Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8][C:7]=1[O:17][CH:18]([CH2:21][CH2:22][N:23]=[N+]=[N-])[CH2:19][CH3:20])=[O:5])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][CH2:8][C:7]=1[O:17][CH:18]([CH2:21][CH2:22][NH2:23])[CH2:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(OC(CC)CCN=[N+]=[N-])CCC(OS(C)(=O)=O)C1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1=C(OC(CC)CCN)CCC(OS(C)(=O)=O)C1
Reaction time: 24 h

Procedure:
(3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-azido-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (46) and Lindlar catalyst in ethanol was added. The flask was charged with hydrogen gas (1 atm) at room temperature. The resulting suspension was vigorously stirred for 24 hours. The reaction mixture was diluted with dichloro methane and the combined organic layers were filtered through a Celite pad. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-amino-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester as a pale yellow liquid, which was used without further purification in the next step. (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-amino-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester was coupled with Fmoc-PEG-acid (16 atoms) in the presence of EDC, HOBT plus DIPEA in dichloro methane. The solution was stirred over a period of 18 hours the room temperature. The crude product was purified by a silica column chromatography using a 8:2 mixture of dichloro methane and hexane. The combined fractions were evaporated and dried over Na2SO4 and the combined organic phases were evaporated on a rotary evaporator to obtain as (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-Fmoc-Peg-amide-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (47).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:25][C@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41]2[C:46]([Cl:47])=[CH:45][N:44]=[C:43](Cl)[N:42]=2)(=[O:33])=[O:32])[CH2:27]1)(C)(C)C>>[Cl:47][C:46]1[C:41]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:31]([N:28]2[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]2)(=[O:32])=[O:33])=[N:42][C:43]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:44][CH:45]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(CC(C)(C)O)CC2
Yield: 65 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as a white solid (80 mg, 65%). mp: 204-205° C., MS (ESI+): 617 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 7.97 (m, 2H), 7.53 (m, 2H), 7.25 (m, 1H), 6.65 (s, 1H), 3.60 (br s, 1H), 3.89 (s, 3H), 3.42 (q, 6 Hz, 3H), 3.30 (m, 2H), 2.87-2.72 (m, 8H), 2.48 (s, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.57 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:26]2[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:32][C:27]1[C:26]([N:12]2[C:13]([S:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:24]#[N:25])(=[O:16])=[O:17])=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[N:11]2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN(Cc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
tert-Butyl({5-[(3-cyanophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (247 mg) was dissolved in ethyl acetate (2 mL) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 184 mg, yield 86%). melting point 237-240° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OC(C)(C)C(=O)O)cc2)CC(C)(C)C1
Yield: 82.5 %

Procedure:
The hydrolysis conditions described for 191 were used. A solution of ethyl 2-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-2-methylpropanoate (227) (0.15 g, 0.33 mmol) in THF/EtOH (1:1, 6 mL) was treated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. Reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up followed by purification afforded 0.115 g (82%) of the title compound 228 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 13.0 (br s, 1H), 9.26 (s, 1H), 7.00 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 1.89 (d, J=4.5 Hz, 4H), 1.48 (s, 6H), 1.25 (br s, 2H), .88 (s, 12H). LCMS (ESI): m/z 421 (M−H)−. Anal. Calcd for C27H4O4.H2O, C, 73.77; H, 8.19; Found: C, 74.78, H, 8.14.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13].Cl.[CH3:20][N:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>CN(C)C=O.C(OCC)C>[CH2:9]([S:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])[CH:7]=1)[CH3:10]
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(NC(=O)CN(C)C)c1
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
A stirred solution of 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (8.35 g.) in dry dimethylformamide (60 ml.) was treated at room temperature with N,N-dimethylglycyl chloride hydrochloride (5.53 g.). The mixture was heated to 40°-50° C. for 45 minutes, then cooled, and diluted with diethyl ether (900 ml.). An oil precipitated which crystallised on standing. This solid was filtered off, washed with diethyl ether (100 ml.), and suspended in a mixture of chloroform (100 ml.) and water (100 ml.). Sodium carbonate (3.5 g.) was added and the mixture was stirred for 20 minutes. The chloroform layer was separated and the aqueous layer was extracted twice with chloroform (2× 50 ml.). The organic layers were combined, dried over magnesium sulphate and evaporated to dryness. The residual solid was recrystallised from isopropanol to give 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-(2-dimethylaminoacetamido)benzene (8.5 g.), m.p. 142° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([N:14]1[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[C:11](=[O:26])[C:12]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:16][C:13]1=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added benzylbromide (130 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 400 mg (79%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:9])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(3-phthalimidoprop-1-yloxy)phenyl]benzamide (760 mg) in ethanol (15 ml) was added hydrazine hydrate (828 mg) and the solution was stirred at ambient temperature for 1 days. After evaporation in vacuo, the residue was diluted with ethyl acetate and then the organic solution was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded 4-nitro-N-methyl-N-[2-(3-aminoprop-1-yloxy)phenyl]benzamide (422 mg) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[CH3:13].[CH3:14][NH2:15].CO>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:15][CH3:14])=[C:3]1[CH3:13]
Reactant: Cc1c(C=O)c2ccccc2n1C
Reactant: CN
Solvent: CO
Product: CN=Cc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1,2-dimethylindole-3-carboxaldehyde (11.50 g, 66.4 mmole) was added a solution of 2 M methylamine in methanol (100 mL, 200 mmole). The reaction was stirred for 4 h at RT then was concentrated to dryness to afford the crude title compound: 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=1.4 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.15 (t, 1H), 7.07 (t, 1H), 3.68 (s, 3H), 3.41 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])[CH3:16])=[CH:11][CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH:15]([C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)[CH3:16])=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (4.80 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.50 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (1.50 g, 43%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH:17]1C=CC=CC=1>>[CH3:17][O:11][C:10](=[O:12])[C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 6-nitro-benzoic acid in benzene was treated with thionyl chloride (2.5 eq) and stirred at reflux for 8 h. After evaporation, the residue was dissolved in chloroform and then treated with methanol. After stirring at reflux for 3 h, the mixture was evaporated to afford compound 3.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][CH2:48][CH2:49][CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][CH2:49][CH2:48][F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCCF
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCCF)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 3-fluoro-propylamine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2FN5O3 [(M+H)+] 724.3191, observed 724.3190.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=3)=[S:28])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Sc2ccnc3ccccc23)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccnc4ccccc34)cc2)ccc1Cl
Yield: 0.1 %

