Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:11]
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2Cl2 was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et2O/hex to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 465.03 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:49]1[CH2:50][CH2:51][CH:46]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:47][CH2:48]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCCCC4)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-piperidinopiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a brown solid (67%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)phenylboronic acid and following the procedures described in EXAMPLE 7, Parts B and C, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 147. 1H NMR(CDCl3) δ: 9.50 (broad s, 1H), 9.30 (broad s, 1H), 7.68 (d, 1H, J=8.1 Hz), 7.50 (t, 1H, J=7.3 Hz), 7.40 (t, 1H, J=7.3 Hz), 7.26 (d, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 3.80 (ABq, 2H, JAB=15.8 Hz), 3.61-3.45 (m, 2H), 3.37-3.05 (m, 6H), 2.90-2.80 (m, 1H), 2.70-2.57 (m, 1H), 2.25-2.10 (m, 2H). LRMS (ES)+: 391.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C.O>[CH2:29]([O:19][C:18]([C:5]1[C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][C:13]3([CH2:15][CH2:14]3)[CH2:16][CH2:17]2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:20])[CH:28]=[CH2:27]
Reactant: O=C(O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid (490 mg) in DMF (2.9 mL) are added K2CO3 (4.4 mmol) and allyl bromide (7.4 mmol) at room temperature. After stirring at 50° C. for 0.5 h, the reaction mixture is cooling and diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give a crude title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=2[O:21]C)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.N1C=CC=CC=1.O>CCOCC>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[OH:21])[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)c(C(C)COCCc2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(COCCc1ccccc1)c1cc(O)ccc1O
Temperature: 190 °C

Procedure:
A mixture of 2-(2,5-dimethoxyphenyl)propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine (0.4 ml., 4.96 mM) and dry pyridine hydrochloride (4 g., 34.6 mM) is heated at 190° C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of the aqueous phase, is dried over magnesium sulfate and evaporated to dryness. The residue is purified via preparative layer chromatography on silica gel plates by elution with ether-pentane.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[H-].[Na+]>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(Oc3ccccn3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A mixture of 60.65 H (318 mmoles) 1-phenylmethyl-4-piperidinol, 500 ml dimethylformamide, 46.25 g, that is 41 ml (475 mmoles) 2-fluoropyridine and 17 g 50% sodium hydride in mineral oil is heated at 100° C. for 1 h. The mixture is cooled in an ice bath, 20 ml water are added, the mixture is stirred for 30 min and concentrated to a residual volume of about 200 ml. 1 1 iced water is added, the mixture is stirred at 0° C. for 30 min, and the precipitate is filtered off, washed and dried. 90.71 g 1-phenylmethyl-4-(2-pyridinyloxy)piperidine are thus isolated. Melting point: 75° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.C[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.[C:30](=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH3:26][C:25]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7]3)[CH:22]=[C:21]([CH3:30])[CH:20]=1
Reactant: Cc1cccc(B(O)O)c1C
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1cc(C)cc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)c1
Temperature: 125 °C

Procedure:
20 g (76 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 13.7 g (1.2 eq.) 2,3-dimethylphenyl boronic acid, 17.75 g sodium carbonate, 250 ml ethylene glycol and 50 ml water were placed in a 1 l—roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 34 mg (0.2 mole %) palladium acetate, 1 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 4 h). 100 ml of water were added and the mixture was extracted three times with 100 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 27.7 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.55 (t, 1H, aromatic), 7.39 (d, 1H, aromatic), 7.28-7.02 (m, 3H, aromatic), 3.34 (m, 1H, (C═O)CH), 2.81-2.69 (m, 2H, benzylic), 2.37 (s, 6H, Ph-CH3), 1.89-0.89 (m, 10H, aliphatic) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][O:15]C(=O)C)[CH2:9]1)=[O:7].[OH-].[Li+]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOC(C)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 3.5 h

