Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]([NH2:21])[CH3:20])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.C[CH:26]([NH2:41])[C:27]1C=[CH:31][C:30](CCC2C=CC=CC=2)=[CH:29][CH:28]=1>>[ClH:1].[CH2:2]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]([N:21]=[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:41]2)[CH3:20])=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(C)N)cc1
Agent: Cl
Product: CCCCCCCCCCCCOc1ccc(C(C)N=C2CCCCCN2)cc1

Procedure:
Following essentially the same procedure described in Example 7 above and substituting p-dodecyloxy-α-methylbenzylamine hydrochloride for the α-methyl-p-phenyethylbenzylamine hydrochloride above, results in the formation of 2-(p-dodecyloxy-α-methylbenzylimino)hexahydroazepine hydrochloride having a M.P. of 186°-8° C (dec.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(C=O)nc2ccc(I)cn12
Yield: 69.2 %

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.0 g) in DCM (20 ml) was added a solution of diisobutylaluminum hydride (1.0 M toluene solution, 3.7 ml) at −78° C. The resultant mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with a mixture of MeOH (2 ml) and water (2 ml) at −78° C. This reaction mixture was then acidified with a few drops of 5 M HCl, and washed with saturated NaHCO3 solution (20 ml). The mixture was extracted with EtOAc (3×150 ml), and the extract was washed with brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (600 mg) as an off-white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].[OH-].[Na+]>O.CCOCC>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a stirred, chilled (-70° C.) solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (15.0 g) and ether (500 ml) was added n-butyl lithium (20.5 ml, 2.5M solution in hexanes) over 15 mins., under a nitrogen atmosphere. The mixture was stirred 1.5 hr, and was transferred under nitrogen to a vessel containing a large excess of dry ice and ether (500 ml). The suspension was stirred at room temperature overnight. The mixture was poured into water (1 L) and the mixture was basified with 2.5N sodium hydroxide solution. The organic phase was removed. The aqueous phase was acidified with 10% hydrochloric acid and extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate, organic phase was concentrated, and the residue was recrystallized from toluene to give 7.10 g (52.8%) of product, mp 196°-197° C.
Reaction SMILES: [Br:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[O:9]1C2N=CCC(=O)[C:12]=2[CH:11]=[CH:10]1.CO>C(#N)C>[Br:1][N:2]1[C:6]2[O:8][CH:3]=[CH:4][C:5]=2[C:10](=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC=Nc2occc21
Solvent: CC#N
Solvent: CO
Product: O=C1CCN(Br)c2occc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-bromosuccinimide (63.16 g, 354.9 mmol) as a solution in anhydrous acetonitrile (480 mL) to a suspension of 5H-furo[3,2]pyridin-4-one (36.9 g, 273 mmol) in anhydrous acetonitrile (740 mL) at 0° C. over 1 hour. Warm to room temperature, add anhydrous methyl alcohol (1.5 L) and stir at room temperature for 18 hours. Quench with water (20 ml) and saturated sodium bicarbonate (20 mL), concentrate to a volume of 1.3 liters, and pour into water (1.3 L). Collection of the precipitate by filtration and drying (vacuum oven 2 days 40-60° C.) gives the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 25 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-3-methylbenzene. Yield 25%. MS M+H calculated 380.1; found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 uM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[C:8]([N+:20]([O-])=O)[CH:7]=1>C(O)(=O)C.[Sn](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[C:8]([NH2:20])[CH:7]=1