Procedure:
4-(4-aminophenylthio)quinoline (3.9 moles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.9 moles, 0.92 g) were reacted according to procedure A to yield of the title compound 1.06 g, 56%. Mass spec (FD) 490. Calculated for C23H15ClF3N3S2 : C, 56.38; H, 3.09, N, 8.58. Found: C, 56.60; H, 3.11; N, 8.42.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[C:15]([C:17]1[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[CH:28][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1)#[N:16]>CN(C=O)C>[C:15]([C:17]1[CH:31]=[C:30]([CH2:32][O:33][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)[CH:29]=[CH:28][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1)#[N:16]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cn1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and 5-(2-cyano-4-(hydroxymethyl)phenoxy)picolinonitrile (67.7 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH:21]([NH:23][C:24](=[O:36])[C@H:25]([CH:33]([CH3:35])[CH3:34])[NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH3:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:20][CH:21]([NH:23][C:24](=[O:36])[C@H:25]([CH:33]([CH3:35])[CH3:34])[NH:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[CH3:22])=[O:9])=[CH:15][CH:14]=1
Reactant: CC(CSc1ccc(F)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(CS(=O)c1ccc(F)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
1.3 g of m-chloroperbenzoic acid was added to a solution containing 2.5 g of N1 -[2-(4-fluorophenylthio)-1-methylethyl]-N2 -isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene chloride, at 0° C. After the mixture was stirred for 5 hours at room temperature, the reaction mixture was filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel, thus obtaining 1.8 g of the desired product in the form of a colorless prism-shaped crystal (yield: 69%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[BrH:10].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:10][CH2:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CC(=O)c1cnn(C)c1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-methyl-1H-pyrazol-4-yl)ethanone (0.602 g, 4.85 mmol) in chloroform (20 mL) and of 33% HBr in acetic acid (3.92 mg, 0.05 mmol) was added dropwise a chloroform solution containing Br2 (0.262 mL, 5.09 mmol) via an addition funnel. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude solid was triturated in ethyl acetate, filtered, washed and dried in vacuo. The free base was obtained by triturating the product in 5% NaHCO3 for 2 h. The solid that formed were collected by filtration, washed with water and isopropyl alcohol and then dried in vacuo. Isolation gave 874 mg of the title compound.
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Cl:15][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C.CCCCCCC>[Cl:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Reactant: C[Si](C)(Cl)Cl
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCCCCCC
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 14 h
Yield: 69.5 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol), dichlorodimethylsilane (1.01 g, 7.80 mmol), tetraethylammonium chloride (0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol) were added to heptane (4 ml), and the mixture was heated to 50-60° C. and stirred for 14 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the mixture was adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give a white powder (0.31 g, yield 73.8%) of 2,6-dichloropurine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Mg+2].[CH2:12]=[O:13].Cl>C(#N)C.C(N(CC)CC)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH:12]=[O:13]
Reactant: Oc1ccc(I)cc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Yield: 66 %

Procedure:
To the mixture of 20 g (91 mmol) of 4-iodophenol and 25.1 g (264 mmol) anhydrous magnesium dichloride in 455 mL of anhydrous acetonitrile was added triethylamine and paraformaldehyde. The mixture was heated to reflux for 4 h, allowed to cool to rt and treated with 500 mL of 5% HCl. The solution was extracted three times with EtOAc. The combined organic extracts were washed with brine (3×) and dried over anhydrous magnesium sulfate. The dried organic solution was evaporated to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (2:8). Concentration of the desired fractions afforded 15 g (66%) of a yellow solid, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[C:39]([CH3:44])[N:40]=[C:41]([CH3:43])[CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (163 mg, 0.5 mmol) according to the general procedure M. Obtained as a white solid (185 mg, 67%).