Procedure:
Combine (+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine (670 mg, 1.35 mmol) and aqueous lithium hydroxide solution (4.2 mL, 1M) in methanol (15 mL). After 3.5 hours, concentrate in vacuo to give a residue. Dissolve the residue in dichloromethane and extract with 1M hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. The residue was dried under high vacuum for 18 hours to give (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine: Rf =0.11 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxobutyric acid ethyl ester (0.75 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 20 hours. The mixture was diluted with water and the pH of this solution this solution was adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and dried to afford title compound as a white solid, 1.0 g.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C:23]([O-:25])=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:36])=O>C1(C)C=CC=CC=1>[C:1]([O:20][CH2:21][CH2:22][C:23]([Cl:36])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.30 g of potassium 3-trityloxypropionate in 75 ml of toluene, cooled to 0° C., was added 0.5 ml of pyridine, and subsequently 15 ml of oxalyl chloride were added within 10 minutes. The mixture was stirred for 30 minutes at room temperature and then evaporated in vacuo. The oily residue was taken up in 30 ml of toluene, and the solvent was evaporated in vacuo. The residue was taken up in 50 ml of methylene chloride and 50 ml of hexane, and the solution was stirred at 0° C. Unsoluble material was filtered off, and the filtrate was evaporated in vacuo to yield 2.81 g of 3-trityloxypropionyl chloride as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23](OCC)=[O:24].C1(CNC([CH:38](C(OCC)=O)[C:39]([O:41]CC)=[O:40])=O)C=CC=CC=1.[H-].[Na+].C1([N:57]=C=O)C=CC=CC=1>O1CCOCC1.ClCCl>[OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:57][CH2:38][C:39]([OH:41])=[O:40])=[O:24]
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)c1c(O)n(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Ethyl 6-hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (420 mg, 1.43 mmoles) was added to a suspension of sodium hydride (60% suspension in mineral oil, 220 mg, 5.5 mmoles) in dry dioxan (10 mL) and stirred for 10 minutes under argon. Phenyl isocyanate (240 uL, 2.21 mmoles) was added and the mixture sealed in a pressure flask heated in a microwave reactor at 110° C. for 1 hour. The mixture was taken up in dichloromethane, washed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (ethyl acetate) gave the title compound (300 mg, 57%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 3 H) 3.99-4.07 (q, J=7.07 Hz, 2 H) 4.94 (s, 1 H) 7.08-7.13 (m, 2 H) 7.21 (ddd, J=8.46, 4.42, 4.29 Hz, 1 H) 7.26-7.33 (m, 5 H) 7.37 (t, J=7.45 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:23]=[C:22]2[C:9]([C:10]3[CH:11]=[CH:12][N:13]=[C:14]([CH:34]=3)[C@@H:15]([NH:26]C(=O)OC(C)(C)C)[CH2:16][CH2:17][CH2:18][C:19](=[O:25])[C:20](=[O:24])[NH:21]2)=[CH:8][CH:7]=1)=[O:4].[CH3:35][Mg]Br>C1COCC1>[NH2:26][C@@H:15]1[C:14]2[CH:34]=[C:10]([CH:11]=[CH:12][N:13]=2)[C:9]2[C:22](=[CH:23][C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])=[CH:7][CH:8]=2)[NH:21][C:20](=[O:24])[C:19]([OH:25])([CH3:35])[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)C(=O)CCC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc2c(c1)NC(=O)C(C)(O)CCC[C@H](N)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 123C (345 mg, 0.736 mmol) in THF (7 mL) was cooled to 0° C. and treated with methylmagnesium bromide (0.245 mL, 0.736 mmol), then stirred at rt for 1 hr. The reaction was cooled to 0° C. again and treated with methylmagnesium bromide (0.491 mL, 1.473 mmol), then stirred at rt for 1 hr. LCMS still showed starting material. The reaction was cooled to 0° C., treated with methylmagnesium bromide (0.491 mL, 1.473 mmol), then stirred at rt overnight. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (3×), and the organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by prep HPLC. The pure material was dissolved in DCM and treated with TFA, then stirred at rt for 2 hrs. The solvent was removed in vacuo and 123D (135 mg, 0.220 mmol, 29.9% yield) was obtained as a yellow solid. The material was used in future steps without purification. MS (ESI) m/z: 385.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].[Br:9][CH2:10][C:11](O)=[O:12].C(#N)C>C(#N)C.CO>[Br-:9].[CH3:7][CH:6]1[C:2]2[S:1][CH:5]=[CH:4][N+:3]=2[CH2:10][C:11](=[O:12])[O:8]1
Reactant: CC(O)c1nccs1
Reactant: O=C(O)CBr
Solvent: CO
Solvent: CC#N
Product: CC1OC(=O)C[n+]2ccsc21
Product: [Br-]
Reaction time: 6 h
Yield: 33.1 %

