Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[C:5]([O:10][C@@H:11]([O:15][C:16]([O:18]C1CC(=O)NC1=O)=O)[CH:12]([CH3:14])[CH3:13])(=[O:9])[CH:6]([CH3:8])[CH3:7].[CH:26]1[C:31]([C@H:32]([CH2:37][NH2:38])[CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=[C:28]([Cl:39])[CH:27]=1>C(OC)(C)(C)C.O>[CH3:14][CH:12]([CH3:13])[C@@H:11]([O:10][C:5](=[O:9])[CH:6]([CH3:7])[CH3:8])[O:15][C:16]([NH:38][CH2:37][C@@H:32]([C:31]1[CH:26]=[CH:27][C:28]([Cl:39])=[CH:29][CH:30]=1)[CH2:33][C:34]([OH:36])=[O:35])=[O:18]
Reactant: CC(C)C(=O)O[C@@H](OC(=O)OC1CC(=O)NC1=O)C(C)C
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C(=O)O[C@@H](OC(=O)NC[C@H](CC(=O)O)c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 20-L pilot plant equipped with a mechanical stirrer and a nitrogen inlet was charged with NHS-carbonate, 1-S-[[[(isobutyryloxy)isobutyroxy]carbonyl]oxy]-2,5-pyrrolidinedione (20b), 1.31 kg, 4.7 mol) and (R)-baclofen (431 g; overall 1.2 eq. of R-baclofen) in a mixture of methyl tert-butyl ether (MTBE) and water (3:1; 10 L). The resulting suspension is stirred for 24 hours at room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1

Procedure:
0.5 g of palladium carbon (containing 10% by weight palladium) was added to a solution of 1.2 g (2.7 mmol) of 1-(4-nitrophenyl)-4-(4-phenyl-1-piperidinyl)piperidine (cf. Example 8) in 100 ml of methanol. Hydrogenation was continued until hydrogen uptake ceased, then the solids were filtered off and the solvent was removed under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[C:14]([NH2:17])=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N-:18]=[C:19]=[O:20].[Na+]>CC(O)=O.O>[NH2:17][C:14]1[C:13]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:19]([NH2:18])=[O:20])=[CH:7][CH:6]=3)=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][N:15]=1
Reactant: Nc1ccc(-c2cccc3onc(N)c23)cc1
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(-c2cccc3onc(N)c23)cc1
Yield: 65.2 %

Procedure:
A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate (26 mg, 0.4 mmol) in HOAc (0.5 mL) and H2O (0.5 mL) was stirred overnight at rt, then diluted with water. The precipitated solid was collected by filtration and recrystallized from THF/hexanes to give an offwhite solid (35 mg, 65%). 1H NMR (300 MHz, DMSO-D6) δ ppm 5.20 (s, 2H) 5.92 (s, 2H) 7.11 (dd, J=7.3, 0.9 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.46 (dd, J=8.5, 1.0 Hz, 1H) 7.57 (d, J=8.5 Hz, 2H) 7.57 (dd, J=8.1, 7.1 Hz, 1H) 8.72 (s, 1H) MS (ESI(+)) m/e 269.0 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(C)(=O)=O)C3)cnc21

Procedure:
1-[(1-Methane sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH:7]1[NH2:16])[CH2:13]2.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH:7]1[NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 12 h

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in ethyl ether (20 ml) was added dropwise to a stirring mixture of 2-adamantylamine hydrochlbride (9.35 g, 0.05 mole) and triethylamine (30.65 ml) in methylene chloride (200 ml) and ethyl ether (200 ml) over a 30 minute period. The solution was stirred for 12 hours, the solid filtered and washed with ethyl ether and the filtrate stripped to an oily material which was taken up in ethyl acetate and hexane and allowed to stand overnight. The solid was filtered, the filtrate concentrated and chilled and the product as an orange solid filtered and dried. The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]2[CH:24]([O:25]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][C@@H:24]([OH:25])[C@H:26]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: Clc1ccc(N2CCCNCC2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
To a solution of 1-(4-Chloro-phenyl)-[1,4]diazepane (1.00 g, 4.80 mmol) in acetonitrile (10 mL) was added 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.925 g, 5.00 mmol) and calcium(II) trifluoromethanesulfonate (0.676 g, 2.00 mmol). The solution was stirred at 80° C. for 17 hours under nitrogen atmosphere. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica gel chromatography (gradient ethyl acetate to 87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.819 g (41%) of the title compound. ESI-MS m/z: 396 (M+1), FAS method rt: 1.25 min
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(COC)OC>[C:5]1([C:11]2[N:1]=[N:2][NH:3][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Nc1cc(-c2[nH]nnc2-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 79 %

Procedure:
Add sodium azide (0.13 g) to a solution of 1-phenyl-2-(3-(isopropylamino)-4-nitrophenyl)acetylene (0.56 g) in dimethoxyethane (5 mL). Heat to reflux for 2 hours. Cool to room temperature. Add 1N hydrochloric acid (10 mL), extract with ethyl acetate (20 mL), and wash with saturated aqueous sodium chloride (2×10 mL). Dry organic phase over sodium sulfate and concentrate under reduced pressure. Subject the reside to silica gel chromatography, eluting with 1:1 ethyl acetate:hexane to provide the desired compound as a yellow solid (0.51 g, 80%).
Reaction SMILES: [C:1]([C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Yield: 39.2 %

