Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[O:12][C:8]=2[CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:16]1([C:14]([NH:13][C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)[CH:20]=[CH:19][C:9]=3[N:10]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (128 mg, 415 μmol) in pyridine (3 mL) were added a solution of 3-(trifluoromethyl)benzoyl chloride prepared above in pyridine (2 mL) and N,N-dimethylpyridine-4-amine (58.9 mg, 482 μmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL) and ethyl acetate (100 mL). This solution was washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (101 mg, 50%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1
Yield: 78 %

Procedure:
3-(1-Methyl-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXLIII (78% yield) was prepared from 6-bromo-1-methyl-1H-indole using the procedure described above for preparation of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[BH4-].[Li+].C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of methyl 4-bromo-3,5-dimethoxybenzoate (133.2 g) in tetrahydrofuran (500 mL) was added lithium borohydride (20.8 g) slowly at room temperature, and the mixture was further stirred for 3 hours under reflux with heating. The reaction mixture was cooled down to room temperature, and ice water (1.5 L) and ethyl acetate (1.2 L) were added, and extraction with ethyl acetate was performed. The resultant organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain 118.8 g of a title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:22]3[C:17]([CH:18]=[C:19]([C:27]([O:29]CC)=[O:28])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH:24]3[CH2:25][CH2:26]3)=[C:22]3[C:17]([CH:18]=[C:19]([C:27]([OH:29])=[O:28])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CC3)c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of compound ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropyl-isoquinoline-3-carboxylate (425 mg, 1 mmol) in EtOH/THF (5 mL) was added NaOH (5 ml, 2 N) followed by stirring for 2 hrs at r.t. After extraction by EA, the residue was concentrated in vacuo to give 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropylisoquinoline-3-carboxylic acid as a yellow solid (400 mg, yield: 95%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]1([N:14]([C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1CCCCC1.Cl>N1C=CC=CC=1>[C:21]1([N:14]([C:8]2[CH:9]=[CH:10][C:11]([CH:1]=[CH:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:27][CH:28]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
All glassware was dried in a drying oven heated to 140° C. Malonic acid was dried on a high vacuum line over P2O5 and then stored in a nitrogen purged glovebox. Pyridine (Aldrich, anhydrous, 99.8%) and piperidine were used as received and stored in the glovebox. In a 100 mL round bottom flask equipped with a stir bar, condenser and nitrogen inlet-outlet was dissolved malonic acid (2.3 g, 22.0 mmol) in 20 mL pyridine. 4-(N,N-Diphenylamino)benzaldehyde (5.0 g, 18.3 mmol) was added and addition of 20 mL pyridine was necessary to obtain a solution. Piperidine (0.18 mL, 1.8 mmol) was added and the solution was heated to reflux. After heating for 25 hours, malonic acid (0.60 g, 5.8 mmol) was added and heating was resumed for an additional 2.5 h after which time no further reaction was observed. The reaction mixture was allowed to cool to room temperature and then poured into a stirring mixture of 12 N HCl in ice water (1:5). The mixture was filtered and the solids rinsed three times with 20 mL water. The solids were collected and the crude product was purified by recrystallization from 5:3 hexanes:EtOAc at 4° C. The mother liquor was concentrated and recrystallized in a similar fashion from 7:3 hexanes:ethyl acetate. The combined crops give 3.1 g of a light brown powder. The yield was 55%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([OH:34])[CH:33]=1.[F:35][C:36]([F:40])([F:39])[CH2:37]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([O:34][CH2:37][C:36]([F:40])([F:39])[F:35])[CH:33]=1
Reactant: FC(F)(F)CI
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(O)c3)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(OCC(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of (S)-2-(1-((6-amino-5-(5-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (49 mg, 0.11 mmol), 1,1,1-trifluoro-2-iodoethane (13 μl, 0.13 mmol) and potassium carbonate (30 mg, 0.22 mmol) in N,N-dimethylformamide (3 ml) was stirred at 120° C. under microwave irradiation for 2 h. Further 1,1,1-trifluoro-2-iodoethane (13 μl, 0.13 mmol) and potassium carbonate (15 mg, 0.11 mmol) were added and the reaction mixture was stirred at 120° C. under microwave irradiation for 2 h. The residue was purified by reverse phase using SP1® Purification System to give 32 mg (55% yield) as a solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](=O)[CH3:8].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14].C(O)(C)C>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=2)[CH:6]=[C:7]([CH3:8])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CC(=O)C=Cc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1cccc(Cl)c1
Yield: 56 %

