Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].ClC1C=CC(N)=CC=1N.[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([CH2:26][NH:25][C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([NH:9][C:4]3[C:5](=[O:8])[C:6](=[O:7])[C:3]=3[NH:50][CH2:49][CH2:48][O:47][CH3:46])[CH:11]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: COCCN
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2Cl)c(=O)c1=O
Agent: Nc1ccc(Cl)c(N)c1
Product: COCCNc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2Cl)c(=O)c1=O

Procedure:
EXAMPLE 47 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]-4-chlorophenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (prepared according to the procedure described in EXAMPLE 1 using 4-chloro-1,3-phenylenediamine instead of 1,3-phenylenediamine) and 2-methoxyethylamine instead of dimethylamine. MS (ES+): m/z 561.9 [M+1]
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]1[C:19](O)=[CH:18][C:17]([F:21])=[CH:16][N:15]=1.O>C[Si](OP(=O)=O)(C)C>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:19]3[C:14]([N:13]=2)=[N:15][CH:16]=[C:17]([F:21])[CH:18]=3)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ncc(F)cc1O
Agent: C[Si](C)(C)OP(=O)=O
Agent: Cl
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2ncc(F)cc2o1
Temperature: 100 °C
Yield: 20 %

Procedure:
2-amino-5-bromo-pyridine-3-carboxylic acid (797 mg) and 2-amino-5-fluoro-pyridin-3-ol, hydrochloride (400 mg) powders were mixed together and the resulting mixture was portionwise added in trimethylsilyl polyphosphate (4.5 g) stirred at 100° C. The mixture was stirred at 140° C. overnight. After cooling, water (20 ml) was added. The resulting precipitate was collected by filtration, washed with a 2N aqueous solution of HCl and water. The resulting solid was triturated in Ethyl acetate, collected by filtration to afford 5-bromo-3-(6-fluorooxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (150 mg). NMR Spectrum: (DMSO-d6) 7.10 (bs, 2H), 7.66 (dd, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 8.49 (dd, 1H); Mass spectrum: M+H+ 309-311.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>O1CCCC1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:28]([NH:27][CH2:26][CH2:25][Cl:24])=[O:29])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Yield: 52.2 %

Procedure:
N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (400 mg), 2-chloroethylisocyanate (150 mg) and tetrahydrofuran (5 ml) were stirred at 80° C. for 1.5 hours. The mixture was returned to room temperature, silica gel was added, and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 280 mg of a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH2:12][NH:13]CCC.C(Cl)Cl.C(N(CC)CC)C.BrCC(Br)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH2:12][NH2:13]
Reactant: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Agent: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: NCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
N-(n-propyl) ethanolamine 2,4,6-trichlorophenylether, 11.3 gm, was added to 100 ml of methylene chloride. 5.6 ml of triethylamine was added to the system. The system was stirred at about -70° C for 5 minutes and then 3.5 ml of α-bromoacetyl bromide was added dropwise. The system was stirred at room temperature for an additional 18 hours. The reaction was stopped and the system poured into 100 ml of water. The product was extracted with methylene chloride. The organic solution was dried over magnesium sulfate and the methylene chloride was then removed by stripping to give the N-(α-bromoacetyl), N-(npropyl) ethanolamine 2,4,6-trichlorophenylether as a brown oil. Listed as Compound No. 3 in Table I.