Reactant: CCN(CC)CCNc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC)CCNc1ccc(C=CC(=O)OC)cc1N
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a pre-stirred solution of 3-[4-(2-diethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (61-1, 280 mg, 1.0 mmol) in glacial acetic acid (5 mL), tin chloride was added (1.18 g, 10.0 mmol). The resulting solution was heated to 45° C. for 17 hours and then cooled to room temperature. The solvent was removed under vacuum. Water (20 mL) and dichloromethane (20 mL) was added to the residue and stirred for 30 minutes. The organic layer was dried (MgSO4), filtered and concentrated to an oily residue. 100 mL diethyl ether was added and stirred for 4 hours. The product 3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methyl ester was obtained in 54.9% yield (207.6 mg). LCMS m/z: 292 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Reactant: BrCCCCCc1ccccc1
Product: O=C(CCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 49 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 5-bromopentylbenzene, the title compound (21 mg, 49%) was obtained as a white solid, using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.45 (m, 2H), 1.68 (quintet, J=7.8 Hz, 2H), 1.86 (quintet, J=7.6 Hz, 2H), 2.62 (t, J=7.6 2H), 3.31 (t, J=7.5 Hz, 2H), 7.18-7.20 (m, 3H), 7.27-7.29 (m, 2H), 7.54 (d 7.9, 5.0, 1.2 Hz, 1H), 7.94 (td, J=7.6, 1.8 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=5.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.4, 28.6, 31.1, 35.7, 40.0, 124.0, 125.7, 126.7, 128.3, 128.4, 137.3, 142.3, 142.6, 150.8, 161.2, 165.1, 187.0; MALDI-FTMS m/z 322.1557 (C19H19N3O2+H+ requires 322.1556).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Temperature: -50 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by adding a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 253 mg in the form of a white powder are obtained with a yield of 35%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].CCN(CC)CC.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:29](=[O:30])[CH2:28][Cl:27])[CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Under N2, a solution of 1,2,3,4-Tetrahydro-quinoline-6-sulfonic acid thiazol-2-ylamide (50 mg, 0.17 mmol), Et3N (17 mg, 24 μl, 0.17 mmol) and CH2Cl2 (0.5 mL) was cooled to 0° C. Chloroacetyl chloride (77 mg, 56 μl, 0.68 mmol) was added dropwise, over a period of 10 minutes. This reaction mixture was stirred at 0° C. for 2 hours. The mixture was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the amide (30 mg, 0.08 mmol, 47% yield). LC/MS (10-99%) M/Z: M+1 obs=372.1; tR=2.51 min.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][C@H:12]3[CH2:14][C@H:9]2[N:10]([CH3:15])[CH2:11]3)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][C@H:12]5[CH2:14][C@H:9]4[N:10]([CH3:15])[CH2:11]5)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CN1C[C@@H]2C[C@@H]1N(c1ccc(I)cn1)C2
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CN1C[C@@H]2C[C@@H]1N(c1ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn1)C2

