Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]C1C=C2C(=C(CSC)C=1)NC=C2.[Cl:14][C:15]1[CH:20]=[C:19](F)[C:18](C(C2CC2)O)=[C:17]([F:27])[CH:16]=1.ClC1C=CC([CH:35]([CH:48]2[CH2:50][CH2:49]2)[C:36]2[C:44]3[C:39](=[C:40]([CH2:45][S:46][CH3:47])[CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)=CC=1>>[Cl:14][C:15]1[CH:16]=[C:17]([F:27])[CH:18]=[CH:19][C:20]=1[CH:35]([CH:48]1[CH2:49][CH2:50]1)[C:36]1[C:44]2[C:39](=[C:40]([CH2:45][S:46][CH3:47])[CH:41]=[C:42]([F:1])[CH:43]=2)[NH:38][CH:37]=1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 200 mg (1.02 mmol) of the compound from Example 11A and 206 mg (1.02 mmol) of the compound from Example 156A in analogy to the synthesis of the compound from Example 227. 247 mg (64% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl.O>[Cl:34][CH2:35][C:36]([N:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH2:18][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:14]1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)CCl)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 24.9 %

Procedure:
To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2Cl2 cooled to 0° C. was added to 1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0° C. and 926 μl of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and H2O. The insoluble solid was filtered off. The organic layer of the filtrate was separated , washed with brine, dried with Na2SO4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzo-diazepine-3-carboxylate (Reference EXample 91). Anal. for C20H21ClN2O6S: Calc'd: C, 53.0; H, 4.7; N, 6.2; Found: C, 51.6; H, 4.6; N, 5.7.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[O:34][C:33]=2CO)[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl.CO>[Br:24][CH2:21][C:33]1[O:34][C:35](=[O:42])[C:36]2[C:41]([C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=c1oc(CO)c(-c2cccc(F)c2)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=c1oc(CBr)c(-c2cccc(F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triphenylphosphine (265 mg, 1.01 mmol) and perbromomethane (335 mg, 1.010 mmol) were added to a solution of 4-(3-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B3, 210 mg, 0.777 mmol) in DCM (6.5 ml) and the mixture was stirred overnight at RT. Further triphenylphosphine (265 mg, 1.010 mmol) and perbromomethane (335 mg, 1.01 mmol) were then added and left on stirring at RT for 6 hrs. The reaction was then diluted with MeOH (1 ml) and straightforward purified on 50 g Biotage silica cartridge eluting with a gradient of Hexane and EtOAc to give the title compound (154 mg, 59.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)S(O[CH2:16][CH:17]([F:19])[F:18])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:16][CH:17]([F:19])[F:18])=[CH:6][N:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1cc(Cl)ncc1O
Product: Cc1cc(Cl)ncc1OCC(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (4.14 g, white solid) from 6-chloro-4-methylpyridin-3-ol (3.0 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (4.92 g, 23.0 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: C1COCC1.O.[N:7]([CH2:10][C:11]1([C:32]([F:35])([F:34])[F:33])[C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:13](=[O:31])[O:12]1)=[N+]=[N-].P(OC)(OC)OC>C(OCC)(=O)C>[NH2:7][CH2:10][C:11]1([C:32]([F:34])([F:35])[F:33])[C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:13](=[O:31])[O:12]1
Reactant: COc1ccc(CN2C(=O)OC(CN=[N+]=[N-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: COP(OC)OC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)OC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixed solution of THF (130 mL) and water (65 mL) containing 4-(azidomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (46 g, 98.0 mmol), trimethyl phosphite (23.1 mL, 195 mmol) was added at room temperature, and the reaction solution was stirred overnight at 60° C. After the reaction solution was left to cool, water was added thereto, and the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. To the residue, a 4 N hydrochloric acid-dioxane solution (200 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, which was washed sequentially with a 2 N aqueous sodium hydroxide solution and saturated brine and the organic layer was dried over magnesium sulfate, whereby the objective compound (30.9 g, 71%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:26][C@H:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@@H]1CCc2ccccc21
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (R)-(−)-1-aminoindan.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C[Si]([N-:14][Si](C)(C)C)(C)C.[Li+].[ClH:20]>C(OCC)C>[ClH:20].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:14])=[NH:8])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(C(=N)N)cc1
Reaction time: 2 h

