Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27](=[O:29])[CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:26](/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)\[C:27](=[O:29])[CH3:28])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)/C(=C\c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 3-benzyloxy-4-nitrobenzaldehyde (83, step A) (1.16 g, 4.5 mmol) and 1-phenylpropane-2-one (0.726 g, 5.4 mmol) in toluene (50 mL) is added a catalytic amount of piperidine/glacial acetic acid and the mixture is refluxed for 3 h using a Dean-Stark apparatus. The mixture is cooled to room temperature and concentrated under reduced pressure. The crude material is purified by flash chromatography using a gradient of 15-50% EtOAc/hexane as eluent to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[C:15]([Br:22])[N:14]=1>CN(C)C=O>[Br:12][C:13]1[CH:18]=[C:17]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)[CH:16]=[C:15]([Br:22])[N:14]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Sc2cc(Br)nc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
1.0 g (0.0056 mol) of 3-trifluoromethylthiophenol was dissolved in 17 ml of dimethylformamide and treated with 0.64 g (0.0056 mol) of potassium tert.-butylate. The mixture was stirred at room temperature for 20 min. and then treated with 1.58 g (0.0056 mol) of 2,6-dibromo-4-nitro-pyridine. The mixture was stirred at room temperature for 3 hrs., the solvent was then removed and the residue was partitioned in water and ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and, after removal of the solvent, the residue was chromatographed on silica gel with ethyl acetate/hexane 1:39. There was obtained 2.08 g (90%) of 2,6-dibromo-4-(3-trifluoromethylphenylsulphanyl)-pyridine as yellow crystals; m.p.: 68-70° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[C:6]([CH3:10])([CH3:9])[C:5](=[O:11])[CH2:4][C:3]1=[O:12].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:34][CH3:35])=[C:31]([Pb+3])[CH:32]=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>ClCCl.Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:34][CH3:35])=[C:29]([CH:4]2[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7](=[O:8])[C:6]([CH3:9])([CH3:10])[C:5]2=[O:11])[CH:28]=1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 80 °C
Yield: 63.9 %

Procedure:
To a mixture of 2,2,4,4-tetramethylcyclohexane-1,3,5-trione (0.6 g, 3.6 mmol), 5-bromo-2-ethylphenyllead triacetate (2.27 g, 4.00 mmol) and N,N-dimethylaminopyridine (2.22 g, 18 mmol) is added anhydrous chloroform (25 ml) and toluene (6.3 ml), and the reaction mixture is heated at 80° C. for 3 hours. The mixture is diluted with dichloromethane (50 ml) and 2M aqueous hydrochloric acid (100 ml), and filtered through diatomaceous earth to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, washed with brine, dried over anhydrous magnesium sulphate then filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography to give 6-(5-bromo-2-ethylphenyl)-2,2,4,4-tetramethylcyclohexane-1,3,5-trione as a white solid (0.84 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[C:37]2[O:36][CH2:35][CH2:34][O:33][C:32]=2[CH:31]=[CH:30][CH:29]=1>>[O:33]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:27][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:23]([C:18]4[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=4)(=[O:25])=[O:24])[N:9]=3)[C:37]=2[O:36][CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1cccc2c1OCCO2
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc4c3OCCO4)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=470.3 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 5-amino-1,4-benzodioxane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: Cc1nc(Oc2ccc(F)c(F)c2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nc(Oc2ccc(F)c(F)c2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.054 g, 0.305 mmol) in dichloroethane (2 mL) was added 2-[(3,4-difluorophenyl)oxy]-4-methyl-1,3-thiazole-5-carbaldehyde (0.072 g, 0.282 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.092 g, 0.434 mmol). The mixture was stirred for 5 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a yellow solid (0.077 g, 51%). 1H NMR (400 MHz, DMSO-d6): δ 7.59-7.47 (m, 2H), 7.18 (m, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 4.23 (s, 2H), 2.47 (m, 1H), 2.17 (s, 3H), 1.59 (m, 1H), 1.29 (m, 1H), 1.18 (m, 1H). ES-MS m/z 416.98 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH2:22]>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2](/[CH:22]=[CH:21]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:3]=3)[N:8]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C=Cc1ccccn1
Product: Cc1ccc(CNc2ccc3cc(/C=C/c4ccccn4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=342.3 (M+H+), was prepared in accordance with the general method of example 2 from 6-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-vinylpyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:14])([F:13])[S:9]([OH:12])(=[O:11])=[O:10].[F:15]F>C(#N)C>[F:7][C:8]([F:14])([F:13])[S:9]([O-:12])(=[O:11])=[O:10].[F:15][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FF
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: c1ccncc1
Solvent: CC#N
Product: F[n+]1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -20 °C
Yield: 97.4 %

