Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:38]3[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=3)=[CH:21][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Yield: 12.2 %

Procedure:
To a solution of (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-one (54 mg, 0.28 mmo), 2N aq Cs2CO3 (2 mL) in dioxane (8 mL) was added Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) under N2. The reaction mixture was refluxed for 2 h and quenched by addition of water. The mixture was extracted with EtOAc (30 mL), and the organic layer was washed with H2O and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to afford (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (14 mg, yield: 10%). LC-MS Method 2 tR=1.2 min, m/z=473.9; 1H NMR (CDCl3): δ1.21 (s, 3H), 1.30 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 2.15-2.26 (m, 3H), 2.33 (dd, J=11.2, 26.4 Hz, 1H), 2.43-2.46 (m, 1H), 2.79-2.85 (m, 1H), 3.63 (s, 3H), 5.62 (q, J=6.8 Hz, 1H), 6.58-6.60 (m, 1H), 6.89-6.94 (m, 1H), 7.00-7.02 (m, 2H), 7.10-7.24 (m, 3H), 7.34-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.48-7.70 (m, 2H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.Cl.CN.C(N(CC)CC)C>C(OCC)(=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][NH:2][CH3:1])[S:9][CH:10]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CNCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.1 %

Procedure:
25.2 g (360 mmol) of sodium cyanoborohydride are added to a solution of 35 g (180 mmol) of 4-bromothiophene-2-carbaldehyde, 62 g (640 mmol) of methylamine hydrochloride and 119 ml (846 mmol) of triethylamine. The reaction medium is stirred at room temperature for 3.5 hours. After addition of water and ethyl acetate and washing with aqueous 1M sodium hydroxide solution, the organic phase is extracted. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 90/10 to 70/30 heptane/ethyl acetate mixture. 19.7 g (52%) of (4-bromothiophen-2-ylmethyl)methylamine are obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Product: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 106 using tert-butyl(3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (1.50 g, 4.10 mmol) and ethyl bromoacetate (460 μl, 4.10 mmol) as starting materials.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C(O)=O.CN([C:12]([O:16]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:43]([N+:47]1[N:51]=[C:50]([CH3:52])[S:49][C:48]=1[CH3:53])[CH2:44][CH2:45][CH3:46]>>[CH2:43]([N:47]1[N:51]=[C:50]([CH3:52])[S:49]/[C:48]/1=[CH:53]\[C:12]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:16])[CH2:44][CH2:45][CH3:46]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1nccs1
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cscn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial thiazole-2-carboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.38 (m, 2 H) 1.69-1.82 (m, 2 H) 2.46 (s, 3 H) 4.12-4.20 (m, 2 H) 6.81 (s, 1 H) 8.24 (s, 1 H) 9.15 (s, 1 H); MS (ESI) m/z 282 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([CH3:41])([C:28]([O:30]CC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH3:27])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1.[Na+:42].[H][H].C(=O)([O-])O.[Na+]>O.O1CCCC1.[Pd]>[Na+:42].[Na+:42].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([CH3:41])([C:28]([OH:30])=[O:29])[CH3:27])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1.[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:41])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]

Procedure:
In a mixture of 25 ml of water and 25 ml of tetrahydrofuran is dissolved 500 mg of sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer), followed by addition of 500 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for one hour. After addition of 25 ml of an aqueous solution of sodium hydrogen carbonate (62 mg), the catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn-isomer).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([N:14]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([O:19][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:17][C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:15]1)[CH3:13]
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
1-fluoro-4-(trifluoromethyl)benzene (22.9 mL, 180 mmol, 6.00 equiv) was added to a mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (6.40 g, 30.0 mmol, 1 equiv) and potassium carbonate (12.4 g, 90.0 mmol, 3.00 equiv) in dimethyl sulfoxide (60 mL) in a high pressure reaction vessel. The vessel was sealed, and the reaction mixture was heated to 160° C. After stirring for 16 hours, the high pressure vessel was cooled to 22° C. and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}benzonitrile (4.70 g, 44%) as a white solid. Calcd (M+1)+: 357.1. Found: 358.0.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:22])=O>>[CH3:1][C:2]([CH3:18])([CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3]([Cl:22])=[O:4]
Reactant: CC(C)(CCC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(CCC(=O)OCc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.1 g of 2,2-dimethyl-4-benzyloxycarbonylbutyric acid and 3.3 ml of oxalyl chloride was refuxed for 1 h. After being cooled to room temperature, the solution was concentrated in vacuo and dried overnight The obtained oil was not further purified for the next reaction.
Reaction SMILES: C([C@@H]1[C@H](N)C2C=CSC=2CC1)CC.[CH2:14]([CH:16]1[CH2:17][CH2:18][C:19]2[O:23][CH:22]=[CH:21][C:20]=2/[C:24]/1=[N:25]\O)[CH3:15]>>[CH2:14]([C@H:16]1[C@H:24]([NH2:25])[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17]1)[CH3:15]
Reactant: CCC1CCc2occc2/C1=N\O
Agent: CCC[C@H]1CCc2sccc2[C@H]1N
Product: CC[C@@H]1CCc2occc2[C@H]1N

