Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH:6]([O:8][CH3:9])[O:5][CH:4]1[O:10][CH3:11].[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH3:13]>O1CCCC1>[CH3:11][O:10][CH:4]1[CH:3]([CH2:2][NH:1][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:22][CH:21]=2)=[O:25])[CH2:7][CH:6]([O:8][CH3:9])[O:5]1
Reactant: COC1CC(CN)C(OC)O1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)NCC2CC(OC)OC2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
2.9 g (18 mmol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran (DE-A 26 45 234) were dissolved in 20 ml of anhydrous tetrahydrofuran. At 0° C., 2.9 g (15 mmol) of 4-ethoxycarbonylphenyl isocyanate dissolved in 10 ml of anhydrous tetrahydrofuran were added dropwise. The mixture was then stirred at room temperature for 1 h and then concentrated under reduced pressure, resulting in 5.5 g of the crude product.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N+:9]([O-:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH:13]=1>>[CH2:7]([C@@H:8]1[C@@H:17]2[CH:12]=[CH:13][CH2:14][CH2:15][C@@H:16]2[O:11][N:9]1[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]([O-])=CCc1ccccc1
Reactant: C1=CCCC=C1
Product: CN1O[C@H]2CCC=C[C@H]2[C@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
N-(2-Phenylethylidene)methylamine N-oxide (797 mg, 5.34 mmol) and 1,3-cyclohexadiene (3 ml) were heated together at 70° C. in a sealed tube under nitrogen for 14 hours. The solution was cooled to room temperature and the excess 1,3-cyclohexadiene was removed under reduced pressure to yield a viscous oil (1.07 g, 87%). This crude product was purified by flash chromatography using 60:40 v/v petroleum ether (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the title compound (Rf=0.34) as a pale yellow oil (375 mg, 35%), υmax (film) 3030, 2920, 2840, 1605, 1495, 1455, 1090 cm-1 ; δH (400 MHz; CDCl3 -Me4Si) 1.80-2.00 (4H, br m), 2.20-2.25 (1H, m), 2.60-2.65 (3H, s), 2.75-2.95 (2H and 1H, m), 4.20-4.25 (1H, br), 5.6-6.0 (2H, br m), 7.20-7.30 (5H, br m); M/z 229 (MH+ 100%) (Found: MH+ 230.1545; C15H19NO requires MH+ 230.1574).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:12]([N:1]1[CH2:11][CH2:10][CH2:9][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 39.5 %

Procedure:
(S)-ethyl nipecotate (309.1 mg; 1.97 mmol) was dissolved in anhydrous methanol (8 ml) and commercially available benzaldehyde (200 μl; 1.97 mmol) was added, followed by sodium cyanoborohydride (234 mg; 3.72 mmol). This mixture was allowed to stir at ambient temperature for 23 hours and was then diluted with dichloromethane. The dichloromethane was washed with water, then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-ethyl 1-benzyl-3-piperidinecarboxylate (192.7 mg) as a colorless oil. MS mi/z (positive ion) 248 (MH+; 100).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[O:40][CH:39]=[N:38][CH:37]=2)O1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(Cl)Cl.CO>[O:40]1[C:36]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:37][N:38]=[CH:39]1
Reactant: CC1(C)OB(c2cnco2)OC1(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: c1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)o1
Temperature: 130 °C
Yield: 28.5 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (150 mg, 0.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (140 mg, 0.71 mmol), 1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (29 mg, 0.004 mmol) in saturated aqueous sodium carbonate solution (0.5 mL) and acetonitrile (5 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as an off-white solid (42 mg, 29%). 1H NMR (DMSO-D6, 400 MHz): 12.42 (s, 1H), 9.12 (d, J=2.2 Hz, 1H), 8.96 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.66 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D): RT=7.76 min, M+H+=410.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18]2)([OH:15])[CH2:10]1)(C)(C)C>O1CCOCC1>[N:17]1([CH2:16][C:11]2([OH:15])[CH2:12][CH2:13][CH2:14][C@@H:9]([NH2:8])[CH2:10]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)(Cn2ncc3ccccc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCCC(O)(Cn2ncc3ccccc32)C1
Reaction time: 0.5 h

Procedure:
In a flask, hydrochloric acid in dioxane (4M, 2 mL) was added to tert-butyl-3-((1H-indazol-1-yl)methyl)-3-hydroxycyclohexylcarbamate (50 mg), and the reaction was stirred for 30 minutes. The resulting solution was concentrated in vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(NCCO)c1cccc(Br)c1
Yield: 97.3 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.45 g, 99%) as a white solid. MS (ISP) 280.0 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[F:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1>>[F:25][C:26]1[N:31]=[C:30]([CH2:32][NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13](/[CH:15]=[C:16]4/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/4)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=3)[CH2:5][CH2:4]2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1cccc(F)n1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cccc(F)n3)CC2)n1