Procedure:
To 40 ml of acetonitrile as solvent were added 1.592 g (20.136 mmol) of pyridine and 2.940 9 (19.588 mmol) of trifluoromethanesulfonic acid (i.e., the amount of pyridine was 1.03 times that of trifluoromethanesulfonic acid in a molar ratio), and the mixture was cooled to -20° C. A mixed gas of fluorine and nitrogen in a volumetric ratio of 1:4 was then introduced to the mixture at a rate of 50 ml/min under stirring. The amount Of fluorine gas introduced was 40.0 mmol. Alter completion of the reaction, the solvent was distilled off, and 4.716 g (19,097 mmol) of N-fluoropyridinium trifluoromethanesulfonate was obtained by crystallizing with ether. The yield was 97.4%. Characteristics and spectrum data of the compound are shown as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12]Br.Br>C(O)(=O)C.O>[Br:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1Br

Procedure:
Bromination of 5-chloro-1-indanone in glacial acetic acid with bromine and with addition of catalytic amounts of 48% strength HBr solution in water affords 2-bromo-5-chloro-1-indanone with a melting point of 94-96° C. A little of the corresponding dibromo compound is obtained as byproduct.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH3:19].ClCCl.CO>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH3:19]
Reactant: CCI
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOc1ccc2[nH]ccc2c1
Temperature: 50 °C
Yield: 90 %

Procedure:
A mixture of commercially available 5-hydroxy-indole (18 g, 13.5 mmol), anhydrous K2CO3 (93.5 g, 5 equiv) and iodoethane (40.5 ml, 3.75 equiv) in acetone (180 mL) is stirred at 50° C. under argon. When TLC (dichloromethane-methanol, 95:5) indicates the disappearance of 5-hydroxy-indole (4 days), the mixture is filtered, the solid is washed with acetone, then the filtrate is concentrated to give 17.67 g (90%) of the title compound, which is sufficiently pure to be used in the next step. M.p. 144-146° C. (from ethanol).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCNCC2)C3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 37, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrimidine in dimethylsulfoxide at 110° C. in the presence of potassium carbonate. LC (method 5): tR=1.28 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li][CH2:9]CCC.[C:13]([Si:17]([CH3:45])([CH3:44])[O:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:23]1=[O:43])([CH3:16])([CH3:15])[CH3:14].CI>C1COCC1>[C:13]([Si:17]([CH3:45])([CH3:44])[O:18][CH2:19][CH2:20][CH2:21][C@:22]1([CH3:1])[O:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[C:23]1=[O:43])([CH3:14])([CH3:15])[CH3:16].[C:13]([Si:17]([CH3:45])([CH3:44])[O:18][CH2:19][CH2:20][CH2:21][C@@:22]1([CH3:9])[O:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[C:23]1=[O:43])([CH3:14])([CH3:15])[CH3:16]
Reactant: [Li]CCCC
Reactant: COc1ccc(CN2C(=O)C(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Reactant: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2C(=O)[C@@](C)(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Product: COc1ccc(CN2C(=O)[C@](C)(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropyl amine (138 mg, 1.36 mmol, 1.3 equiv) in THF (6.0 mL) at −78° C. was added n-BuLi (0.79 mL, 1.6 mL in heptane, 1.26 mmol, 1.2 equiv) and the resulting solution was stirred at −78° C. for 10 minutes. To the solution was added a solution of 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (500 mg, 1.05 mmol, 1.0 equiv) in THF (2 mL) and the solution was stirred at −78° C. for 30 mins. MeI was added and the solution was stirred at −78° C. for 1 hour then slowly warmed to room temperature over 2 hours. The reaction was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 20% to give product (S)-2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-one 110 mg and product (R)-2-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-one 205 mg.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=3)[NH:6][C:5]=2[CH:10]=1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3cc(F)c(F)cc3[nH]2)c1C

Procedure:
A suspension of 23 g of 5,6-difluoro-2-benzimidazolethiol in 740 ml of alcohol was treated with 22.1 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. A solution of 10 g of sodium hydroxide in 350 ml of water was added dropwise thereto while cooling with ice, the mixture was left to boil at reflux overnight and then concentrated to about 1/3 of its volume in a vacuum. After the addition of 1200 ml of water the crystals were filtered off and thereupon washed thoroughly first with water and then with ether. There was obtained 5,6-difluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 216°-218°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:18]O)[CH:15]=[CH:16][CH:17]=2)=[N:5][C:4]([NH2:20])=[N:3]1.P(Br)(Br)[Br:22]>C(Cl)Cl>[BrH:22].[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Br:22])[CH:13]=2)=[N:5][C:4]([NH2:20])=[N:3]1
Reactant: BrP(Br)Br
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CO)c1
Solvent: ClCCl
Product: Br
Product: Cn1nc(N)nc1NCCCOc1cccc(CBr)c1

