Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (160 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with water and ethyl acetate. The organic layer was further washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded crude 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide as a yellow solid. Recrystallization from 2/1 hexanes/ethyl acetate afforded pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide (114 mg, 44%) as a white solid: mp 195–196° C.; EI-HRMS m/e calcd for C18H22N2OS2 (M+) 346.1174, found 346.1171.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3(O)[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C=C(c2ccc3c(N)ncnn23)CCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (2.77 g, 8.31 mmol) in pyridine (55 mL) was added trifluoroacetic anhydride (2.35 mL, 14.1 mmol), dropwise. The ice bath was removed and the mixture was stirred at rt for 17 h. The mixture was concentrated to dryness. The crude solid was triturated with 3:1 EtOAc/hexanes then with MeOH to afford 2.09 g (76%) of the desired product. ES-MS m/z 316.04 [M+H]+, HPLC RT (min) 2.50.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:35])=[CH:38][CH:39]=1
Reactant: O=C(O)C(O)COc1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(O)COc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.0 g, 20 mmol) and N,N-diisopropylethylamine (10 g, 78 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 3-(4-chloro-phenoxy)-2-hydroxy-propionic acid (4.3 g, 20 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.5 g, 22 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 3-(4-chloro-phenoxy)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-propionamide (Compound E1.24).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[CH3:10].O>C(O)(=O)C>[Br:1][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([CH3:3])=[CH:5][C:6]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C)c(C)cc1Br
Reaction time: 0.25 h

Procedure:
Bromine (5.08 mL, 99.1 mmol) was added over 1 h to a stirred solution of N-(3,4-dimethylphenyl)acetamide 1-6 (13.5 g, 82.6 mmol) in acetic acid (200 mL) at approximately 15° C. After 15 minutes, water (400 mL) was added until no further precipitation was observed. The resultant solid was filtered, washed with water (until white) and dried in vacuo to afford 1-7 as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([OH:13])[N:6]=[CH:7]2.[CH3:14][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:14])=[C:3]2[C:8]=1[CH:7]=[N:6][C:5]([OH:13])=[CH:4]2
Reactant: C[Zn]C
Reactant: Oc1cc2c(Br)ccc(F)c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c2cnc(O)cc12

Procedure:
A solution of 5-Bromo-8-fluoroisoquinolin-3-ol (76.5 mg, 0.316 mmol), 2.0 M of dimethylzinc in toluene (0.40 mL, 0.80 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in THF in a microwave reactor tube was heated in the microwave reactor to 80° C. for 60 min. The reaction solution was poured into sat. aq. NH4Cl, and the resulting mixture was extracted with DCM (3×25 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with Et2O. The resulting light greenish-yellow solid was washed with Et2O and dried in vacuo to give the title compound as light greenish-yellow solid. It was used in the next step without further purification. MS(ES+): m/z=178.17 (100) [MH+]. HPLC: tR=2.36 min (polar—5 min, ZQ2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.C[C:14]1(C)[C:18]2(CS(O)(=O)=O)[C:19](C[CH:15]1[CH2:16]C2)=[O:20]>C1COCC1.O1C=CCCC1>[O:20]1[CH2:19][CH2:18][CH2:14][CH2:15][CH:16]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: C1=COCCC1
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 1414.9 %

Procedure:
To a solution of 1H-benzo[d]imidazole-5-carboxylic acid (1.62 g, 10 mmol) in THF (20 mL), 3,4-dihydro-2H-pyran (2 mL) and CSA (100 mg) were added. The mixture was heated at reflux for 24 h under argon. Removal of solvent followed by SiO2 chromatography afforded 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid as a light red solid (1.5 g, 60% yield).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[K].O.O1CCO[CH2:40][CH2:39]1>C(Cl)Cl>[CH2:39]([C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2)[CH3:40]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (200 mg, 0.46 mmol), cesium carbonate (601 mg, 1.8 mmol), potassium ethylrifluoroborate (125 mg, 0.92 mmol) in dioxane (3 mL)/H2O (0.3 mL) Pd(OAc)2 (21 mg, 0.092 mmol) and Ru-Phos (CAS 787618-22-8, 86 mg, 0.18 mmol) were added and then the mixture was stirred at 90° C. for 15 h. The reaction mixture was cooled to room temperature, and diluted with CH2Cl2. The organic phase was separated and washed with H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 3/2) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.75 (d, J=3.79 Hz, 1H), 7.57 (d, J=8.34 Hz, 2H), 7.31 (d, J=8.34 Hz, 2H), 6.95 (s, 1H), 6.91 (d, J=3.79 Hz, 1H), 4.90 (d, J=11.24 Hz, 1H), 4.65 (d, J=11.24 Hz, 1H), 4.61-4.64 (m, 1H), 3.79-3.92 (m, 1H), 3.41-3.54 (m, 1H), 2.71 (q, J=7.58 Hz, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H), 1.16 (t, J=7.58 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (420 mg, 1.48 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (742 mg, 2.78 mmol) in acetonitrile (8 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to yield the product as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[C:3]=1[N+:11]([O-])=O>[Pd].CCO.C1COCC1>[NH2:11][C:3]1[C:4](=[O:10])[N:5]([CH2:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CCn1ccc(N)c([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1ccc(N)c(N)c1=O
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of 4-amino-1-ethyl-3-nitro-1H-pyridin-2-one (0.94 g, 5.13 mmol) in 1:3 EtOH/THF (20 mL) was hydrogenated over 10% Pd/C (0.55 g, 0.51 mmol) at room temperature. After 1 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-ethyl-1H-pyridin-2-one (0.75 g, 95% yield). 1H-NMR (DMSO): δ 6.87 (d, 1H, J=7.2 Hz), 5.76 (d, 1H, J=7.6 Hz), 5.10 (m, 2H), 3.87 (m, 2H), 3.79 (q, 2H, J=7.2 Hz), 1.14 (t, 3H, J=7.2 Hz). MS: calculated for C7H11N3O+H 154.1; found: 154.2.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:43]([O:46][CH2:47][C:48](Cl)=[O:49])(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:46][CH2:47][C:48]([N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:4]2)=[O:49])(=[O:45])[CH3:44]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
3-(8-Azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (80 mg, 0.159 mmol; prepared in Example 174, step C) was dissolved in CH2Cl2, and triethylamine (88.6 μL, 0.635 mmol) and 2-chloro-2-oxoethyl acetate (25.6 μL, 0.238 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford 2-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl acetate (95.9 mg, 0.159 mmol, 100% yield) as a crude foam.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH3:26][Mg]Br>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH3:26])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and methylmagnesium bromide.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=O.C(N(CC)CC)C.[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C>[O:10]=[C:8]1[C:7]2[C:2]([C:3]3[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=3)[NH:5][CH:6]=2)=[N:35][N:34]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2c(C(=O)OCC)[nH]cc2c1Cl
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Temperature: 75 °C

Procedure:
One equivalent of crude diethyl 4-chloro-6H-pyrrolo[3,4-b]pyridine-3,7-dicarboxylate was dissolved in ethanol (0.2 M) under an atmosphere of nitrogen. Following the addition of 2 equivalents of triethylamine and 1.2 equivalents of phenyl hydrazine, the reaction was heated at 75° C. for 21 hours. After cooling to room temperature a large excess of 1 N NaOH was added and after 5 hours the reaction was concentrated to dryness. 10% HCl (aq.) was added and the brown precipitate was collected by filtration and washed with methylene chloride to afford the product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (br. s., 3H) 4.23-4.52 (m, 2H) 6.96-7.22 (m, 1H) 7.26-7.54 (m, 2H) 7.64-7.89 (m, 1H) 7.99-8.27 (m, 3H) 11.60-11.89 (m, 1H) 13.04-13.29 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1.C12CC(C=C1)C(=O)N2>>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@@H]1CC=C(CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=C1NC2C=CC1C2
Product: Nc1nc(Cl)c(NC=O)c(N[C@@H]2CC=C(CO)C2)n1

Procedure:
By the method of Example 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate-methanol gave title compound as white crystals, m.p. 148-150° C.; mass spectrum (Cl/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, =CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920 -4.4°, [α]57820 -5.2°, [α]546 20 -4.8°, [α]43620 -20.0°, [α]365 20 -60.4° (c 0.25, methanol).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-].[CH2:7]([N+:14](C)(C)C)[C:8]1C=CC=C[CH:9]=1.C(#N)C=C>C(O)(=O)C>[CH2:1]([O:5][CH:8]([CH3:9])[C:7]#[N:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CCCCO
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C=CC#N
Product: CCCCOC(C)C#N
Yield: 74 %

Procedure:
A mixture of 148 grams (2.0 moles) of n-butanol and 2.0 grams of 40% benzyltrimethylammonium hydroxide (Triton B) is combined in a 1 liter 4-neck round bottom flask stirred at reflux while 106 grams (2.0 moles) of acrylonitrile is added at a rate such that the temperature does not exceed 45° C. The mixture is stirred an hour after all the acrylonitrile has been added, made acidic with acetic acid, and fractionated under vacuum through a Vigreux column. The product boils at 75° C./2 mm (literature value: 98° C./20 mm). The product totalled 188.0 grams of 99.0% pure material which constituted a 74.0% yield. The density of the product was determined to be 0.93 grams/ml. The nuclear magnetic resonance and infrared spectra were obtained and were determined to be consistent with the expected structure of the product.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (1 drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol) in methylene chloride (1 ml). The resulting solution was stirred 1 h with ice-bath cooling, 1 h at ambient temperature, then was evaporated at reduced pressure to give crude 4-(cyclohexylmethyloxy)-3-nitrobenzoyl chloride as an oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccccc2)CC1
Yield: 23.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (1.5 g) and 4-benzyloxybutyl bromide (1.0 g) were reacted and treated in the same manner as in Example 168 to give 0.32 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-benzyloxybutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=NO)[C:4]=2[N:3]=1.[OH2:14]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[N:3]=1
Reactant: ON=C1CCCc2cnc(Cl)nc21
Reactant: O
Solvent: CC(C)=O
Product: O=C1CCCc2cnc(Cl)nc21
Temperature: 80 °C

Procedure:
2-Chloro-6,7-dihydro-5H-quinazolin-8-one oxime (Example 257a)(620 mg; 3.1 mmol) is dissolved in HClconc (12 ml), combined with water (50 ml) and acetone (12 ml) and heated to 80° C. for 20 minutes. The yellow solution is cooled and poured on Na2CO3/water (12 g/150 ml) and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as yellow crystals (480 mg; 84%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:22]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 82.3 %

Procedure:
0.5 g (0.00216 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene, treated with 0.313 ml (0.0027 mol) of benzoyl chloride and boiled at reflux for 6 hrs. The suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3) as the eluent. 0.525 g (82%) of 1-benzyl-piperidin-4-yl benzoate was obtained as yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.O>CC(C)=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([NH2:21])=[S:23]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(C(N)=O)cc1N
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1NC(N)=S
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methoxybenzamide (2.49 g, 15.0 mmol, Alfa) in acetone (30 mL) at reflux was added benzoyl isothiocyanate (2.22 mL, 16.5 mmol) and the mixture was stirred at reflux for 30 min, then was poured into water. The precipitate was collected by vacuum filtration and was treated with 10% aq. NaOH (15 mL). The mixture was heated to reflux for 40 min, cooled to room temperature, and poured into a mixture of ice and 6 N aq. HCl. The mixture was basified to pH 10 with conc. aq. NH4OH and the resulting white solid precipitate was collected by vacuum filtration, affording the crude title compound, which was used without further purification.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].[NH3:23]>C(Cl)Cl.C(O)C>[NH2:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13]
Reactant: N
Reactant: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Solvent: ClCCl
Solvent: CCO
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g (10 mmol) of the intermediate from step B were suspended in 40 ml CH2Cl2. 50 ml of a 2M solution of NH3 in ethanol were added and the reaction mixture was stirred for 16 h at ambient temperature. The mixture was poured into an ice/water mixture and the precipitate was separated. The precipitate was redissolved in ethyl acetate. This organic phase was washed with 2M aqueous HCl. The aqueous phase was made alkaline (pH=8-9) and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield 1.7 g of the intermediate.