Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)([O-])C.[K+].[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33]Br)([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33][O:17][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
N-CBz-L-valine (16.25 g, 65 mmole) was dissolved in DMF (40 ml). To the solution was added potassium t-butoxide (7.24 g, 65 mmole). After 10 min, 4-bromobutyric acid t-butyl ester (12 g, 53 mmole) was added. The reaction mixture was kept at 65° C. for 2.5 hr and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography. 20.1 g.
Reaction SMILES: [N+](C1C=CC(OC(NC2SC(C3C=CC=CC=3)=CN=2)=O)=CC=1)([O-])=O.C(O)(C(F)(F)F)=O.C1(C2SC(NC(N[N:47]3[CH2:52][CH2:51][N:50]([C:53]4[N:58]=[CH:57][CH:56]=[CH:55][N:54]=4)[CH2:49][CH2:48]3)=O)=NC=2)C=CC=CC=1>>[N:54]1[CH:55]=[CH:56][CH:57]=[N:58][C:53]=1[N:50]1[CH2:51][CH2:52][NH:47][CH2:48][CH2:49]1
Reactant: O=C(Nc1ncc(-c2ccccc2)s1)NN1CCN(c2ncccn2)CC1
Agent: O=C(Nc1ncc(-c2ccccc2)s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCNCC2)nc1

Procedure:
In a manner identical to that described above in Scheme 2, from 100 mg (0.29 mmol) of 2-(4-nitrophenoxycarbonyl)amino-5-phenylthiazole and 48 mg (0.29 mmol) of 4-(2-pyrimidinyl)piperazine was obtained the bis TFA salt of 3 as a fluffy white amorphous solid after lyophilization. H1 NMR (DMSO-d6): 3.61 (m, 4H), 3.72 (m, 4H), 6.70 (m, 1H), 7.45 (complex, 6H), 7.80 (s, 1H), 8.20 (m, 2H). High Res. FAB MS: Theo. Mass=367.1336; measured mass=267.1337.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 7, Step 1, using the following starting materials: (6-fluoro-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][CH:29]=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:31]([Mg]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][CH:29]([OH:30])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC=O)cc3)cc2)CC1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(O)Cc4ccccc4)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-{4′-[3-Methyl-4-(3-oxo-propyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.250 g, 0.62 mmol) was dissolved in THF and cooled to 0° C. under N2 atmosphere. Benzylmagnesium bromide (19% in THF, 0.62 mL, 0.62 mmol) was added and the reaction was allowed to slowly warm to room temperature. After 1.5 hours, the reaction was cooled to 0° C. and additional benzylmagnesium bromide (19% in THF, 0.1 mL, 0.10 mmol) was added, and the reaction was stirred for 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried and concentrated and the residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[C:20]#[N:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To a stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarbonitrile (275 mg, 0.78 mmol) in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 12 hr, the mixture was quenched with MeOH, poured into a 1N sodium brine, extracted with ethyl acetate (2×100 mL), dried (MgSO4), concentrated and purified by HPLC to give 142 mg (39% yield) of (2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine as the TFA salt. MS found: (M+H)+=358.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=O)[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C>ClC(Cl)C.CCOC(C)=O>[CH2:23]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CN1CCCc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 0.5 h

Procedure:
To a solution of 250 mg of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2.5 ml of dichloroethane were added 0.175 ml of isobutyryl chloride and 0.4 ml of triethylamine, followed by elevating the temperature to 60° C. and stirring for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1 M hydrochloric acid, water, a 1 M aqueous sodium hydroxide solution, and saturated brine, and the solvent was concentrated. To the resulting residue was added 2 ml of THF and 3.5 ml of a 1 M solution of a borane-THF complex in THF was added thereto in an ice-bath, followed by stirring at room temperature overnight. The reaction mixture was ice-cooled, and EtOH was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 213 mg of t-butyl 1-isobutyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[C:18]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:17]=2[CH3:32])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH3:31][O:30][C:28](=[O:29])[CH2:27][C:18]1[C:17]([CH3:32])=[C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[CH:19]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCNCC2)c1C
Reaction time: 4 h

Procedure:
A solution of 4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (410 mg, 0.92 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (2.5 mL) at room temperature, and stirred for 4 hours. The resulting mixture was concentrated in vacuo to afford [6-fluoro-3-methyl-4-(piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid methyl ester trifluoroacetate as a viscous oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:31](OC)=[O:32].S(=O)(=O)(O)O>C(OCC)C>[CH:31]([O:18][CH2:17][C:14]1[CH:15]=[CH:16][C:5]2[O:4][CH:3]([C:2]([Cl:1])([Cl:19])[Cl:20])[O:8][CH:7]([C:9]([Cl:12])([Cl:10])[Cl:11])[C:6]=2[CH:13]=1)=[O:32]
Reactant: COC=O
Reactant: O=Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=COCc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 2 h