Procedure:
(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 6-fluoropicolinaldehyde (26.1 mg, 59 mg theoretical, 43.9%). LC-MS m/z 459 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:30]1([C:35]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.76 g (5.08 mmol) of ethyl 5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate were dissolved in 12 ml of dichloromethane, and 0.77 g (7.62 mmol) of triethylamine were added at 0° C. 0.89 g (6.61 mmol) of cyclopentanecarbonyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 2.1 g (100% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:13]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][O:9][CH3:13])[CH:7]=1
Reactant: CI
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-2-fluorophenyl)methanol (5.00 g) in THF (100 ml) was added 60% sodium hydride (1.08 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.80 ml) was added, and the mixture was stirred for 1.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane→hexane:ethyl acetate=50:1) to give the title compound (4.86 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[F:14][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:12]=[C:11]([NH:13][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[S:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(F)c(C)c3)cs2)cc1

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (31.5 m) with puriy >90%. MS (pos) m/z 391.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1>O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 96 °C
Reaction time: 12 h

Procedure:
A mixture of 2-cyanophenol (13.2 g), potassium carbonate (20.7 g), polyethylene glycol 400 (20.0 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 -methoxypropenoate (32.8 g) and water (77 g) was heated at 96° C. for 16 hours. The temperature of the solution was then raised to 105° C. and held for a further 12 hours. Any distillates were allowed to come off under atmospheric conditions. (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (86.6 area %).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH2:12][C:13]([OH:15])=O)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Cl.Cl.[OH:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[CH2:23][NH:24][NH2:25]>C(O)C>[Br:9][C:6]1[CH:5]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:15])[N:24]([CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([OH:19])[CH:21]=3)[N:25]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: NNCc1cccc(O)c1
Reactant: O=C(O)CCC(=O)c1cc(Br)c(O)c(Br)c1
Agent: Cl
Solvent: CCO
Product: O=C1CCC(c2cc(Br)c(O)c(Br)c2)=NN1Cc1cccc(O)c1
Yield: 49.1 %

Procedure:
A stirred mixture of 4-(3,5-dibromo-4-hydroxyphenyl)-4-oxobutanoic acid (H) (150 mg, 0.426 mmol) and 3-hydroxybenzylhydrazine dihydrochloride (135 mg, 0.639 mmol) in ethanol was heated to reflux. After heating for 16 h, the reaction mixture was cooled down and the precipitate formed was collected and dried in vacuo. This gave the title compound as a red solid (95 mg, 49%)1H NMR δ (ppm) (DMSO-d6): 2.59 (2 H, t), 3.01 (2 H, t, J=8.2 Hz), 4.88 (2H, s), 6.67 (1 H, d, J=8.2 Hz), 6.69-6.76 (2 H, m), 7.14 (1 H, t, J=7.8 Hz), 7.92 (2 H, s), 9.39 (1 H, s), 10.44 (1 H, s). LCMS (10 cm_apci_formic) Rt 3.33 min; m/z 453/455/457 [M+H].
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.O>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (2.59M, in hexane) (8.76 ml) was added dropwise to a solution of 1,4-diiodobenzene (7.49 g) in anhydrous THF (50 ml) at −78° C., and the resulting mixture was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (2.09 ml) was added dropwise thereto and the resulting mixture was stirred at −78° C. for 1.5 hours. After stirring the mixture for another 3 hours at room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from cyclohexane/ethyl acetate mixed solvent to obtain tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (4.12 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH2:23][C:24]=2[CH2:25]Cl)[CH:20]([NH:27][C:28](=[O:30])[CH3:29])[C:19]3=[O:31])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:32].[Na+]>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH2:23][C:24]=2[CH2:25][I:32])[CH:20]([NH:27][C:28](=[O:30])[CH3:29])[C:19]3=[O:31])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CSC12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CSC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(acetylamino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1, 155 mg, 0.34 mmol) and sodium iodide (253 mg, 1.7 mmol) in 5 mL of acetone was stirred for 1 hr at room temperature. The reaction mixture was concentrated on the rotary evaporator and diluted with 5 mL water. The suspension was extracted with 25 mL of ethyl acetate, and the organic phase was washed with 10% sodium thiosulfate (5 mL×2), brine (5 mL×3) and dried over anhydrous magnesium sulfate. The slightly orange powder 2 (152 mg, 0.45 mmol) was used without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 3 h
Yield: 50 %