Procedure:
Prepared according to general working method I from (1S,4S)-2-(5-iodo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane (45 mg, 0.14 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (51 mg, 0.24 mmol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(N)(=O)=O
Reactant: NCC1COc2ccccc2O1
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1COc2ccccc2O1
Temperature: 25 °C

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (4.4 g, 26 mmol) and sulfamide (5.1 g, 53 mmol) were combined in 1,4 dioxane (100 mL) and refluxed for 2 h. The reaction was cooled to room temperature and a small amount of solid was filtered and discarded. The filtrate was evaporated in vacuo and the residue was purified using flash column chromatography (DCM:Methanol-10:1) to yield a white solid. The solid was recrystallized from DCM to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](C=O)[CH:16]=1>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][N:14]=[C:19]2[CH:18]=[CH:17][CH:16]=[N:15][CH2:20]2)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1cccnc1
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Agent: Cl
Product: Clc1nnc(NN=C2C=CC=NC2)cc1N1CCCC1

Procedure:
3-Chloro-6-hydrazino-4-(pyrrolidin-1-yl)pyridazine (1.0 g, 4.69 mmol) and 3-pyridinecarboxaldehyde (443 ml, 4.69 mmol) were stirred in 0.2M hydrochloric acid (20 ml) for 2 h. The precipitated imine was then collected by filtration and dried (1.06 g, 75%). MS (ES+) 303 [MH]+, 305 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:16]
Reactant: CNC1CCCCC1
Reactant: COc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-methyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[Cl:12])C.[OH-].[Li+].Cl>O1CCCC1>[Cl:12][C:6]1[N:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (prepared according to the method of J. Med. Chem., 1993, 36(18), 2676–88, page 2684, column 2, 3rd example, ethyl-2-chloro-5-fluoropyridine-3-carboxylate) was dissolved in tetrahydrofuran (350 mL) and a 2M aqueous solution of lithium hydroxide (247 mL, 0.495 mol) added. The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to pH 1 by addition of 6M hydrochloric acid and then extracted with dichloromethane (×3). The combined extracts were dried over magnesium sulphate and the solvent concentrated in vacuo to give a solid which was triturated with diethyl ether and then dried to give the title compound as a white solid, 40.56 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH3:7])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:32][C:33]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:34]=1[C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)=[CH:40][N:39]=1)=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:32][C:33]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:34]=1[C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)=[CH:40][N:39]=1)=[O:36])=[O:14])[CH3:7])[CH3:19]
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3ccc(C)c(C)c3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (118.8 mg, 0.45 mmol, 1.50 equiv) in dichloromethane (24 mL), EDC.HCl (171.6 mg, 0.90 mmol, 3.00 equiv), 4-dimethylaminopyridine (182.4 mg, 1.49 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.29 mmol, 1.00 equiv). The resulting solution was stirred for 8 h at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 139.2 mg (62%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.37 (s, 1H), 11.30 (s, 1H), 8.75 (d, J=6 Hz, 2H), 8.22 (d, J=9 Hz, 1H), 8.054 (s, 1H), 7.93 (d, J=6.3 Hz, 1H), 7.68˜7.60 (m, 2H), 7.53 (s, 1H), 7.31˜7.20 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 3.40˜3.12 (m, 13H), 2.59 (s, 2H), 2.32˜2.27 (m, 4H), 2.16 (s, 3H), 1.68 (m, 4H), 1.58˜1.57 (m, 2H), 1.21˜1.16 (m, 6H). MS (ES, m/z): 648 [M−H]+.
Reaction SMILES: [CH3:1]OC1C(C=O)=CC2N(C)C(=O)CCC=2N=1.[CH2:17]([CH:19]1[NH:24][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]([NH:31][CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[N:35][C:34]=2[O:45][CH3:46])[CH2:21][CH2:20]1)[CH3:18]>CCCCCCC.C(O)C>[CH3:46][O:45][C:34]1[N:35]=[C:36]2[C:41](=[CH:42][C:33]=1[CH2:32][NH:31][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:17][CH2:18][CH3:1])[NH:24][C@H:23]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:40]([CH3:43])[C:39](=[O:44])[CH2:38][CH2:37]2
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CCC1CCC(NCc2cc3c(nc2OC)CCC(=O)N3C)C(c2ccccc2)N1
Solvent: CCCCCCC
Solvent: CCO
Product: CCC[C@H]1CC[C@H](NCc2cc3c(nc2OC)CCC(=O)N3C)[C@H](c2ccccc2)N1

