Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3]C.[CH3:14]C(O)(CCCCCCC)CCC>>[CH3:3][C:2]([OH:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:14])[CH3:1]
Reactant: CCCCCCCCC(C)(O)CC
Reactant: CCCCCCCC(C)(O)CCC
Product: CCCCCCCCCC(C)(C)O

Procedure:
3-methyl-3-undecanol; 4-methyl-4-undecanol;
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:14][C:13](C=O)=[CH:12][CH:11]=1)[CH3:9].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH2:8]([C:10]1[S:14][C:13](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(/C=C/C(=O)O)s1
Temperature: 80 °C
Reaction time: 17 h
Yield: 96.2 %

Procedure:
To a solution of malonic acid (5.9 g) and 5-ethyl-2-thiophenecarboxaldehyde (4.0 g) in dry pyridine (12 mL) was added piperidine (0.42 mL). The reaction mixture was stirred at 80° C. for 17 hours, chilled and diluted with water (70 mL). This mixture was acidified with concentrated HCl (14 mL) and the white precipitate was collected by filtration, washed with water (5×10 mL) and dried under vacuum giving (2E)-3-(5-ethyl(2-thienyl))prop-2-enoic acid (5.0 g). Yield=96%
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:28][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(N)C(=O)OC(C)(C)C)CCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-Amino-3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)carbamoyl]-cyclopentyl}propanoic acid t-butyl ester (0.605 g, 1.48 mmole) was dissolved in dry dichloromethane (25 ml) and treated at 0° C. with triethylamine (0.45 g, 4.4 mmole) and benzene sulphonyl chloride (0.24 ml, 1.84 mmole). After stirring for 16 hours at room temperature under nitrogen the dichloromethane was removed under vacuum, the residue taken up in diethyl ether (25 ml), washed with dilute hydrochloric acid, dilute sodium hydrogen carbonate and water, dried (Na2SO4) and the solvent evaporated under vacuum to give the crude product. Purification by column chromatography on silica, eluting with diethyl etherdichloromethane mixtures, gave pure title compound as a white foam (0.60 g, 74%). Found: C,61.38; H,7.85; N,5.06. C28H42N2O7S requires C,61.06; H,7.69; N,5.09%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3)ccn2)ccn1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
A solution of Example A9 (0.440 g, 1.985 mmol) in dioxane (8 mL) was sparged with Ar, treated with a solution of K2CO3 (0.549 g, 3.97 mmol) in water (2 mL) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.565 g, 2.58 mmol), sparged again with Ar, treated with Pd(PPh3)4 (0.229 g, 0.199 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (490 mg, 89%) as a light brown solid. MS (ESI) m/z: 279.2 (M+H+).
Reaction SMILES: O=C1CCC(=O)N1C(CCCC)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:33]=[C:34]1[CH2:38][CH2:37][C:36](=[O:39])[N:35]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]=[C:46]=[O:47].[F:48][C:49]1[C:50](=[O:56])[NH:51][C:52](=[O:55])[NH:53][CH:54]=1>C1C=CC=CC=1.C(N(CC)CC)C>[O:33]=[C:34]1[CH2:38][CH2:37][C:36](=[O:39])[N:35]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([N:53]1[CH:54]=[C:49]([F:48])[C:50](=[O:56])[NH:51][C:52]1=[O:55])=[O:47]
Reactant: O=C=NCCCCCN1C(=O)CCC1=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: CCCCC(C(=O)O)N1C(=O)CCC1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1CCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 6-[(2,5-dioxopyrrolidin-1-yl)hexanoic acid and diphenylphosphoryl azide in a solutuon of triethyl amine and benzene provided a solution comprising 5-(2,5-dioxopyrrolidin-1-yl)pentyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-[5-(2,5-dioxopyrrolidin-1-yl)pentyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 13.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.Br[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])([F:41])[F:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:49])([F:40])[F:41])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-13) (1.0 equiv.) dissolved in DMF (0.14 M) was added a solution of diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate (6-14: described in Example 7—Step 1) (1.3 equiv.) in DMF (0.7 M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-15) as an oil which upon standing became a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[CH2:30]([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:37]4[CH:36]=[N:35][N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:38]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Cn1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.459 g, 3.07 mmol), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 g, 9.23 mmol) tetrakis(triphenylphosphine)palladium (0.355 g, 0.307 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 5.4 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate) to yield 1.047 g (76%) of the title compound: mass spectrum (m/z): 450(M+2).