Procedure:
1,1-dimethylethyl 6-cyano-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 14) (1.15 g), hydroxylamine hydrochloride (1.18 g) and sodium bicarbonate (1.76 g) were heated at 60° C. in ethanol (100 ml) for 18 hours under argon. The cooled reaction was evaporated to dryness, partitioned between DCM (100 ml) and water (100 ml). The DCM layer was collected and the water layer washed with DCM (50 ml). The combined DCM layers were dried and evaporated. The title compound (506 mg) was isolated by chromatography eluting with 5% methanol in DCM. δH (400 MHz, CDCl3) 7.27 (1H, s) 7.16-7.13 (2H, m), 5.38 (1H, br. s), 3.58-3.55 (4H, m), 3.05 (2H, br. s), 2.89 (2H, br. s) 1.46 (2H br. s), 1.12 (9H, br. s); MS (ES) C16H23N3O3 requires 305; found 306 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol) in DMF (5 mL) were added 2-hydroxy-2-methylpropionic acid (31 mg, 0.294 mmol), DIPEA (230 μL, 1.34 mmol) and HATU (153 mg, 0.401 mmol). Stirring at RT was continued for 18 h then the crude reaction mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 121 as a pale beige solid (33 mg, 31%). LCMS: RT 2.28 min [M+H]+ 449.1. 1H NMR (CDCl3, 400 MHz): δ 8.51 (1H, s), 7.98 (1H, s), 7.79 (1H, d, J=7.80 Hz), 7.36-6.99 (4H, m), 5.32 (1H, bs), 5.02-4.88 (2H, m), 4.78 (1H, bs), 4.59-4.49 (1H, br), 2.64-2.44 (2H, m), 2.37-2.22 (1H, m), 2.05 (1H, d, J=12.70 Hz), 2.95-1.49 (11H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[I:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24](O)=[O:25])[CH:22]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:24](=[O:25])[CH2:23][N:21]4[CH:22]=[C:18]([I:17])[CH:19]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc(I)cn1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1cc(I)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.400 g, 1.83 mmol), 2-(4-iodo-pyrazol-1-yl)acetic acid (0.554 g, 2.2 mmol) and NEt3 (0.642 mL, 4.59 mmol) in DMF (5 mL) was added HATU (0.836 g, 2.2 mmol). The mixture was stirred at rt for 40 min. It was then quenched with water. The mixture was partitioned between EtOAc (100 mL) and sat. NaHCO3 (50 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (SiO2, with a gradient elution of 0˜30% EtOAc/CH2Cl2) to yield 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-(4-iodopyrazol-1-yl)ethanone (0.82 g, 100%).
Reaction SMILES: Br[CH:2]1[CH2:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH:3]1[F:16]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[C:5](=[CH:4][C:3]([F:16])=[CH:2][CH:11]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1=C(C(=O)OC)CC(Br)C(F)C1
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1C(=O)OC
Reaction time: 4 h

Procedure:
Dimethyl 5-bromo-4-fluoro-3,4,5,6-tetrahydrophthalate was dissolved in methylene chloride and stirred over basic alumina for 4 hours. An aliquot was removed and the major product shown to be dimethyl 4-fluorophthalate by GC analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](Cl)=[N:11][OH:12])[CH:5]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[CH:16].N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[O:12][N:11]=2)[CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-c2cc(-c3ccc(C)cc3)on2)c1
Temperature: 25 °C

Procedure:
In a 25 ml round flask, 1.9 g (8.9 mmol) of 3-[chloro-(hydroxyimino)-methyl]-benzoic acid methyl ester and 1.03 g (8.9 mmol) of 1-ethynyl-4-methyl-benzene are dissolved in 12 ml of CHCl3 at 0° C. To this solution, 36 μl (0.4 mmol, 0.05 eq.) of pyridine and subsequently 1.24 ml (8.9 mmol) of triethyl amine are added and the mixture is stirred under warming to room temperature for 2 h. Then, the mixture is poured onto water, extracted twice with CH2Cl2, the organic layers are dried with brine and Na2SO4 and then concentrated. Chromatographic purification (250 g SiO2; gradient elution, eluent: hexane/ethyl acetate 95:5→9:1) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 294.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]([CH:9]([CH3:12])[CH2:10][OH:11])[C:24](=[O:25])[CH2:23][Br:22])=[CH:5][CH:4]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CNC(C)CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)CBr)C(C)CO)cc1