Procedure:
By a procedure similar to the previous example 74: starting with cis-2-phenyl-3-amino-trans-6-(n-propyl)-piperidine (Scheme J) and 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde (Example 74, step 5) and using the above coupling procedure (Example 74, step 6) 7-[(6-ethyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one was obtained. Using a CHIRALPAK AD (10×50 cm) and a mobil phase of 95:5 heptane/ethanol containing 0.025% diethyl amine (flow rate=275 ml/min) 6-methoxy-1-methyl-7-[(2(S)-phenyl-6(S)-propyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one (retention time 11.479 min) was isolated as a pure enantiomer. 1H NMR (CDCl3) δ 7.40 (m, 2H), 7.30 (m, 2H), 7.22 (m, 1H), 6.95 (s, 1H), 4.20 (s, 1H), 3.72 (s, 3H), 3.80, 3.62 (d,d, 2H), 3.20 (m, 1H), 3.10 (s, 3H), 2.90 (m, 2H), 2.85 (m, 1H), 2.62 (m, 2H), 2.10 (m, 2H), 1.90 (m, 3H), 1.70 (m, 1H), 1.42 (m, 1H), 1.30 (m, 3H), 0.9 (t, 3H). Mass spectrum: m/e=423.2 (p+1). The corresponding enantiomer 6-methoxy-1-methyl-7-[(2(R)-phenyl-6(R)-propyl-piperidin-3(R)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one (retention time 11.592 min) was also isolated. NMR and mass spectrum was identical to the above spectra.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2occc2C1)C(=O)O
Yield: 53.4 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.5 g, 1.16 mmol) was added to a mixture of ethanol (20 mL) and sodium hydroxide (0.32 g, 8.0 mmol) in water (6.6 mL). The mixture was heated to reflux for 6.5 hours. Evaporated solvent under reduced pressure and water (20 mL) was added to the residue. The aqueous solution was washed with a mixture of ethyl acetate/heptane 1/10 (10 mL), and the extract was discarded. The aqueous fraction was acidified with concentrated hydrochloric acid to pH=6 and the product was extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid (0.25 g, 46.9%) as a yellow oil. The material was dissolved in diethyl ether (5 mL) and added to hydrochloric acid solution (2N HCl in diethyl ether, 0.34 mL). Water (12 mL) was added and after mixing the aqueous portion was separated and freeze dried to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid, hydrochloride salt (Compound Io hydrochloride, 0.16 g, light yellow powder, 59.3% yield). 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.77 (br s, 1H), 7.63-7.48 (m, 5H), 6.37 (br s, 1H), 5.05 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.02 (m, 2H), 2.36-2.24 (m, 2H), 1.42-1.40 (m, 2H), 1.32 (m, 2H), 1.20-1.18 (m, 4H), 1.11 (s, 6H), 1.08-0.92 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm): 181.70, 147.11, 144.55, 137.40, 132.15, 131.89, 130.08, 128.21, 129.87, 112.37, 109.71, 66.34, 52.10, 50.05, 43.07, 41.60, 35.10, 31.67, 30.56, 26.64, 25.85, 22.31. HRMS (HR, DIP-CI): Calculated for C23H30ClNO3 (M+H)+: 404.1987, found 404.2009. CHN analysis: Calculated; 62.73 C, 7.09 H, 3.18 N, 16.10 Cl, found; 59.13 C, 7.04 H, 3.03 N, 13.58 Cl.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(F)cc(CO)cc1F
Reaction time: 1.08 h

Procedure:
2,6-Difluoro-4-formylbenzonitrile (1.36 g, 8.13 mmol; see step (ii) above) was dissolved in 25 mL of methanol and cooled on an ice bath. Sodium borohydride (0.307 g, 8.12 mmol) was added in portions with stirring and the reaction was left for 65 min. The solvent was evaporated and the residue was partitioned between diethyl ether and aqueous sodium bicarbonate. The ethereal layer was washed with more aqueous sodium bicarbonate and brine, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. Yield: 1.24 g (90%).
Reaction SMILES: O1C=CC([C:6]2S[C:9]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]([O:26]C)=O)[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=N1.CO.Cl.[NH2:31][OH:32].[OH-].[K+]>CS(C)=O>[CH2:9]([S:11]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([NH:31][OH:32])=[O:26])[CH:20]=2)[CH2:15]1)(=[O:12])=[O:13])[CH2:8][CH2:7][CH3:6]
Reactant: COC(=O)c1ccc2c(c1)CCN(S(=O)(=O)c1ccc(-c3ccon3)s1)C2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCS(=O)(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
To a solution of methyl 2-[(5-isoxazol-3-yl-2-thienyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylate obtained in step 1 in methanol (2 mL, 50 mmol) was added hydroxylamine hydrochloride (80 mg, 1 mmol) and potassium hydroxide (200 mg, 4 mmol). The reaction was left to stir for 2 hours at 80° C. Upon cooling to room temperature the solvent was removed in vacuo. The residue obtained was dissolved in DMSO (1 mL), the residual solids were removed by filtration and the resulting residue following evaporation was purified via reverse phase prep HPLC to afford the title compound as a white solid after lyophilization (Yield: 6.1%). LCMS (FA) ES+ 313; 1H NMR (400 MHz, d6 DMSO) δ: 0.87 (t, J=7.32, 7.46 Hz, 3H), 1.38 (q, J=7.545, 7.25, 7.57 Hz, 2H), 1.63 (q, J=7.76, 7.55, 7.80 Hz, 2H), 2.91 (t, J=5.29, 6.47 Hz, 2H), 4.44 (s, J=8.06, 7.81 Hz, 2H), 3.49 (t, 2H, 6.03 Hz, J=5.95), 4.44 (s, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), and 7.58 (s, 1H).