Procedure:
After heating a solution of 18.1 g of 3-chlorobenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 3 hours, 2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 140°C (isopropanol) is obtained. Yield: 56 percent of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][C:26]3([CH3:31])[CH3:30])[C:17]=2[N:32]=1)[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][C:26]3([CH3:31])[CH3:30])[C:17]=2[N:32]=1)[C:6]([NH:66][CH:67]1[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]1)=[O:8]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1(C)C)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1(C)C)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
A mixture of 0.043 g (0.0001 mole) of (rac)-3-methoxy-4-[5-methyl-9-(2,2-dimethyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-59a), 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.044 mL (0.00025 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.048 g of (rac)-3-methoxy-4-[5-methyl-9-(2,2-dimethyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(1-methyl-piperidin-4-yl)-benzamide (I-59) as a white solid.
Reaction SMILES: ClC1C=C(C[CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40]CC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][CH:28]1[CH2:29][CH2:30][CH:25]([N:11]([CH2:10][CH2:9][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: Cc1ccc(CCCC(=O)O)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methyl-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([F:14])[F:13])[CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][CH:12]([F:14])[O:11][C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1ccc(Br)cc1OC(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(-c2ccc([N+](=O)[O-])c(OC(F)F)c2)cn1

Procedure:
A suspension of 4-bromo-2-(difluoromethoxy)-1-nitrobenzene (Preparation 215, 174 mg, 0.65 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150 mg, 0.72 mmol), Pd(dppf)Cl2.DCM (55 mg, 0.068 mmol), Na2CO3 (2M, 0.65 mL, 1.3 mmol) in THF (4 mL) was stirred at 65° C. for 18 hours.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CS(C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 4 h
Yield: 88 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 60 ml of dimethyl sulfoxide is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at +40° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 4 hours at +40° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and filtered through silica gel. The solution is separated by distillation, affording 36.5 g (88% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[CH2:10][CH2:11][CH:12]=O)=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])[CH2:10][CH2:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=CCCC(=O)Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCC=C1c1ccc(F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of 8 g of 1-(4-fluorophenyl)-5-oxo-2-pentanone in 300 mL of MeOH was treated with 2 g of NaOMe. The mixture was stirred for 2 h and then quenched with 5 mL of HOAc. The solvent was evaporated and the residue purified by flash chromatography, eluting with 3:1 hexane/EtOAc to give 7 g of the title product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(/C=C/c2nc(-c3ccc4ccccc4c3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Methyl (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzoate (9.30 g) was suspended in THF (250 ml), and lithium aluminum hydride (955 mg) was added little by little at 0° C. After mixture stirring at room temperature for 1 hour, water (5 ml) was added; the insoluble substances were filtered off. The filtrate was concentrated under reduced pressure; the resulting crystal was recrystallized from dichloromethane-methanol to yield (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzyl alcohol (8.00 g, 93%) as colorless prisms having a melting point of 173°-174° C.
Reaction SMILES: [C:1](=S)([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.Br.C(SCC1C=CC=CC=1)(=N)C1C=CC=CC=1.N1C=CC=CC=1.[NH2:41][CH:42]([C:48]#[N:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1.C(Cl)(Cl)Cl>[NH2:49][C:48]1[NH:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:41][C:42]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(N)C#N
Agent: Br
Agent: BrCc1ccccc1
Agent: N=C(SCc1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)[nH]c1N
Temperature: 25 °C
Yield: 69.2 %