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate (0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.43 g, 1.5 mmol, from Example 108, Step 1) and DIPEA (0.53 mL, 3.0 mmol) in ethanol (6 mL) was heated at 100° C. overnight. The mixture was concentrated and purified on silica gel column (eluting with 0 to 100% EtOAc in hexanes) to give tert-butyl 3-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate. LCMS calculated for C28H38 ClN6O4 (M+H)+: m/z=557.3. found: 557.3. The Boc intermediate isolated was treated with trifluoroacetic acid (0.8 mL, 10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour. The mixture was stripped to dryness to give the desired product as TFA salt. 4 mg of the salt was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 100.7 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (62 g; 0.19 mole) was hydrogenated in ethyl acetate (400 ml) at atmospheric pressure using Pd/C (10%) as catalyst. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (yield 100%) of 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Combine in a round bottom flask equipped with a Dean Stark trap 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 mL and 30 mL respectively), K2CO3 (1.25 g, 9.04 mmol), and 4-fluorobenzonitrile (0.72 g, 6.04 mmol). Reflux the reaction under a nitrogen atmosphere for 4 hours then cool to room temperature. Add water to the reaction mixture and extract the product from the water layer using ethyl acetate. The product, a white solid, precipitates out from the ethyl acetate to afford 1.93 g, 5.5 mmol (87% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.5-7.6 (2H, m); MS m/z 249 (M-CO2t-Bu).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=[O:12].[CH3:16]O.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH3:15])[CH2:10][C:11]([O:13][CH3:16])=[O:12]
Reactant: CCC(CC(=O)O)c1cccc(O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCC(CC(=O)OC)c1cccc(O)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 500 mL round bottom flask was charged with 77.E (21.5 g, 101 mmol), MeOH (300 mL), and sulfuric acid (1.08 mL, 20.3 mmol). The solution was stirred for 1 hour at 80° C., cooled to room temperature, and diluted with ether. The organic layers were washed with saturated aqueous NaHCO3, water, and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 77.F (20.6 g, 90% yield) as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[C@@H:25]([OH:29])[CH2:26][C@@H:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:28]([OH:38])=[O:30])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Analogously to Example 1i), 0.502 g (1.00 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(phenylmethyl)-dihydrofuran-2-(3H)-one in 16 ml of dimethoxyethane and 8.6 ml of water are hydrolysed with 4 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 49 ml of sat. NH4Cl solution, 4.1 ml of 10% citric acid solution and methylene chloride, and ethanol is added until the precipitated solid has dissolved. The aqueous phase is extracted with 2 portions of methylene chloride/ethanol approximately 9:1, and the organic phases are washed with brine, dried with Na2SO4 and concentrated by evaporation: TLC Rf (A)=0.22.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)(=O)C>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:12]([CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[C:10](=[O:11])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)Oc1ccc(CC(=O)N(c2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N1CCC(N(C(=O)Cc2ccc(O)cc2)c2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.5 parts of {4-[2-{(4-chlorophenyl)[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl} ethyl carbonate and 50 parts of a sodium hydroxide solution 10% is stirred for 90 minutes at 45° C. The reaction mixture is cooled to room temperature and acidified with acetic acid to pH 5.5-6. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60° C., yielding 1.9 parts of N-(4-chlorophenyl)-4-hydroxy-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide monohydrochloride; mp. 242.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.[CH:18]([NH2:21])([CH3:20])[CH3:19].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:18]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1cccc(O)c1
Reaction time: 16 h

