.483 mmol) in CH2Cl2 (10 mL) and DIPEA (0.170 mL, 0.966 mmol) was added methyl bromoacetate (0.055 mL, 0.579 mmol), and the reaction mixture was stirred for 17 hr at room temperature. Saturated NaHCO3 (10 mL) was added to the reaction mixture, which was then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by radial chromatography on silica gel (20:1:0.5 CH2Cl2:MeOH:NH4OH) to give {4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-acetic acid methyl ester (154 mg, 83%). 1H NMR (CDCl3) δ 1.86-1.92 (m, 4H), 1.98-2.07 (m, 2H), 2.08 (s, 6H), 2.45-2.50 (m, 1H), 2.96-2.99 (m, 2H), 3.17 (s, 2H), 3.71 (s, 3H), 3.83 (s, 4H), 7.07 (dd, 2H, J=4.8, 7.5 Hz), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz).