Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][NH:4][C:3]1=[O:15].[C:16]1([C:22]2[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH2:7][N:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:27][CH:26]=3)=[O:29])[C:3](=[O:15])[NH:4][N:5]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: NN1CC(c2ccc(F)cc2)=NNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NN1CC(c2ccc(F)cc2)=NNC1=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 49 h
Yield: 25 %

Procedure:
To a slurry of 4-amino-6-(4-fluoro-phenyl)-4,5-dihydro-2H-1,2,4-triazin-3-one (0.26 g, 1.23 mmol), 2-phenyl-pyrimidine-5-carboxylic acid (0.25 g, 1.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g, 1.94 mmol) in DMF (12 mL) is added Et3N (0.2 mL, 1.435 mmol) under N2 and the reaction mixture is stirred at rt for 49 h. The mixture is diluted with EtOAc (120 mL), and washed successively with saturated aqueous NH4Cl (2×50 mL), water (2×50 mL), and saturated aqueous NaCl (50 mL). The organic phase is dried (MgSO4), filtered, and concentrated in vacuo. The residue is triturated with EtOH (30 mL) to afford 2-phenyl-pyrimidine-5-carboxylic acid [6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide (0.12 g, 25%). MS: 391 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.58 (s, 1H), 9.31 (s, 2H), 8.47 (dd, J=7.7, 1.8 Hz, 2 H), 7.70-7.86 (m, 2 H), 7.49-7.67 (m, 3H), 7.18-7.34 (m, 2H), 4.77.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH:12](OCC)=[O:13].O>C(OCC)C>[OH:13]/[CH:12]=[CH:9]/[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: O=C(/C=C/O)Cc1ccccc1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-phenylpropan-2-one (1.78 g, 13 mmol) in anhydrous diethyl ether (50 ml) containing sodium cut in small pieces (299 mg, 13 mmol), ethyl formate (1.4 g, 20 mmol) was added slowly with stirring and ice-cooling. After standing overnight at rt, water was added, and the ether layer was washed with water. The organic phase was dried, concentrated, and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (1.2 g, 57%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[C:42]2[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:44](=[O:49])[O:45][C:46]([CH3:48])([CH3:47])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:47][C:46]1([CH3:48])[O:45][C:44](=[O:49])[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:55])[CH3:56])[C:42]2[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: CC1(C)OC(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)OC3(C)C)cc1

Procedure:
Analogously to Method D, 0.30 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.28 g of 8-bromomethyl-4,4-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.68.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([Cl:21])=[O:20]>C(N(CC)CC)C>[ClH:21].[N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:19](=[O:20])[CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: C1CCN(CC2COCCN2)C1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cc1cccs1)N1CCOCC1CN1CCCC1
Yield: 76.6 %

Procedure:
The procedure described in Example 17 was repeated, but using 0.88 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 0.45 g of 2-thienylacetyl chloride, to afford 0.71 g of the title compound, melting at 215° C. (dec.).
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([OH:21])=O)[CH2:9][CH2:8][CH2:7]1>C(OCC)C>[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([Cl:5])=[O:21])[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)C1=C(C2CCC2)N2CCCN=C2S1
Reactant: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C1=C(C2CCC2)N2CCCN=C2S1
Yield: 115.6 %

Procedure:
To 20 ml of thionyl chloride was suspended 5.0 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid obtained in Example 1, followed by reflux under heating for 30 minutes. Under cooling, an anhydrous diethylether was added dropwise to the reaction mixture to precipitate. The crystals were collected by filtration and washed with anhydrous diethylether to yield 5.4 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl chloride as a pale yellow crystals. To the mixture of 60 ml of pyridine and 20 ml of dimethyl formamide was suspended 2.7 g of the crystal. To the mixture was added 1.5 g of 3,5-dichloroaniline and 60 mg of dimethylaminopyridine, followed by stirring at 70° C. for 17 hours. The solvent was removed under reduced pressure to obtain a residue. Addition of water to the residue caused precipitation of the crystals and the crystals were collected by filtration. After washing with cold methanol, the crystals were suspended to saturated hydrogenchloride ethanol solution. After washing with diethylether, the crystals were collected by filtration to obtain 1.2 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10](B1OC(C)(C)C(C)(C)O1)[CH:11]=2.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1)[CH:11]=2
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CCC(NC(=O)C(C)C)C2)nn1
Temperature: 140 °C
Yield: 24.7 %