Procedure:
Benzothioamide (1.37 g, 10 mmol) and benzylbromide (1.71 g, 10 mmol) in dry THF were heated to 60° C. for 2 h. After it was allowed to cool to room temperature, the reaction mixture was filtered. The desired benzyl benzimidothioate hydrobromide as a white solid (2 g, 65%) without further purification. To a solution of benzyl benzimidothioate hydrobromide (1.54 g, 5 mmol) in dry CHCl3 was added in one portion dry pyridine (5 mmol) at ambient temperature followed by ethyl 2-amino-2-cyanoacetate (0.64 g, 5 mmol). The reaction mixture was then heated to 65° C. for 2 h. After cooling to room temperature, the mixture was filtered to give the ethyl 5-amino-2-phenyl-1H-imidazole-4-carboxylate as a yellow colored solid (0.8 g, 68%). This solid (0.46 g, 2 mmol) was added with dry THF, Boc2O (0.87 g, 4 mmol), DMAP (24 mg, 0.2 mmol). The reaction was heated to 65° C. for 5 h. The solvent was evaporated in vacuo to give crude product. This crude product was then dissolved in MeOH—H2O (30 mL, 1:1) and LiOH was added in one portion. The reaction mixture was heated at 70° C. until starting material disappeared by TLC (˜4 h). The mixture was then cooled to ˜0-4° C. and 1N aq HCl was added cautiously dropwise until pH ˜5. The resulted mixture was extracted with DCM (3×20 mL). Combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC. The desired product 5-(tert-butoxycarbonylamino)-2-phenyl-1H-imidazole-4-carboxylic acid was obtained as white solid (0.1 g, 16%). 1H-NMR (DMSO, 500 MHz) δ (ppm): 9.01 (s, 1H), 8.05 (s, 2H), 7.35-7.42 (m, 3H), 1.45 (s, 9H); MS (ESI) m/z: 304 [M+H+].
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br.O[CH2:7][CH2:8][NH:9][C:10](=[O:35])[C@@H:11]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>C(O)(=O)C>[C:1]([O:4][CH2:7][CH2:8][NH:9][C:10](=[O:35])[C@@H:11]([NH2:24])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)OCc1ccccc1
Agent: Br
Product: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
A 30% hydrogen bromide acetic acid solution (13.1 mL, 65.9 mmol) was added to an acetic acid (4.4 mL) solution of benzyl (1S)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethylcarbamate (9.36 g, 22.0 mmol) prepared in Reference Example 6 (6b) under ice-cooling with stirring. The mixture was stirred at room temperature for 4 hours, and then ice water (300 mL) was added thereto. The reaction solution was washed with diethyl ether (50 mL, three times), and subsequently the water layer was neutralized with sodium bicarbonate (about 40 g) and extracted with methylene chloride (300 mL, three times). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give 5.89 g of the title compound (yellow solid, yield: 80%).
Reaction SMILES: [I:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([I:11])[C:5]([N+:12]([O-])=O)=[C:4]([I:15])[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[Sn].Cl>>[I:1][C:2]1[C:7]([NH2:8])=[C:6]([I:11])[C:5]([NH2:12])=[C:4]([I:15])[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2c(I)c([N+](=O)[O-])c(I)c([N+](=O)[O-])c2I)cc1
Agent: Cl
Agent: [Sn]
Product: Cc1ccc(-c2c(I)c(N)c(I)c(N)c2I)cc1

Procedure:
The nitro groups of 2′,4′,6′-triiodo-3′,5′-bis(nitro)-4-methylbiphenyl (7) are reduced to amines by reaction with tin and hydrochloric acid to yield 2′,4′,6′-triiodo-3′,5′-bis(amino)-4-methylbiphenyl (8). The product is used in the preparation of Examples 1, 2, and 3 of the present invention.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH:22]C(OC(C)(C)C)=O)[CH2:16][C:17]2[N:18]=[N:19][NH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C@@H:15]([NH2:22])[CH2:16][C:17]2[N:18]=[N:19][NH:20][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c[nH]nn2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2c[nH]nn2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 739 mg 4-[(S)-2-tert-Butoxycarbonylamino-3-(1H-[1,2,3]triazol-4-yl)-propionyl]-piperazine-1-carboxylic acid butyl ester in 8 ml dichloromethane were added 1.3 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 1.32 g.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])C.[F:24][C:25]([F:37])([F:36])[CH:26]([CH3:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH:26]([CH3:35])[C:25]([F:24])([F:36])[F:37])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)[CH:7]([OH:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1 step C from a mixture of (3RS,4SR)-1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester and (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine. Light yellow solid. MS (ESI): 449.2 (MH+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(S(C)(=O)=O)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a suspension of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (122.4 mg, 0.39 mmol) and N,N-diethylethanamine (103.9 mg, 1.03 mmol) in DCM (10 mL) was added methanesulfonyl chloride (98.4 mg, 0.86 mmol). The reaction mixture was stirred at rt for 2 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (64.8 mg, 42.4%).