Procedure:
A suspension of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (0.09 g., 0.3 mmol), (2-chloro-ethyl)-dimethyl-amine hydrochloride (0.056 g., 0.39 mmol) and potassium carbonate (0.095 g., 0.69 mmol) in 0.7 mL ethyl acetate was refluxed for 1 hour. To the reaction mixture was added 0.75 mL water, and reflux was continued for 3 hours. 30 mL Ethyl acetate was added, and the reaction mixture was washed three times with 15 mL water, dried over magnesium sulfate and concentrated in vacuo. The residue was purifed by flash chromatography (0 to 5% methanol in dichloromethane) to afford 0.055 g (0.15 mmol, 50%) of 7-benzenesulfonyl-4-(2-dimethylamino-ethyl)-4H-benzo[1,4]oxazin-3-one. MS: 361 (M+H)+, mp: 232.9-235.3° C. (HCl salt).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCNC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
4-[2-(Piperidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49A, Step 2) (340 mg, 0.94 mmol) was dissolved in CH2Cl2 (15 mL) under nitrogen and cooled to 0° C. Isobutyryl chloride (0.29 mL, 2.82 mmol) was added followed by dropwise addition of triethylamine (0.52 mL, 3.76 mmol). The mixture was warmed to r.t. and stirred for about 16 hours. Methylene chloride (20 mL) was added, and the solution was washed with saturated NaHCO3 (20 mL)and brine (20 mL), and then dried over magnesium sulfate. The solvents were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1), to afford the final compound as a white solid (322 mg, 80%). TLC (SiO2): Rf=0.42 (1:1 ethyl acetate/hexanes)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CO[NH2:14].CC(C)([O-])C.[K+].[Cl-].[NH4+]>CS(C)=O.[Cl-].[Zn+2].[Cl-]>[NH2:14][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: CON
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.9 %

Procedure:
6-Methoxy-3-nitropyridine (154 mg, 1 mmol) and O-methylhydroxylamine (71 mg, 1.5 mmol) were dissolved in DMSO (2 ml), and a resulting solution was added dropwise to a DMSO solution (3 ml) containing potassium tert-butoxide (336 mg, 3 mmol) and zinc (II) chloride (136 mg, 1 mmol) at 25° C. After completion of the addition, the resulting mixture was stirred at 25 ° C. for 9 hours and an aqueous saturated ammonium chloride solution (50 ml) was added, followed by extraction with ethyl acetate (80 ml). A resulting organic layer was dried over anhydrous magnesium sulfate, and then isolated and purified by subjection to silica gel thin layer chromatography [eluent: ethyl acetate/hexane=1/1] to obtain 147 mg of 2-amino-6-methoxy-3-nitropyridine (yield: 87%).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:21][C:22]1[C:27]([N:18]2[CH2:19][CH2:20][C@@H:16]([NH:15][C@@H:13]([C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH3:14])[CH2:17]2)=[N:26][CH:25]=[CH:24][N:23]=1
Reactant: Clc1nccnc1Cl
Reactant: C[C@@H](N[C@@H]1CCNC1)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](N[C@@H]1CCN(c2nccnc2Cl)C1)c1cccc2ccccc12
Yield: 35.1 %

Procedure:
To a solution of 162 mg of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 79.0 mg of 2,3-dichloro-pyrazine in 5 ml of ethanol was added 345 mg of potassium carbonate, and the mixture was stirred under reflux for 16 hours. The reaction mixture was filtered, and the solvent was evaporated, and to the residue was added a saturated aqueous sodium bicarbonate solution and chloroform, and the liquids were separated. The organic layer was dried, and the solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate-97:34→80:20) and by silica gel chromatography (hexane:ethyl acetate=90:10→0:100) to obtain 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine. (2) In 2 ml of chloroform was dissolved 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine, and 3 ml of a solution of 4M hydrochloric acid in dioxane was added to the mixture, and the resulting mixture was stirred. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitates were collected by filtration, washed with diethyl ether, and dried to obtain 63.9 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine dihydrochloride (the following Table A2, Example 2.001).
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]O>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][Br:1]
Reactant: Br
Reactant: OCCc1ccccc1F
Agent: O=S(=O)(O)O
Product: Fc1ccccc1CCBr
Temperature: 0 °C
Yield: 99 %

Procedure:
To a mixture of aqueous hydrobromic acid (48%, 360 mL) and concentrated sulfuric acid (103.6 mL) at room temperature was added dropwise 2-(2-fluorophenyl)ethanol (250 g, 1.78 mol, Aldrich). The reaction mixture was refluxed for 7 h, poured onto 600 ml of ice and the mixture was extracted with diethyl ether. The diethyl ether extracts were washed successively with saturated sodium carbonate and brine. The organic phase was dried (MgSO4) and concentrated in vacuo to give 359.9 g (99%) of 2-(2-fluorophenyl)-ethylbromide as a brown oil. This product was used without further purification. NMR (CDCl3 : d 7.6-6.9 (m. 4H, ArH), 3.6 (t, 2H CH2), 3.2 (t, 2H, CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58](O)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1>CN(C=O)C>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=3)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and at RT, 25 mg (0.13 mmol) of tert-butyl 4-aminobenzoate, 44 μl (0.26 mmol) of N,N-diisopropylethylamine and 74 μl (50% strength in DMF, 0.13 mmol) of T3P were added to a solution of 30 mg (0.09 mmol) of 2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) in 2 ml of DMF, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (71% of theory)