Procedure:
Dissolve N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23) (150 mg, 0.31 mmol) and 3-chloro-6-methylpyridazine (39 mg, 0.31 mmol) in dioxane (2.5 mL) and 2M Na2CO3 (388 μL). Sparge the solution with nitrogen for 5 min, add dichlorobis(triphenylphosphine)palladium (II) (11 mg, 0.016 mmol) and seal the reaction vessel. Heat to 140° C. in a microwave reactor for 30 min, then dilute with water (20 mL). Extract into EtOAc (3×25 mL), dry organics (MgSO4), filter, and concentrate in-vacuo to give the crude product (179 mg) as a brown solid. Purify the crude product on silica gel (12 g), eluting with 25-70% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes to afford 35 mg (25%) of the title compound as a white solid. MS (ES): m/z 457 (M+1), 455 (M−1); HPLC (Method B) Rt=3.37 min (100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:23])=[CH:16][CH:15]=1)=[O:4]
Reactant: Cc1ccc(-c2nc3ccccc3n2C(=O)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(n1c(-c2ccc(CBr)cc2)nc2ccccc21)C(F)(F)F
Temperature: 25 °C

Procedure:
A stirred solution of 213.0 g (0.7 mole) of 1-trifluoroacetyl-2-(4-methylphenyl)benzimidazole, 125.0 g (0.7 mole) of N-bromosuccinimide, and 3.39 g (2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from tetrahydrofuran.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:14][S:15]([N:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]4[C:35]5[C:40]([CH:41]=[CH:42][C:27]3=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:22][CH:21]=2)[CH3:19])(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.[CH2:43]=O.[C:45]([BH3-])#[N:46].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:43][N:46]([CH3:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:14][S:15]([N:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]4[C:35]5[C:40]([CH:41]=[CH:42][C:27]3=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:22][CH:21]=2)[CH3:19])(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)S(=O)(=O)CC1(c2ccccc2N)C=CC=CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: CN(C)c1ccccc1C1(CS(=O)(=O)N(C)c2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)C=CC=CC1
Yield: 36.6 %

Procedure:
1-(2-Aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide (18 mg, 0.036 mmol) mentioned above, zinc chloride (12 mg, 0.090 mmol), formalin (2.7 mg, 0.090 mmol), and sodium cyanoborohydride (5.7 mg, 0.090 mmol) were dissolved in methanol, and the solution was refluxed by heating for 5 hours under a nitrogen atmosphere. After the disappearance of the starting materials was confirmed, the reaction mixture was treated in a conventional manner to give the title compound (8 mg, yield 42%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:17]1[NH:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=S)N1
Reactant: COc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccccc1C=C1NC(=S)NC1=O
Yield: 85.4 %

Procedure:
A mixture of 2-methoxybenzaldehyde (2.5 g, 18 mmoles), 2-thiohydantoin (2.0 g, 17 mmoles), sodium acetate (4.0 g, 49 mmoles), acetic anhydride (μml), and acetic acid (15 ml) is stirred under an inert atmosphere and heated to reflux. After 1 hour the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times and dried. The product is triturated in boiling methanol, filtered off, and dried to afford the pure product (3.4 g), mp 234°-235° C.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>CN(C=O)C>[CH2:23]([O:15][C:12]1[CH:13]=[CH:14][C:9]([S:1][C:2]2[CH:7]=[CH:6][C:5]([O:19][CH2:16][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCBr
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(Sc2ccc(OCCCCCCC)cc2)cc1

Procedure:
4,4′-thiodiphenol (bis(4-hydroxyphenyl) sulfide) (1 eq, 10 g, 45.8 mmol), potassium carbonate (2.5 eq, 15.8245 g, 114.5 mmol, 138.205 g/mol), and 1-bromoheptane (2.5 eq, 20.5070 g, 18 mL, 114.5 mmol, 179.10 g/mol, d=1.14 g/mL) were dissolved in DMF (100 mL) at 80° C. The reaction was stirred until complete as determined by TLC. The reaction was poured into water and extracted with dichloromethane (DCM). The aqueous layer was discarded and the DCM was back-extracted three times to remove residual DMF. The resulting organic solution was dried with sodium sulfate, filtered, and concentrated on a rotary evaporator. The product was recrystallized from ethanol, filtered, and then washed with cold ethanol. The product was subsequently put through a silica plug with 50-50 hexanes-DCM and concentrated on a rotary evaporator to yield a white powder (compound characterized by Structure B: bis(4-(heptyloxy)phenyl)sulfane). The product was dried under high vacuum for 24 hours at 50° C. to remove residual solvents and 1-bromoheptane. The yield was 5 g (26.3%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 1H-indazole-5-carboxylic acid (6.0 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq) and EDCI (8.5 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (15 g, 4.0 eq) dropwise at 0° C. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (4.4 g, 58%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.56 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:21]([CH:27]=O)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][C:20]1[C:21]([CH2:27][NH:17][CH2:16][CH2:15][C:13]2[N:12]=[CH:11][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=3)(=[O:9])=[O:8])[CH:14]=2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCN)c2)cc1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1