Procedure:
3-Hydroxybenzoic acid (0.966 g, 7.0 mmol), N-methylmorpholine (2.3 mL, 21 mmol), iso-propylamine (1.78 mL, 21 mmol) and CH2Cl2 (30 mL) were dissolved together and hydroxybenzotriazole (1.03 g, 7.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.47 g, 7.7 mmol) was added; stirred 16 h, diluted with CH2Cl2 (70 mL) and the organic phase was washed with satd aq NaHCO3, H2O, 0.3 N HCl, H2O, and satd aq NaCl, dried (Na2SO4) and concentrated to afford 443 mg as a white foam. 1H NMR (CDCl3): d 7.23 (m, 3), 6.90 (m, 1), 4.22 (m, 1), 1.25 (d, 6).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.C(O[C:16](=[O:18])[CH3:17])(=O)C.S(=O)(=O)(O)O.[C:24]([OH:27])(=O)[CH3:25]>CO.N1C=CC=CC=1>[C:2]([O:1][C@H:2]1[O:8][C@@H:7]([CH2:9][O:10][C:16](=[O:18])[CH3:17])[C@H:5]([O:6][C:24](=[O:27])[CH3:25])[C@@H:3]1[O:4][C:5](=[O:6])[CH3:7])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 57 %

Procedure:
In Non-Patent Document 2, L-ribose is used as a starting material, the alkylation of the hydroxyl group at 1-position is carried out in methanol that contains hydrochloric acid, the acetylation is carried out with acetic anhydride in pyridine, and the acetolysis is carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. By recrystallizing from ethyl ether, 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose is obtained at a total yield of 57%. Hereinafter, in the present specification, 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose may be referred to as β-L-TAR at times, and 1,2,3,5-tetra-O-acetyl-L-ribofuranose may be referred to as L-TAR at times.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:13]([OH:31])[C@H:12]2[OH:32])=[C:4]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>ClCCl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[NH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:12]([OH:32])[C@@H:13]1[OH:31]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol (10.3 g, 15.50 mmol) is dissolved in dichloromethane (50 ml). TFA (25 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo to give the title compound. 1H nmr (MeOD, 400 MHz); 7.90 (s, 1H), 7.30-7.10 (m, 10H), 4.65 (m, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 4.10 (m, 2H), 3.50 (m, 1H), 2.75 (m, 1H), 2.15 (m, 1H), MS (ES+) m/e 465 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.N1C=CC=CC=1CC(=O)C>CS(C)=O>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[O:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccccn1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(Oc3ccccn3)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 64.4 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (300 mg, 0.57 mmol; Compound 346, Step 1), CuBr (3.6 mg, 0.025 mmol), Cs2CO3 (320 mg, 0.98 mmol), 2-iodopyridine (103 mg, 0.50 mmol), 1-(pyridin-2-yl)propan-2-one (15 mg, 0.11 mmol), and DMSO (1 mL) was degassed with three vacuum/N2 cycles, heated at 80° C. for 5 h, heated at 90° C. for 2 h, and then stirred at rt for 14 h. The reaction was diluted with EtOAc and filtered through Celite. The organic filtrate was washed with H2O (50 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (10%-30% EtOAc in hexanes) to give 193 mg of (E)-ethyl 3-(4-((E)-2-(3-(pyridin-2-yloxy)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.13 (dd, 1H), 8.11 (s, 1H), 7.69-7.75 (m, 2H), 7.64 (s, 1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.30 (t, 1H), 7.23 (dd, 1H), 7.06-7.10 (m, 2H), 6.90-6.95 (m, 3H), 6.85-6.88 (m, 1H), 6.65 (d, 1H), 6.52 (d, 1H), 5.85 (d, 1H), 4.16 (q, 2H), 3.87-3.92 (m, 1H), 3.70-3.78 (m, 1H), 2.38-2.48 (m, 3H), 1.95-2.08 (m, 2H), 1.70-1.81 (m, 1H), 1.56-1.62 (m, 2H), 1.25 (t, 3H), 0.94 (t, 3H); LCMS: 600 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.CI.[C:23](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:4]=2[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83.9 %

Procedure:
A mixture of 4-chloro-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (0.43 g, 1.5 mmol), MeI (0.103 ml, 1.65 mmol), potassium carbonate (0.41 g, 3.0 mmol) and DMF (5 ml) was stirred at room temperature for 19 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 0.38 g (98%) of the title compound as crystals.
Reaction SMILES: O.[NH2:2]N.[F:4][C:5]([F:12])([F:11])[C:6](OCC)=O.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18]>C(O)C>[F:4][C:5]([F:12])([F:11])[C:6]1[N:19]=[CH:17][NH:18][N:2]=1
Reactant: NN
Reactant: N=CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1nc[nH]n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
4.76 g of hydrazine hydrate was dissolved to 160 ml of ethanol, and it was cooled to 0° C. 14.21 g of ethyl 2,2,2-trifluoroacetate was dropped to it over the period of 30 minutes, followed by stirring at 0° C. for 1 hour. 9.89 g of formamidine acetic acid salt was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 200 ml of acetic acid was added to the residue, followed by stirring at 100° C. for 5 hours. The reaction mixture which was cooled to room temperature was concentrated under reduced pressure. Saturated aqueous solution of sodium hydrogen carbonate was added to the residue so as to be pH 6. And then it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.44 g of 3-(trifluoromethyl)-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:20](=[O:21])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)Cc1ccccc1
Yield: 74.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-phenylacetyl chloride (60 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 64 mg of N-methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetamide as a brown oil (Yield: 74%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH3:5].CS(O[CH2:11][CH2:12][S:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]2[CH2:22][C@@H:17]1[C:18]2([CH3:24])[CH3:23])(=O)=O.O>ClCCl>[CH3:23][C:18]1([CH3:24])[C@H:17]2[CH2:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11][N:4]([CH2:3][CH2:2][OH:1])[CH3:5]
Reactant: CNCCO
Reactant: CC1(C)[C@H]2CC[C@@H](CCSCCOS(C)(=O)=O)[C@@H]1C2
Solvent: O
Solvent: ClCCl
Product: CN(CCO)CCSCC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
10 ml of N-(2-hydroxyethyl)-N-methylamine were added to the solution of 2-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethylthio]ethyl methanesulfonate in dichloromethane obtained above. The dichloromethane was then distilled off under reduced pressure, and the remaining reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was worked up by adding 30 ml of water and extracting the mixture with ethyl acetate. The organic phase was separated and concentrated. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 2.6 g of N-(2-[2((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethy lthio]ethyl]-N-(2-hydroxyethyl)-N-methylamine were obtained.