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-methoxybenzylamino)propan-1-ol (11 g, 56.41 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of triethylamine (5.7 g, 56.44 mmol, 1.00 equiv). To this was added a solution of 2-bromoacetyl bromide (11.4 g, 56.44 mmol, 1.00 equiv) in dichloromethane (50 mL) dropwise with stirring at −17˜−25° C. The resulting solution was stirred for 1 h at −17˜−25° C. in a liquid nitrogen bath. The resulting mixture was washed with 3×100 mL of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. This resulted in 16 g (90%) of N-(4-methoxybenzyl)-2-bromo-N-(1-hydroxypropan-2-yl)acetamide as yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][CH:8]([CH2:10][CH2:11][CH3:12])[CH:7]([CH2:13][CH3:14])[CH:6]=N1)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+].O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:10]([C:8]1[C:7]([CH2:13][CH3:14])=[CH:6][C:1]([CH2:2][CH3:3])=[CH:4][N:9]=1)[CH2:11][CH3:12]
Reactant: CCCC1N=CC(CC)C(CCC)N1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CCCc1ncc(CC)cc1CC

Procedure:
Into a mixture of 62.9 grams of 2.4-di-n-propyl-5-ethyl-2,3,4,5-tetrahydropyrimidine, 4 grams of ammonium acetate and 4 grams of copper (II) acetate was introduced oxygen gas. Under continuous stirring and introduction of oxygen gas, the mixture was heated for 3 hours at 96°-128° C. The resulting reaction mixture was distilled under diminished pressure. The fraction b20 122°-126° was collected as 37.2 grams (67.8% of theory) of 2-n-propyl-3.5-diethyl pyridine; nuclear magnetic resonance spectrum, no solvent, τ in ppm 1.62 doublet 1H; 2.62 doublet 1H; 7.33 multiplet 6H; 8.20 multiplet 2H; 8.82 triplet and 9.03 triplet 9H.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C.[CH3:29][NH2:30]>CO>[F:27][C:23]1[CH:22]=[C:21]([S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[CH:8]([CH2:7][NH:6][CH2:5][C:4]([NH:30][CH3:29])=[O:3])[CH2:9][CH2:10][CH2:11]3)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: CN
Reactant: CCOC(=O)CNCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Solvent: CO
Product: CNC(=O)CNCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-acetic acid ethyl ester (0.42 g) was dissolved in 20 m of 1.1 molar methylamine in methanol. The solution was stirred at room temperature for 24 hours and then concentrated to an oil under reduced pressure. The oil was dissolved in ethanol and 1N HCl in diethyl ether was added to precipitate 2-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-N-methyl-acetamide as a hydrochloride salt. Yield 0.045 gms, M+H=391.
Reaction SMILES: [F-].[Cs+].CN1CCCC1=O.Cl.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:36][CH:35]=1>O>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[O:41])=[CH:38][N:39]=4)[CH2:29][CH2:30]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NC1CCN(c2ccc(C(=O)N3CCOCC3)cn2)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 96 °C
Yield: 15.3 %

Procedure:
To a vial containing CsF (684 mg, 4.50 mmol) and 1-methyl-2-pyrrolidinone (NMP, 2 mL) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide hydrochloride (247 mg) and (6-chloropyridin-3-yl)(morpholino)methanone (170 mg, 0.750 mmol). The reaction mixture was heated to 96° C. for 24 hrs. After allowing the reaction to cool to room temperature the reaction was diluted with H2O (3 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 5% MeOH: DCM) gave 6-(3-fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide (55 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, s), 8.53 (1H, d, J=7.7 Hz), 8.30 (1H, dd, J=8.4, 1.6 Hz), 8.23 (2 H, d, J=11.9 Hz), 8.15 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.9 Hz), 7.98 (1H, br. s.), 7.53-7.61 (1H, m), 7.26-7.37 (1H, m), 5.02 (1H, br. s.), 4.45 (1H, br. s.), 4.24 (1H, br. s.), 3.86 (1H, br. s.) 3.73 (1H, br. s.), 3.30 (3H, br. s.), 1.87-2.05 (5H, m), 1.61 (2H, br. s.), 0.75 (3H, t, J=7.3 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7]
Reactant: N#CCOc1cc(F)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCOc1cc(F)ccc1F
Temperature: 25 °C

Procedure:
The solution of 2.44 g of (2,5-difluorophenoxy)acetonitrile in 40 ml of tetrahydrofuran is added dropwise at 20-30° C. to the stirred mixture of 1.13 g of lithium aluminium hydride in 16 ml of diethyl ether. The reaction mixture is stirred at reflux over 2 hours and subsequently cooled to room temperature. 2 ml of water and 6.5 ml of 1N NaOH are successively added dropwise. The suspension is stirred at room temperature over 14 hours. The reaction mixture is poured onto 80 ml of water and extracted with diethyl ether (2×80 ml). The organic phases are washed successively with water (2×80 ml) and brine (1×50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.24 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=2.37.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][OH:8])=[O:2].C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O:8][CH2:7][CH2:6][C:5]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:4][NH:3][CH:1]=[O:2])(=[O:30])=[O:29]
Reactant: O=CNCC(CCO)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(CNC=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a suspension of 4-formylamino-3,3-diphenylbutanol (21.5 g) in methylene chloride (250 ml) were added triethylamine (22 ml), 4-dimethylaminopyridine (catalyst amount) and tosyl chloride (15.3 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and dissolved in water-ethyl acetate. The ethyl acetate layer was washed with 1N-hydrochloric acid, further washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4:1~1:1) to provide the title compound (32 g) as colorless syrup.