Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:55]([NH:54][CH2:52][CH3:53])=[O:56])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CCNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and ethyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.03 (t, 7 Hz, 3H), 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 3.07 (q, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated for C39H43N5 O5 661; found 662 (M+H, 100%).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]>C(Cl)(Cl)Cl>[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1.[ClH:9].[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(NCC1CCNCC1)c1ccccc1

Procedure:
N-(4-Piperidinylmethyl)benzamide was synthesized by the dropwise addition of 0.12 mole benzoyl chloride to a mixture composed of 0.12 mole 4-pyridylmethylamine and 0.122 mole triethylamine in 75 ml. dry chloroform with constant stirring over a period of 30 minutes. The contents of the reaction vessel were maintained at 10°-15° C. throughout the addition of the benzoyl chloride and for a period of thirty minutes thereafter. Triethylamine hydrochloride, which formed during the course of the reaction, was removed by filtration and the remaining filtrate evacuated in vacuo to yield the crude N-(4-pyridylmethyl)benzamide intermediate. The crude product was recrystallized from aqueous alcohol to give pure product, melting point 176.7° C., 80.5% yield.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[C:4]([CH3:15])[C:3]=1[C:16]([O:18]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]#[N:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>Cl.O1CCOCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:29][C:30]1[NH:31][C:16](=[O:18])[C:3]2[C:4]([CH3:15])=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[S:6][C:2]=2[N:1]=1
Reactant: CCCCOC(=O)Cc1sc(N)c(C(=O)OCC)c1C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOC(=O)Cc1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A mixture of 900 mg of butyl 5-amino-4-ethoxycarbonyl-3-methyl-2-thiopheneacetate, 558 mg of (3,4-dichlorophenyl)acetonitrile and 20 mL of 4N hydrochloric acid/1,4-dioxane solution was stirred at room temperature overnight. Ice water was added to the reaction mixture, followed by neutralization with 25% aqueous ammonia, extraction with chloroform, drying over anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 500 mg (38%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36].C1COCC1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)ccc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)ccc3C)c(=O)n(C)c2n1
Yield: 44 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (56 mg, 0.117 mmol) and 2.0N methylamine in THF (0.71 mL, 1.421 mmol) were combined to afford 1-(3-tert-butylisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (29 mg, 44% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.46 (s, 9H), 2.04 (s, 3H), 2.89 (s, 3H), 3.52-3.60 (m, 3H), 5.74 (s, 1H), 7.08-7.10 (m, 1H), 7.22-7.25 (m, 1H), 7.33-7.36 (m, 2H), 7.65 (s, 1H), 7.78 (s, 1H), 7.68-7.82 (m, 1H), 8.25 (s, 1H), 8.53 (s, 1H), 8.60-8.65 (m, 1H); MS (ESI) m/z: 462.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[OH:27])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(N(CC)C(C)C)(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc2c(C(=O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate (57 mg, 0.12 mmol) in dichloromethane (6 mL) was added Dess-Martin periodinane (154.1 mg, 0.34 mmol). After 15 minutes, the reaction was quenched with saturated Na2S2O3(aq) (10 mL) and extracted with dichloromethane (3×10 mL). The combined organics were washed with water (30 mL) and brine (30 mL), and dried over Na2SO4. To the crude solution was added N,N-diisopropylethylamine (0.05 mL, 0.26 mmol), 4-(dimethylamino)pyridine (6.8 mg, 0.05 mmol), and di-tert-butyl dicarbonate (120.9 mg). After 90 minutes, the reaction mixture was washed with water (2×30 mL), dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (0-50% ethyl acetate/hexane) afforded tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate as an amber residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35]Cl)(=[O:34])=[O:33])=[CH:30][CH:31]=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[N:35][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=NS(=O)(=O)c4ccc(C)cc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
The N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (213 mg, 0.603 mmol) was dissolved in dry CH2Cl2 (11.5 mL) and then treated with hexadecyl-tributylphosphonium bromide (138 mg, 0.271 mmol). To this clear, colorless solution, the chloramine-T (165 mg, 0.723 mmol) was added. The resultant cloudy solution was stirred at room temperature for three hours. At this time, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was transferred to a separatory funnel and diluted with CH2Cl2 (10 mL). This solution was washed with cold 5% NaOH (20 mL), water (20 mL), and brine (20 mL). The aqueous portions were combined and then back-extracted with more CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resultant material was chromatographed on silica gel (100 g), eluting with a gradient of 0%-6% MeOH in 10% CH3CN/CHCl3 to give 314 mg (99%) of the title compound as a white solid which decomposes at 79° C. and has a HRMS (FAB) calculated for C23H28FN4O5S2 (M+H)+, 523.1485, found 523.1477.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[C:16]([C:17]2[N:21]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:19]=3[N:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[CH:23]1([CH2:22][N:21]2[C:20]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:19]=3[N:18]=[C:17]2[C:16]2[C:11]([O:9][CH2:8][CH:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: OCC1CCCC1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a suspension of sodium hydride (20 mg, 0.51 mmol, 60%) in dry N,N-dimethylformamide (5 ml) at 25° C. was slowly added a solution of cyclopentyl-methanol (30 mg, 0.30 mmol; CAS Reg. No. 3637-61-4) in dry N,N-dimethylformamide (5 ml) and the suspension was stirred for 0.5 h. A solution of 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (90 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (20-30% ethyl acetate/n-hexane) to afford the title compound as a colorless solid (54%). MS (Turbo Spray): m/z=426.3 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.[CH2:21]([C:23]1[CH:28]=CC=C[CH:24]=1)C.[CH3:29][O:30][C:31](=[O:55])[CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:34]=1.BrCC(C)=C>C1COCC1>[CH3:29][O:30][C:31](=[O:55])[CH:32]([C:33]1[CH:34]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[CH2:24][C:23]([CH3:28])=[CH2:21]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCc1ccccc1
Agent: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A 2M solution of LDA in THF-heptane-ethylbenzene (21.5 mL, 43.0 mmol) was added dropwise over 12 min to a stirred solution of (3,5-bis-benzyloxyphenyl)acetic acid methyl ester (prepared in Example 1, step (a)) (13.0 g, 35.9 mmol) in THF (80 mL) at −78° C. under a nitrogen atmosphere. The temperature was maintained below −70° C. for an additional 50 min, then 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added in one portion and the reaction mixture was warmed to 0° C. After 2 h the mixture was concentrated in vacuo, diluted with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-10% EtOAc in petroleum ether) to afford the title product as a yellow oil (14.1 g, 94%). 1H-NMR (400 MHz, CDCl3): δ7.42-7.25 (m, 10H), 6.58 (s, 2H), 6.52 (s, 1H), 5.02 (s, 4H), 4.74 (s, 1H), 4.66 (s, 1H), 3.74 (t, 1H), 3.64 (s, 3H), 2.79 (dd, 1H), 2.38 (dd, 1H), 1.70 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:17]1[CH2:16][CH2:15][N:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
Potassium carbonate (3.4 g, 25 mmol) was added to a mixture of N-Boc-piperazine (3.0 g, 16 mmol) in acetonitrile (20 mL). Methyl bromoacetate (1.5 mL, 16 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was filtered over celite. Filtrate was concentrated in vacuo. Residue was treated with diethyl ether (10 mL), filtered and concentrated in vacuo. Bulb to bulb distillation (165° C. at 700 mtorr) gave the title compound as clear colorless oil in 60% yield. MS m/e (M+H)+=259.4.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[S:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:25]([O:27]CC)=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[S:21][CH3:1]
Reactant: CCOC(=O)c1ccc(OC)c(SCl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)O)cc1SC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Triphenylphosphine (20.5 g; 78.2 mmol) was introduced a little at a time into a solution of 5c (5.1 g; 18.3 mmol) in toluene (50 ml). The reaction mixture was stirred at room temperature for 4.5 h. The precipitate (triphenylphosphine oxide) was filtered off, and the yellow filtrate was extracted with 10% strength aqueous sodium hydroxide solution (4×). Dimethyl sulfate (2 ml) was added to the combined aqueous extract, and the reaction mixture was stirred at room temperature for 2 h. The precipitate obtained was dissolved by heating to reflux temperature. The clear solution was cooled and adjusted to pH 1 using 20% strength hydrochloric acid. The precipitate (7c) was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: [CH3:1][Li].[O:3]1[C@H:5]2[CH2:6][C@H:7]3[C@:22]([CH3:24])([CH2:23][C@@H:4]12)[C@@H:21]1[C@H:10]([C@H:11]2[C@:18]([CH3:26])([CH2:19][C:20]1=[O:25])[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[Cl-].[NH4+]>CCOCC>[OH:3][C@@H:5]1[C@@H:4]([CH3:1])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
A 1.6 molar solution of methyl lithium in ether (30 ml.) was added to a stirred suspension of cuprous iodide (4.56 g.) in dry ether (100 ml.) under nitrogen at -20°. A cold solution of 2α,3α-epoxy-5α-pregnane-11,20-dione (1.33 g.) in dry ether (20 ml.) was then added and the mixture was maintained at 0° for 40 hours and then at room temperature for 4 hours. The mixture was then poured into aqueous ammonium chloride solution and extracted into ethyl acetate. The organic extract was washed with water, dried (MgSO4) and evaporated in vacuo. The residue (2.9 g.) was purified by preparative TLC and crystallisation from methyl acetate/petroleum ether to give the title compound (0.5 g.) m.p. 142°-146° [α]D + 121+ (c 0.8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:14][C:15]([Cl:19])([CH3:18])[CH:16]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:20]1([CH:16]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([Cl:19])([Cl:14])[CH3:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: COc1cc(OC)cc(C(N)=O)c1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(OC)cc(C(=O)NC(n2nnc3ccccc32)C(C)(Cl)Cl)c1