Procedure:
To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl ether was added 23 g of solid lithium bis(trimethylsilyl)amide at ambient temperature. The mixture was stirred for 2 hours then hydrolysed-with 10% HCl at 0° C. The mixture was stirred for an additional 30 minutes and then concentrated to dryness to yield 6 g of 4-methylbenzamidine hydrochloride which was used in the next step without further purification
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C(C)C)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 13.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(4-isopropylpiperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (79 mg, 0.121 mmol) was hydrolyzed by lithium hydroxide (55 mg, 1.21 mmol), THF/Methanol/water (15/5/5 ml) to yield 8 mg (13.3% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.0 (b, 1H), 8.55 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.7 (s, 1H), 7.46-7.3 (m, 3H), 7.2-6.9 (m, 3H), 5.389 (s, 2H), 3.4 (m, 4H), 2.7 (m, 4H), 1.4-1.0 (m, 7H). MS: m/z=495.4 (M+1); HPLC: 89.22% in method B.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>O>[CH3:1][C:2]1([CH3:15])[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Oc2cc3nc(SCc4ccccn4)[nH]c3cc2O1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 4.45 g of 2,2-dimethyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 100 ml of alcohol, were added dropwise while stirring 1.63 g of sodium hydroxide in 50 ml of water and, after 30 minutes, there were added 3.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of 3N sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from acetonitrile. There were obtained 4.6 g (73.4% of theory) of 2,2-dimethyl-6-[(2-pyridyl-methyl)thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 210°-211° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:10])[CH3:17]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Sodium hydride (4.08 g of a 60% dispersion in mineral oil, 0.10 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (50 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (13.0 g, 0.093 mole) was added in small portions over a 45-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. Ethyl bromoacetate (0.75 mL, 0.097 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (200 mL) and water(200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed through silica gel using 0-20% ethyl acetate/dichloromethane as eluent to afford 15.7 g (75% yield) of the title compound as yellow solid. Rf =0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][N:37]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:38]5[CH:39]=[CH:40][N:41]=[C:36]([Cl:35])[N:37]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (45.9 mg) in DMF (2 mL) was added diisopropylethylamine (73 μL) followed by 2,4-dichloropyrimidine (24.9 mg). The resulting solution was heated to 100° C. for 16 h then the mixture concentrated in vacuo. This crude was purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 18.3 mg of 2-((S)-1-phenylethylamino)-4-(5-(2-chloropyrimidin-4-yl)aminobenzimidazol-1-yl)pyrimidine (L-860,182). 1H NMR (500 MHz, CDCl3, partial): δ 8.51 (br s, 1H); 8.42 (d, J=5.5 Hz, 1H); 8.13 (d, J=5.9 Hz, 1H); 7.75 (s, 1H); 7.45 (d, J=7.3 Hz, 2H); 7.40 t, J=7.7 Hz, 2H); 6.77 (d, J=5.3 Hz, 1H); 6.56 (d, J=6.0 Hz, IH); 1.66 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 443.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17](Cl)=O>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[CH2:17][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>ClCCl.O>[C:16]([N:6]1[CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])(=[O:18])[CH3:17]
Reactant: C[C@H]1CC[C@@H](C(=O)O)NC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C[C@@H](C)CC[C@H]1C(=O)O
Reaction time: 72 h
Yield: 97.8 %

Procedure:
15.9 g (111 mmol) of the (2S*,5S*)-5-methylpiperidine-2-carboxylic acid described above was dissolved in 220 ml of a dichloromethane/water (1:1). 93.3 g (1.11 mol) of sodium hydrogencarbonate and 21.0 ml (222 mmol) of acetic anhydride were added thereto in this order at room temperature, followed by stirring for 3 days. The reaction solution was poured into 6N-hydrochloric acid under cooling with ice, and the extraction with chloroform was conducted. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure to give 20.1 g of the title compound as a colorless oil. Yield 98%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: O=[N+]([O-])c1cccc(F)c1C(Cl)=Nc1c(F)cncc1F
Reactant: NC(N)=S
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(F)c1-c1nc2c(F)cncc2s1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A suspension of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoyl chloride (12.05 g, 36.4 mmol), thiourea (12.05 g, 159 mmol) and pyridine (16 mL, 200 mmol) in isopropanol (200 mL) under a nitrogen atmosphere was heated under reflux for 4 hours. Et3N (33.2 mL, 239 mmol) was added over 5 minutes and the reaction mixture was heated under reflux for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×5) and the combined organic layers were dried (Na2SO4) and concentrated to dryness. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in cyclohexane to afford the title compound as a yellow solid (4.33 g, 41% yield). LCMS (Method D): RT=3.21 min, m/z: 294 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=O)=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[N:37]1C=CC=CC=1C(=O)C.[OH-:46].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:46])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:37]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: [OH-]
Reactant: CC(=O)c1ccccn1
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccn4)ccc3c1)n2C1CCCCC1
Yield: 61 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyridin-2-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (66 mg, 61% yield). MS: 449.19 (M+H+); HPLC Procedure A, retention time=9.85 min.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:48][CH:49]=[CH:50][N:51]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:42]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:51][CH:50]=[CH:49][N:48]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55][C:24]2[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=2)[N:42]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
1-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)-amino]-3-pyridyl}ethan-1-one was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-yl]ethylamine and 1-(6-chloro-3-pyridyl)-ethanone (prepared as described in Tetrahedron 48:9233 (1992)) in accordance to the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH:42][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CCOC(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of acetylalanylalanylproline (2 mmole) and N-methylmorpholine (2 mmole) in dry tetrahydrofuran (20 ml) at -20° to -25° C. is added isobutyl chloroformate (2 mmole). After 5 minutes a solution of 2-azaalanine ethyl ester (2 mmole) in tetrahydrofuran (3 ml) is added dropwise and the reaction mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 4 hours. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography on silica gel (50 gm) and elution with 10% methanol in chloroform gives pure acetylalanylalanylprolyl-2-azaalanine ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[N:43]2[CH2:48][CH2:47]N[CH2:45][CH2:44]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.N1(C(OCC2C=CC=CC=2)=[O:56])CCNCC1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:37][CH:38]=3)=[CH:29][C:28]=2[N:43]2[CH2:44][CH2:45][O:56][CH2:47][CH2:48]2)[C:23]([F:25])([F:26])[F:24])[N:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(N3CCNCC3)c2)cc1
Product: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(N3CCOCC3)c2)cc1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36e) substituting morpholine for benzyl piperazine-1-carboxylate.