Reaction SMILES: CN(C)CCOCCN(C)C.C([Mg]Cl)(C)C.N#N.I[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[N+:28]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=[O:42])([O-:30])=[O:29].Cl>C1COCC1>[OH:42][CH:41]([C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]=1[N+:28]([O-:30])=[O:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]
Reactant: N#Cc1cccc(I)c1
Reactant: O=Cc1ccc2ccccc2c1[N+](=O)[O-]
Agent: CC(C)[Mg]Cl
Agent: CN(C)CCOCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccc3ccccc3c2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of bis(2-dimethylaminoethyl)ether (5.62 mL, 29.8 mmol) in THF (125 mL) was added a solution of 2M isopropylmagnesium chloride in THF (14.9 mL, 29.8 mmol) dropwise under N2 atmosphere at room temperature, and stirred for 20 min. To the mixture was added 3-iodobenzonitrile (5.69 g, 24.9 mmol), and stirred for 30 min. To an ice-cold solution of the resultant mixture was added 1-nitro-2-naphthaldehyde, and stirred at room temperature for 1 hour. To the reaction mixture was poured 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound as a green orange oil (7.37 g, yield 97%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH:22]=O.O>CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: C[C@H](NCc1cc(Cl)cc(Cl)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
To a solution of the amine (4) (105 mg, 0.40 mmol) and 3,5-dichlorobenzaldehyde (95 mg, 0.52 mmol) in methanol (4 mL) was added borane-pyridine complex (130 μL, 1.21 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (7) as a white solid (76 mg, Yield: 45%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:22]([C:19]1[CH:18]=[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[NH:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92.9 %

Procedure:
DIPEA (92 mg, 0.12 mL, 0.71 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (59 mg, 0.28 mmol) in DMF (2 mL). HOBT (40 mg, 0.29 mmol) and EDCI (57 mg, 0.29 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (100 mg, 0.28 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 131 mg (91.6% yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.28%. 1H NMR (DMSO-d6): δ 13.8 (d, 1H), 8.0 (m, 1H), 7.6 (m, 3H), 7.2 (m, 4H), 7.1 (m, 1H), 4.1 (d, 2H), 3.5 (m, 4H), 3.35 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O.[Cu]>[I:21][C:6]1[C:5]([CH3:11])=[C:4]([CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:2]
Reactant: Cc1c(N)cccc1CO
Reactant: [I-]
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1c(I)cccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A stirred solution of 3-hydroxymethyl-2-methylaniline hydrochloride (43.4 g, 0.25 mole) and 17.2 ml of concentrated sulfuric acid in ice-water was cooled to 0°, and a solution of sodium nitrite (17.3 g, 0.25 mole) in water was added dropwise. Upon complete addition, the reaction mixture was stirred for an additional 0.5 hour, then an additional 8 ml of concentrated sulfuric acid was added dropwise. With the temperature maintained at 0°, a solution of potassium iodide (49.8 g, 0.30 mole) in water was added dropwise to the reaction mixture, followed by the addition of 0.1 gram of copper powder. The reaction mixture was slowly warmed to 70° where it stirred for 1 hour. The reaction mixture was then allowed to stand for 18 hours while cooling to room temperature. The reaction mixture was then taken up in water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated solution of sodium bisulfite, then with water. The chloroform layer was dried and filtered. The filtrate was evaporated under reduced pressure to give 3iodo-2-methylbenzyl alcohol (15.2 g) as a dark solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([CH3:21])=[CH2:20]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:20][C:19](=[CH2:18])[CH2:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)CCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(C(C)=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
1-(4-Hydroxyphenyl)ethanone (1.36 g, 10 mmol) was dissolved in acetone (50 mL), tetrabutyl ammonium iodide (370 mg, 1.0 mmol), potassium carbonate (2.76 g, 20 mmol) and 3-chloro-2-methyl-1-propene (1.5 mL, 15 mmol) were added sequentially, and the mixture was stirred at 70° C. overnight. The reaction solution was filtered, washed with acetone and concentrated in vacuo. The obtained residue was added water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with 1N-aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-(4-(2-Methylallyloxy)phenyl)ethanone (1.71 g (yield 90%)) was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:14][CH:13]=1