Procedure:
A suspension of 3,5-dimethoxybenzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:19][N:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]=[C:15]1[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CNc1ccccc1N
Agent: [Na+]
Product: Cn1c(Cc2nc(N3CCOCC3)cc(=O)[nH]2)nc2ccccc21
Yield: 60.2 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 280 mg of N-methyl-1,2-phenylenediamine in place of the 4-bromobenzene-1,2-diamine. After purification by silica column chromatography, eluent: a gradient of the pure CH2Cl2 eluent to CH2Cl2/MeOH: 90/10, 225 mg of 2-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([N:19]2[C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[N:21]=[CH:20]2)[N:11]=1>CS(C)=O>[ClH:9].[ClH:9].[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([C:12]3[N:11]=[C:10]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]4)[N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[CH:20]=[N:21][C:22]=2[CH:27]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc2c(c1)ncn2-c1nc(Cl)nc2[nH]cnc12
Solvent: CS(C)=O
Product: COc1ccc2c(c1)ncn2-c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Product: Cl
Temperature: 120 °C

Procedure:
969 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (70° C.), 5100 mg of product obtained in stage 1 above (no name) and 10 ml of DMSO are added in a single step, and the mixture is then heated at 120° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH—NH4OH: 98-2 mixture for eluent. The purified product is dissolved in ethanol and HCl-AcOEt is then added. Partial drying and drying under vacuum at 60° C. are carried out. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 75-23-2 mixture for eluent. 258 mg of expected product are obtained, in the form of beige-colored crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]([CH:30]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27](O)=[O:28])([CH3:21])([CH3:20])[CH3:19].P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:34]([C:31]1[CH:30]=[C:24]([CH:23]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)=[O:28])([CH3:36])([CH3:37])[CH3:35]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1ccc(N2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Yield: 74 %

Procedure:
To a solution of 18.75 g. (80 mmole) ethyl 4-(piperazin-1-yl)-benzoate and 22.1 g. (80 mmole) 3,5-di-tert.-butyl-4-hydroxycinnamic acid in 160 ml. anhydrous pyridine is added dropwise, with ice cooling, a solution of 5.5 g. (40 mmole) phosphorus trichloride and 25 ml. anhydrous pyridine and the reaction mixture is further stirred for 1 hour with ice cooling, then poured on to ice and acidified with concentrated hydrochloric acid. The aqueous phase is extracted with ethyl acetate and the extracts are washed three times with 0.5N hydrochloric acid, dried and evaporated. The residue is recrystallised twice from a mixture of 240 ml. ethanol and 80 ml. water to give 29.2 g. (74%) of the desired product; m.p. 147°-150° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=4[F:26])=[O:18])[CH2:13][CH2:12]3)=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1.[CH3:27][C@@H:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[NH:29]1>>[CH:1]1([C:4]2[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:29]5[C@H:28]([CH3:27])[CH2:32][CH2:31][S:30]5(=[O:34])=[O:33])=[CH:21][C:20]=4[F:26])=[O:18])[CH2:13][CH2:12]3)=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C2CC2)c1
Yield: 45.7 %

Procedure:
Using [4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (627 mg) described in Preparation Example 183 and (R)-3-methylisothiazolidine 1,1-dioxide (182 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (291 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)N(C)C)CC2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (6.4 mg, 0.059 mmol) was added to a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.3 mg, 0.030 mmol) and triethylamine (12 μL, 0.089 mmol) in DCM (300 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (11.1 mg, 63.8%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.3 Hz, 6H), 1.91-2.01 (m, 2H), 2.09-2.18 (m, 2H), 2.86 (t, J=5.7 Hz, 2H), 2.90 (s, 6H), 3.03-3.11 (m, 2H), 3.39-3.47 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 4.14 (quin, J=6.4 Hz, 1H), 4.27 (s, 2H), 4.49 (tt, J=7.3, 3.6 Hz, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.