Procedure:
A solution of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxaldehyde (1.0 g.) in diethylether (10 ml.) was added to a mixture of aluminium chloride (1.17 g.) and lithium aluminium hydride (0.95 g.) in diethyl ether (15 ml.). A vigorous reaction was observed during this addition, the mixture was stirred for 11/2 hours, and then a solution of methyl formate (5 ml.) in diethyl ether (20 ml.) was added at 0° C. The reaction mixture was allowed to reach ambient temperature, and 20% sulphuric acid (25 ml.) was added. The organic layer was separated, dried, and concentrated under reduced pressure to give an oily product which readily solidified on trituration with petroleum ether (b.p. 60°-80° C.) to give 6-formyloxymethyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 75°-77° C.
Reaction SMILES: C(Cl)CCl.[CH2:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][NH:17][CH3:18])[CH3:6].Cl.[O:20]=[C:21]1[CH2:26][O:25][C:24]2[CH:27]=[C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)[CH:29]=[N:30][C:23]=2[NH:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][N:17]([CH3:18])[C:33](=[O:35])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[N:30][C:23]2[NH:22][C:21](=[O:20])[CH2:26][O:25][C:24]=2[CH:27]=1)[CH3:6]
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CCc1c(CNC)[nH]c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)[nH]c2ccccc12
Reaction time: 8 h
Yield: 42.4 %

Procedure:
EDC (116 mg, 0.6 mmol) was added to a solution of (3-ethyl-1H-indol-2-yl)-N-methylmethanamine (87 mg, 0.46 mmol), (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (123.65 mg, 1.05 mmol), HOBT.H2O (62 mg, 0.46 mmol) and DIPEA (0.33 mL, 1.8 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (76.2 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.46 (t, J=7.9 Hz, 2H), 7.25 (d, J=7.9 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.95 (t, J=7.1 Hz, 2H), 4.92 (s, 2H), 4.90-4.74 (rotamers, s, 2H), 4.68 (s, 3H), 3.08 (m, 2H), 1.13 (t, J=7.4 Hz, 3H); MS (ESI): m/e 391.1 (C22H22N4O3+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH2:17][CH2:18][CH:19]=[CH2:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:21]1O[CH2:22]1>C1C=CC=CC=1.CCO>[CH2:17]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:22][CH2:21]1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCC(C(=O)OCC)P(=O)(OCC)OCC
Reactant: C1CO1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: C=CCCC1(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 3.02 g, 75.5 mmol) in dry benzene (100 mL), at 22° C. and under nitrogen, was added dropwise ethyl 2-(diethoxyphosphoryl)hex-5-enoate with anhydrous EtOH (0.044 mL, 0.76 mmol) over 30 minutes. Stirred for 30 minutes, this reaction, cooled at 0° C. and attached with a dry ice/acetone condenser, was added via cannula ethylene oxide (12.7 g, 289.3 mmol), then refluxed at 50° C. for 5 hours. Quenched at 22° C. with 1N aqueous NH4Cl (100 mL), the reaction solution was extracted with Et2O (3×200 mL). The combined Et2O layers were washed with aqueous saturated NaHCO3 (100 mL), water (70 mL), brine (70 mL), dried over Na2SO4, filtered and concentrated. The residue was flash chromatographed on 120 g silica gel 60, eluting with 20-100% EtOAc/Hexane, to give the title product (5.07 g, 48%). LRMS (ESI) m/z 169.2 [(M+H)+; calcd for C10H17O2: 169.1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([NH2:27])=O)[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]#[N:27])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: COc1ccc(C2Cc3c(C(N)=O)cc(OC)cc3C3CCCCC23)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2Cc3c(C#N)cc(OC)cc3C3CCCCC23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carboxylic acid amide (0.69 g, 0.19 mmol), and triethylamine (0.038 g, 0.38 mmol) in methylene chloride (2.5 ml) at 0-5° C. and add trifluoroacetic anhydride (0.044 g, 0.21 mmol). Let stir at r.t. for 15 minutes. Add water, separate organic layer. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield preparation 122 (0.066 g, 100%). 1H NMR (CDCl3): 7.24 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.8, 2H), 3.86 (m, 6H), 3.2 (m, 4H), 2.5 (m, 1H), 2.1 (m, 1H), 1.8-0.8 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:25])[N:3]=[CH:4]1
Reactant: O=C(O)c1cccnc1
Reactant: NC(=O)c1c(N)ncn1Cc1cccc(Cl)c1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1Cc1cccc(Cl)c1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (5.98 mmol) of 4-amino-1-(3-chlorobenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 51 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.65 g of 1-(3-chlorobenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.I[C:15]1[CH:16]=[C:17]([C:22]2[NH:26][C:25]3[CH:27]=[C:28]([CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH:29]=[CH:30][C:24]=3[N:23]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].CCN(C(C)C)C(C)C.CN(C=O)C>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.[Cu]I.O>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][C:15]3[CH:16]=[C:17]([C:22]4[NH:26][C:25]5[CH:27]=[C:28]([CH2:31][N:32]6[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]6)[CH:29]=[CH:30][C:24]=5[N:23]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1ccc(NC2CCC2)nn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CCC2)nn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
N-Cyclobutyl-6-ethynylpyridazin-3-amine (62 mg, 0.36 mmol), 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (134 mg, 0.3 mmol), Pd(PPh3)4 (18 mg, 0.015 mmol) and CuI (4.3 mg, 0.023 mmol) were placed in a two neck flask with a rubber plug. The mixture underwent 3 cycles of vacuum and filling with Ar2, a solution of DIPEA (58 mg, 0.45 mmol) and DMF (2 mL) was injected to the flask. The mixture was stirred at rt for 20 hrs, and then was poured into 25 mL water, extracted with CH2Cl2 (20 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3 to 97:6) to give 0.12 g crude product, continue to purify via preparation TLC (CH2Cl2/CH3OH 120:8) to give 87 mg product as a pale yellow solid. Mp:148-150° C.; 1H NMR (300 MHz, CDCl3) δ: 8.07-8.10 (1 H, d, J=9.0 Hz), 7.90 (1 H, s), 7.63-7.66 (1 H, d, J=9.0 Hz), 7.63 (1 H, s), 7.26-7.24 (1 H, d, J=6.0 Hz), 7.20 (1 H, m), 7.15 (1 H, m), 6.60-6.63 (1 H, d, J=9.0 Hz), 5.63 (1 H, s), 4.26-4.33 (1 H, m), 3.62 (2 H, s), 2.58 (8 H, brs), 2.35 (3 H, s), 2.31 (3 H, s), 1.94-2.03 (2 H, m), 1.82-1.85 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H34N7: 492.2870. found: 492.2856.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][C:12](OCCCC)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCCCO)cc1
Temperature: -5 °C