Procedure:
Using General Procedure B: Reaction of 2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethylamine and 3,5-dimethyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccc(F)n1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.51 g, 35.6 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (7.60 g, 42.7 mmol) and 2,2′-azobis(isobutyronitrile) (290 mg, 1.78 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(6-fluoropyridin-2-yl)-3-oxopropionate (7.51 g, 35.6 mmol) in 1,2-dimethoxyethane (70 ml) was added sodium hydride (60% in oil, 1.42 g, 35.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (7.74 g, 52%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:15][C:16](=[O:41])[C:17]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:18][C:19]1[S:20][C:21]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][C:28]=2[F:36])=[O:25])=[CH:22][CH:23]=1)C1C=CC=CC=1>CC(O)C.O.[OH-].[Pd+2].[OH-]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([C:21]2[S:20][C:19]([CH2:18][C:17]([CH2:39][CH3:40])([CH2:37][CH3:38])[C:16]([OH:41])=[O:15])=[CH:23][CH:22]=2)=[O:25])=[C:28]([F:36])[CH:29]=1)(=[NH:34])[NH2:35]
Reactant: CCC(CC)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCC(CC)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoic acid benzyl ester trifluoroacetic acid salt (4.3 g, 7.21 mmol) was dissolved in 2-propanol (160 mL) and water (40 mL), palladium hydroxide (0.9 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water and acetonitrile was added to the residue, the mixture was lyophilized to give the title compound (3.61 g, 7.12 mmol, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[NH:22][C:28]2=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI (668 mg), and DBU (1.2 mL) in THF (25 mL) was heated at 60° C. overnight. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=97/3 to 9/1) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (993 mg) as a pale brown solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:39][C:40]([C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:54]1([CH2:60][C@H:61]([NH:71][C:72]([C@@H:74]([NH:81][C:82]([C@@H:84]([CH2:92][C:93]([C@@H:95]2[CH2:99][CH2:98][CH2:97][N:96]2[C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])=[O:94])[CH2:85][C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)=[O:83])[CH2:75][C:76]2[N:77]=[CH:78][NH:79][CH:80]=2)=[O:73])[C@@H:62]([OH:70])[CH2:63][C@@H:64]([CH:67]([CH3:69])[CH3:68])[CH:65]=[CH2:66])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:39][C:40]([C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])=[O:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:54]1([CH2:60][C@H:61]([NH:71][C:72]([C@@H:74]([NH:81][C:82]([C@@H:84]([CH2:92][C:93]([C@@H:95]2[CH2:99][CH2:98][CH2:97][N:96]2[C:100]([O:102][C:103]([CH3:106])([CH3:104])[CH3:105])=[O:101])=[O:94])[CH2:85][C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)=[O:83])[CH2:75][C:76]2[N:77]=[CH:78][NH:79][CH:80]=2)=[O:73])[C@@H:62]([OH:70])[CH2:63][C@@H:64]([CH:67]([CH3:68])[CH3:69])[CH2:65][CH3:66])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C
Product: CC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C
Product: CC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C

Procedure:
In a manner analogous to that described in Example 2, by catalytically hydrogenating t-butyl (S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]-phenethyl]acetyl]-1-pyrrolidinecarboxylate and t-butyl (S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate, there was obtained t-butyl (S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate (less polar isomer) and t-butyl (S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-acetyl]-1-pyrrolidinecarboxylate. MS: 736 (M+H)+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[OH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:26]3[CH2:27][CH2:28][CH:23]([CH2:22][OH:21])[CH2:24][CH2:25]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Reactant: OCC1CCNCC1
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCC(CO)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 4-hydroxymethyl-piperidine, praeparative HPLC (Method C) (37%, off-white crystals). HPLC-MS m/z=375.2 (M+1), Rt: 3.41 min.