Procedure:
A solution of 3-[3-[(1-methyl-3-amino-1H-1,2,4-triazol-5-yl)amino]propoxy]benzene methanol (1.9 g) in methylene chloride (25 ml) was treated with phosphorus tribromide (3.27 g) at room temperature for 76 hrs. The resulting oil was purified by column chromatography using ethyl acetate/methanol, 8:1 as eluant to yeild the title compound as a white solid) 1.7 g). TLC silica ethyl acetate, water, isopropanol 0.88 ammonia (25:8:15:2) Rf 0.72. m.p. 129°-130°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.[O:23]1CCC[CH2:24]1>[Pt].C(O)C>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:24](=[O:23])[NH:20][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C)ccc32)CC1
Reaction time: 7 h

Procedure:
A mixture of 8.23 g of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate, 200 mL of tetrahydrofuran, 225 mL of ethanol and 2 g of 5% platinum on carbon was stirred under an atmosphere of hydrogen for 7 h. The catalyst was filtered off and the filtrate concentrated to to a thick oil. To an ice cold, vigorously stirred solution of the resulting crude ethyl 4-(4-methyl-2-aminoanilino)-1-piperidinecarboxylate in 500 mL of ethyl acetate was added 500 mL of saturated sodium carbonate followed by 20 mL of 1.9M phosgene in toluene dropwise over 30 min. After stirring overnight at room temperature, the layers were separated and the organic layer dried over MgSO4 and concentrated to dryness. Trituration of the residue with ether-hexane gave 8 g of ethyl 4-(5-methyl-2-oxo-1-benzimidazolinyl)piperidine-1-carboxylate as a white crystalline solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19](Br)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a suspension of 8-bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 28b) (139.9 mg, 0.288 mmol), N-methylpiperazine (48 μL, 0.43 mmol), and 4 Å sieves in 15 mL anhydrous toluene was added Pd2 (dba)2 (15.3 mg, 16.7 μmol), BINAP (63.0 mg, 0.101 mmol) and cesium carbonate (0.436 g, 1.345 mmol). The resulting wine colored mixture was heated at reflux under nitrogen for 20 hours. The reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol to afford the desired product as a yellow solid (96.9 mg, 67%). 1H NMR (300 MHz, DMSO, d6) δ 10.06 (s, 1 H, C(O)NH), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′ & H6′), 7.58 (s, 1 H, ArH3), 7.58 (d, 2 H, Jo=9.0 Hz, ArH3′ & H5′), 6.95 (d, 1 H, Jm=2.7 Hz, ArH5), 6.76 (d, 1 H, Jm=2.7 Hz, ArH7), 3.90 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.37 (bs, 4 H, ArNCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.01 (s, 6 H, N(CH3)2), 2.71 (bs, 4 H, ArNCH2CH2N), 2.35 (s, 3 H, R2NCH3); Mass Spec.: calc. for [C28H36N6O3+H]+ Theor. m/z=505; Obs.=505.5.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C(Cl)Cl.CO>[CH:20]1([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
2.9 g of the compound from Example 23 were acylated with oleoyl chloride as described in Example 6. Column chromatography with the eluting agent CH2Cl2 /CH3OH=15/1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C)C=O>[CH3:39][S:40]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(S(C)(=O)=O)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (40 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (0.175 mL, 1 mmol) followed by methanesulfonyl chloride (11.5 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 h, then concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (27.2 mg, 0.04 mmol, 40%). (m/z): [M+H]+ calcd for C24H37N5O3S, 476.27. found 476.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=1.66 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 70 °C
Yield: 77.6 %

Procedure:
To a solution of 16.3 g of the N-[3-[3-(piperidinomethyl)phenoxy]propyl]phthalimide in 150 ml of methanol was added 2.3 g of hydrazine monohydrate, and the mixture was heated at 70° C. for 4 hours. The mixture was cooled, then the solvent was distilled off, 30 ml of 6N hydrochloric acid was added to the residue, and the mixture was heated at 60° C. for 15 minutes. The resulting mixture was cooled, the insolubles were then filtered off, the solution was made alkaline with potassium hydroxide and subjected to extraction with a mixture of ethyl acetate and diethyl ether (1:1), and the organic layer was dried over magnesium sulfate and thereafter distilled to remove the solvent, giving 8.3 g of pale yellow oily 3-[3-(1-piperidinomethyl)phenoxy]propylamine (yield 78% ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][C:15]2([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[C:15]([CH3:22])([CH3:21])[CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: CC1(C)CNc2ccc(F)cc21
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2ccnc(Cl)c2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (1.1 mmol) 2-chloroisonicotinic acid, 0.18 g (1.1 mmol) 5-fluoro-3,3-dimethyl-2,3-di-hydro-1H-indole, 0.28 mL (2.0 mmol) TEA and 3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirred overnight at RT. The reaction mixture was purified by HPLC.