Reactant: COC(=O)CCCCCc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
6-(Biphenyl-4-yl)hexanoic acid methyl ester (0.67 g, 2.4 mmol) in THF (5 ml) was added dropwise to lithium aluminium hydride (0.2 g, 5.3 mmol) in THF cooled to 0° C. After stirring for 1 day at room temperature, water (1 ml) then 5M sodium hydroxide (1 ml) followed by water (2 ml) were added cautiously followed by stirring at room temperature for 2 hours. The precipitate was filtered off and filtrate was evaporated to give 6-(biphenyl-4-yl)hexanol as a solid (MS: M+ =254).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:10]2[CH:9]=[C:8]([OH:21])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:29](=O)([O:35]C(C)(C)C)[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:21])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1

Procedure:
7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10.8 g) and triethylamine (14.01 mL, 101 mmol) were dissolved in dry tetrahydrofuran (200 mL). Di-tert-butyl carbonate (7.31 g, 33.5 mmol) was added in small portions at room temperature. The reaction mixture was stirred over night. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The ethyl acetate solution of the crude product was dried (Na2SO4). The solvent was evaporated in vacuo and the crude product was used for the next step without further purification. Yield: 12.2 g.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O=[C:35]1[CH:40]2[CH:38]3[CH:39]2[CH2:41][CH:36]1[CH:37]3[C:42]1[NH:50][C:49]2[C:48](=[O:51])[N:47]([CH2:52][CH2:53][CH3:54])[C:46](=[O:55])[N:45]([CH2:56][CH2:57][CH3:58])[C:44]=2[N:43]=1>C1(C)C=CC=CC=1>[CH3:2][O:3][CH:4]=[C:35]1[CH:40]2[CH:38]3[CH:39]2[CH2:41][CH:36]1[CH:37]3[C:42]1[NH:50][C:49]2[C:48](=[O:51])[N:47]([CH2:52][CH2:53][CH3:54])[C:46](=[O:55])[N:45]([CH2:56][CH2:57][CH3:58])[C:44]=2[N:43]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=COC)C53)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methoxymethyl-triphenyl-phosphonium chloride (1.1 g) was taken in toluene (10 ml) at 0° C. Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 12.8 ml) was added and stirred at 0° C. for 1 hr. 8-(5-Oxo-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 1) (1 g) was added to the reaction mixture, which was then warmed to room temperature and stirred overnight. The next day, the reaction mixture was quenched with water, and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water and brine, and dried over Na2SO4. After concentration, the crude product (620 mg) was purified by column. Mass (ES+ 371).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.[Li]C(C)(C)C.CN([CH:26]=[O:27])C.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:26]=[O:27]
Reactant: c1ccc(CCn2cnc3ccccc32)nc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2n1CCc1ccccn1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of Ar, 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole (0.46 g, 2.1 mmol) (Ichikawa, M. et al. Chem. Pharm. Bull. 1981, 29, 3042-7) was dissolved in anhydrous THF (10 mL), cooled to −40° C., and treated with tert-BuLi (1.5 mL, 1.7M, 2.5 mmol) for 30 minutes. DMF (0.80 mL, 10.3 mmol) was then added and the solution slowly warmed to room temperature. After 1 hour, water (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added and the medium was extracted with EtOAc (3×25 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography with silica gel (50:1:0.1 MeOH:NH4OH:CH2Cl2) to afford 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole-2-carbaldehyde as a brown liquid that was used immediately in the next reaction (147 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:6][O:5][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:18]3)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1([CH3:34])[CH2:6][O:5][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)=[N:3]1
Reactant: COc1cccc(-c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)c1C1=NC(C)(C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3[nH]ccc3c2)c1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
4,4-dimethyl-2-[2-(1-triisopropylsilylindol-5-yl)-6-methoxyphenyl]-2-oxazoline (8.5 g, 17.8 mmoles) was dissolved in 300 ml of THF. The solution was cooled to 0° C. Tetrabutylammonium fluoride (17.8 mmoles, 178 ml of 1M in THF) was added dropwise. The reaction was stirred at 0°-5° C. for 40 minutes, poured into ice water, and extracted into ether. The organic phase was dried over sodium sulfate, and the solvent was removed. The reaction produced 5.7 g of 4,4-dimethyl-2-[2-(indol-5-yl)-6-methoxyphenyl]-2-oxazoline. (MS)