Procedure:
This ester 21.0 g was dissolved in 500 ml dry ether and cooled to -5° C. in an ice/acetone bath. To the cold solution was added, cautiously, a slurry of 3.5 g lithium aluminum hydride in 100 ml dry ether. After one hour the excess lithium aluminum hydride was destroyed by the cautious addition of 200 ml ethyl acetate, then 50 ml water. The solution was filtered and the filtrate partitioned between 200 ml ether-200 ml water. The organic layer was removed, dried, and evaporated to a yellow oil which was vacuum distilled (116° C./0.35 mm) over potassium carbonate to a clear colorless oil, 3-p-t-butylphenoxypropanol, 10.1 g (64%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]=[O:59])=[CH:54][CH:53]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].CC(=CC)C.Cl([O-])=[O:79].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([C:58]([OH:79])=[O:59])=[CH:56][CH:57]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C=O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C(=O)O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg) in tert-butanol (1.0 mL) was added 2-methyl-2-butene (250 mL) followed by 0.5 mL of an aqueous solution of sodium chlorite (41 mg) and sodium dihydrogen phosphate (48 mg), and the mixture stirred at room temperature. After 1.5 hours, the mixture was concentrated and redissolved in ethyl acetate:hexane (1:1) and washed with water. The organic portion was dried over sodium sulfate, and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (4:1) +1% methanol +0.5% acetic acid) to give the title compound (43 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19](Cl)[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]#[CH:28].C(N(CC)CC)C.CN(C=O)C>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.[Cu]I.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([C:28]#[C:27][C@@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:25])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Reactant: Clc1ncc2nc(-c3ccc(OCc4ccccc4)cc3)oc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](C#Cc1ncc2nc(-c3ccc(OCc4ccccc4)cc3)oc2n1)NC(=O)OC(C)(C)C

Procedure:
A mixture of 4-(benzyloxy)benzoic acid (1.04 g) and phosphorus oxychloride (12.2 mL) was stirred at room temperature for 5 min, and 2,4-dichloropyrimidin-5-amine (500 mg) was added thereto, and the obtained mixture was stirred at 100° C. for 2 hr. The reaction mixture was added to 1M aqueous sodium hydroxide solution at 0° C., and the precipitate was collected by filtration, and dissolved in THF and ethyl acetate. The obtained solution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (3.07 g) as a mixture with impurity. A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and DMF (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. In another reaction container, A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and toluene (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. The two reaction mixtures were combined, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.4 mg).