Procedure:
Following the procedure for the preparation of cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine but substituting (4E) and (4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.02, 1.30-1.73, 2.50-2.67, 4.46, 6.10, 7.24; HRMS (FAB) calcd for C10H15NO+H 166.1232, found 166.1231. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33; H, 9.14; N, 8.08
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:33]1([CH2:34][O:26][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:27])[CH2:31][CH2:32]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: BrCC1CC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1

Procedure:
A 0.15 quantity of the compound obtained in Example 327 and 0.18 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of ethanol, 0.15 g of (bromomethyl)cyclopropane was then added to the obtained solution, and the obtained mixture was heated and refluxed overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 42 mg of white powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:22]([CH3:37])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25](Cl)[N:24]=3)[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].[F:38][C:39]([F:44])([F:43])C(O)=O>>[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:22]([CH3:37])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([N:1]2[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]2[C:39]([F:44])([F:43])[F:38])[N:24]=3)[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-n3c(C(F)(F)F)nc4ccccc43)nc21

Procedure:
Following General Procedure J for Multi-Step Benzimidazole formation, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine was converted to 464 with trifluoroacetic acid. LCMS: M+H+=558.3
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].O>CN(C)C=O>[C:1]([C:5]1[C:6]([O:17][CH2:2][CH2:1][CH2:5][CH3:12])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 85 °C
Yield: 217.8 %

Procedure:
4.0 g of 3,5-di-tert.-butyl-2-hydroxybenzaldehyde (CAS # 37942-07-7) was dissolved in dimethylformamide (DMF). This was treated with 0.89 g of sodium hydride (50% in oil suspension) and stirred at 25° C. until hydrogen was no longer evolved. To this was added 2.01 ml n-bromobutane and the mixture was heated to 85° C. for 14 hr. This was cooled and poured into water. The aqueous was extracted with ether. The ether layer was washed with water, dried (MgSO4), and solvent was removed. Purification was accomplished by florsil column chromatography (15% ether/hexane) to give 5.4 g of 3,5-di-tert.-butyl-2-butyloxybenzaldehyde; 1H NMR (CDCl3) δ 10.31 (s, 1H,aldehyde), 7.70 (dd,4H,aromatics), 3.94 (t,2H,—OCH2—).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[Li]CCCC.[CH3:23][C:24]1[C:25]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:26]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=2.CCOC(C)=O>C1COCC1.O>[CH2:15]([O:14][P:10]([CH:1]=[CH:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][C:26]2[C:27]3[C:32](=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=3)[CH:33]=[C:24]([CH3:23])[C:25]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:44][CH:43]=1)(=[O:17])[O:11][CH2:12][CH3:13])[CH3:16]
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(C=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirring solution of tetraethyl methylenediphosphonate (0.11 mL, 0.537 mmol) in hexanes (1 mL) was slowly added 1.6 M nBuLi (0.051 mL, 0.537 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was cooled to 0° C. then a solution of 4-[(6-methoxy-3-methyl-2-phenyl-1-naphthyl)oxy]benzaldehyde (8) (0.198 g, 0.537 mmol) in THF (1 mL) was added dropwise. After addition, reaction mixture was stirred at above temperature for 10 min then heated at 80° C. for 3 h. Reaction mixture was cooled to room temperature then diluted with water followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over MgSO4, filtered and concentrated to give oil. The crude oil was chromatographed with 9% EtOAc in hexanes followed by straight MeOH to give 0.151 g (56%) of the title compound (197) as oil. 1H NMR (400 MHz, d-CDCl3): δ 1.33 (t, J=7.1 Hz, 6H), 2.25 (s, 3H), 3.93 (s, 3H), 4.07-4.11 (m, 4H), 6.01 (t, J=17.6 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 7.03 (dd, J1=2.4, J2=9.2 Hz, 1H), 7.12-7.14 (m, 3H), 7.22-7.28 (m, 5H), 7.30-7.36 (m, 1H), 7.40 (s, 1H), 7.69 (d, J=9.1 Hz, 1H).
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[C:18]=[O:19].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:18]([NH:17][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]4)=[O:19])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azepanyl)-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.50 (s, 1H), 8.67 (s, 1H), 8.60 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 7.83 (t, 1H, J=8.1 Hz), 7.56 (t, 1H), 7.04 (m, 2H), 6.90 (m, 1H), 4.26 (d, 2H, J=6 Hz), 3.32 (m, 4H), 2.79 (s, 3H), 1.75 (m, 4H), 1.55 (m, 4H); MS (ESI) 407 (M+H)+; Anal. Calcd for C24H27FN4O.2HCl: C, 60.13; H, 6.10; N, 11.69. Found: C, 60.09; H, 6.35; N, 11.47.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([CH3:19])[C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:29][C:30]5[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=5)[N:21]=4)=[CH:17][C:10]=3[N:9]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (90 mg, 60%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.31 (s, 1H), 8.05 (br s, 1H), 7.72-7.80 (m, 3H), 7.46 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.78 (s, 2H), 5.66 (d, J=6.0H, 1H), 4.62 (d, J=5.4 Hz, 2H), 4.17 (s, 2H), 3.63 (s, 3H), 3.44 (s, 3H). MS (ESI) m/z=563 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[CH2:10]([O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:10]([O:14][C:15]1[N:20]=[C:19]([CH2:21][NH:1][C:2]2[N:6]=[CH:5][NH:4][C:3]=2[C:7]([NH2:9])=[O:8])[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1cccc(C=O)n1
Reactant: NC(=O)c1nc[nH]c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCOc1cccc(CNc2nc[nH]c2C(N)=O)n1
Reaction time: 2 h