Procedure:
1-(2-Thiazolyl)ethanol (0.5 g, 3.87 mmole), bromoacetic acid (0.537 g, 3.86 mmole), and acetonitrile (0.125 mL) were heated in an oil bath with stirring at 105 C for 6 hr. The mixture was dissolved in 5 mL 4:1 acetonitrile/methanol and stored at 4 C for 17 hr. The crystals which separated were filtered out and combined from two identical runs, and recrystalized from methanol/acetonitrile/ether to give a total of 0.32 g of the title compound, mp 214–215.5 C. Calcd for C7H8NO2SBr: C, 33.5; H, 3.20; N, 5.59; found: C, 33.62; H, 3.16; N, 5.61.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[O:16][C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:17])[CH:14]=2)[NH:11][C:10](=[O:18])[CH:9]=[CH:8]3)[CH2:5]1.[H][H]>O.[Pd]>[NH2:2][CH2:3][CH:4]1[O:16][C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:17])[CH:14]=2)[NH:11][C:10](=[O:18])[CH2:9][CH2:8]3)[CH2:5]1
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CN)O2
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)CC(CN)O2
Yield: 63.6 %

Procedure:
A hydrochloric acid salt of 2-aminomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one (1.0 g) was dissolved in water (50 ml). To the solution, 10% palladium-on-carbon (1 g) was added, followed by stirring at 80° C. for 1.5 hours in the atmosphere of hydrogen. After the catalyst was removed by filtration, the mixture was condensed. The resultant residue was recrystallized from methanol--ether to obtain 642 mg of a hydrochloric acid salt of 2-aminomethyl-5-methyl-1,2,8,9-tetrahydrofuro-[3,2-f]quinoline-7-one as colorless prisms (63.7%).
Reaction SMILES: [C:1]1([C:7]2([C:19]#[N:20])[CH2:12][CH2:11][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:34]([O-])([O-:36])=[O:35].[K+].O>C(#N)C>[N+:34]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:19]#[N:20])[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12]2)=[CH:6][CH:5]=1)([O-:36])=[O:35]
Reactant: N#CC1(c2ccccc2)CCN(C(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
4-Phenyl-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile was dissolved in Acetonitrile (12.0 mL), Trifluoroacetic anhydride (4.00 mL, 28.3 mmol) was added and the mixture was cooled in an ice bath. Potassium nitrate (1.58 g, 15.6 mmol) was then added and the reaction was stirred at 0° C. for 2 h, then water (100 mL) was added at 0° C. The mixture was extracted with EtOAc (2×50 mL), the organics were washed with 1:1 brine:satd. NaHCO3 (2×50 mL), dried over sodium sulfate and then filtered through 8 mL silica gel, washing with 100 mL EtOAc. The filtrate was conc. in vacuo. 1H-NMR indicated a mixture of nitration products and starting material. Resubjection to the nitration conditions (12 mL MeCN, 4 mL TFAA, 1.59 g KNO3, rt, overnight). Work up as before, conc. in vacuo to afford an oil, 1H-NMR showing -2.6:1 ratio of nitration products. The crude oil was dried in vacuo and then dissolved in DCM, loaded onto a 25 g ISCO cartridge and purified (120 g column, 0%, then 5-30% EtOAc:Hex) to afford partial separation of the nitro products, the major eluting first. Clean fractions were conc. in vacuo to afford 4-(4-Nitro-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile (1.29 g; Yield=31.4%) as a white solid. 1H-NMR (DMSO-d6): 8.31 (d, 2H, J=8.8 Hz), 7.91 (d, 2H, J=8.8 Hz), 4.52 (m, 1H), 4.07 (m, 1H), 3.55 (m, 1H), 3.17 (m, 1H), 2.27 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=O)=[CH:13][CH:12]=1.[NH2:24][C:25]([CH:32]([CH3:34])[CH3:33])=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:24][C:25]([CH:32]([CH3:33])[CH3:34])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:15]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:23][CH:22]=3)[C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C=C(N)C(C)C
Solvent: OCCO
Product: CCOC(=O)C1=C(C(C)C)NC(c2ccc(F)cc2)=C(C(=O)OC)C1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl 4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in 150 ml of ethylene glycol at a bath temperature of 130° C. The mixture is cooled to room temperature, extracted three times using 300 ml of diethyl ether, the combined ether phases are concentrated, and the residue is dissolved in 100 ml of toluene and chromatographed on 700 ml of silica gel (0.04-0.063 mm) using toluene as an eluent.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][CH2:28][C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (70 mg, 73%), MS (ISP) m/z=385.4 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-hydroxy-acetic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH3:24].O>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][N:12]([CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
A mixture of a solution of 5 g of the product of Step D of Example 3 in 50 ml of dimethylformamide, 7 g of sodium carbonate and 2.3 ml of n-propyl iodide was stirred for 16 hours under an inert atmosphere and was then poured into 250 ml of iced water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture. The eluate was distilled to dryness under reduced pressure to obtain 4.84 g of 3-(3-methoxyphenyl)-1-propyl-1,2,5,6-tetrahydropyridine.