Procedure:
5-Aminoimidazole-4-carboxamide (0.30 g, 2.4 mmol) was added to the solution of 6-butoxypyridine-2-carbaldehyde (0.43 mg, 2.4 mmol, obtained from Example 17(d)) in anhydrous ethanol (30 mL) and the reaction mixture was refluxed. After 2 h, the reaction mixture was concentrated in vacuo. The light pink solid was suspended in anhydrous ethanol (25 mL), and acetic acid (0.27 mL, 4.8 mmol) was added. After 1.5 h, sodium cyanoborohydride (0.30 g, 4.8 mmol) was added to the mixture. After stirring o.n. at ambient temperature, the reaction mixture was concentrated in vacuo. The resulting 1.2 g of crude title compound was used in the next step without further purification. MS (ESI) m/z 290 (M+1)
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C(O)(=O)C>[NH2:37][C:36](=[N:38][C:56](=[O:55])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:35]1[CH:34]=[CH:33][C:32]([NH:31][C@H:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetic acid salt [CAS No. 951803-91-1] (5.6 g) and DMF (200 mL), benzoic acid 4-nitrophenyl ester (2.89 g) and triethylamine (4.7 mL) were added, and the resulting mixture was stirred overnight at room temperature. Acetic acid (6.5 mL) was added to the reaction solution, and then the solvent was evaporated under reduced pressure. The residue obtained was crudely purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid), and the crudely purified product obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (4.48 g).
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH:16]=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:9]([Si:6]([O:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH:16]=[CH2:1])([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCC(C=O)CO[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(CC)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
(Methyl)triphenylphosphonium bromide (59.1 g, 165 mmol) was suspended in tetrahydrofuran (330 mL). To the suspension, n-butyllithium (1.57 M hexane solution, 97.3 mL, 153 mmol) was gradually added with stirring at 0° C. The mixture was stirred at this temperature for 1 hour, and a tetrahydrofuran solution (110 mL) of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)butanal (Tetrahedron 2004, 60, 9307) (27.6 g, 127 mmol) was then gradually added thereto. The mixture was stirred at 0° C. for 2 hours, and the reaction was then terminated by the addition of a saturated aqueous solution of ammonium chloride and water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (19.9 g, 73%).