Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl.N1C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:1](=[O:2])[CH3:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of Pyridine (3 mL) and AcCl (1.017 g, 13.043) in DCM (15 mL) was added the solution of 4-nitrobenzenamine (1.5 g, 10.870 mmol) in pyridine (3 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was washed with water (10 mL×3), dried under reduced pressure to afford N-(4-nitrophenyl)acetamide as yellow powder (1.9 g, yield: 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2].Cl.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH:17]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:37])[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(C#N)cc1OC(C(=O)C1CCN(c2ccncc2)CC1)[C@H]1CCCN1
Reaction time: 8 h

Procedure:
570 mg (1.89 mmol) of ethyl 3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate was dissolved in 10 ml of DMF. 504 mg (2.1 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg (2.8 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml (5.7 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:21][S:22]([C:25]3[S:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)(=[O:24])=[O:23])[C:17]([O:19][CH3:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[CH3:20][O:19][C:17]1[C:16]([NH:21][S:22]([C:25]2[S:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:24])=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCNCC2
Yield: 107.4 %

Procedure:
A solution of the Boc-protected amine D7 (1.05 g, 0.00199 moles) in 1.4-dioxane (20 ml) and 4M HCl in dioxane (10 ml) was stirred under argon at room temperature overnight. The resultant mixture was evaporated to dryness to give the hydrochloride salt of the title compound D9 as a cream solid (0.96 g, 100%). M-H 448.5. 1H NMR: δ DMSO-d6 3.08 (4H, m), 3.32 (4H, br s), 3.52 (3H, s), 6.85 (1H, s), 7.10 (1H, s), 7.41 (1H, d), 7.49–7.53 (3H, m), 7.69 (1H, s), 7.73 (1H, s), 9.27 (2H,br s), 9.74 (1 H, br s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([N:30]=[C:31]=[O:32])=[CH:24][C:23]=2[O:22]1.O.CCOCC>CN(C=O)C>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[C:19]5[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=5)[NH:13][N:12]=4)[CH2:7][CH2:6]3)=[O:32])=[CH:24][C:23]=2[O:22]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)OCO2)OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
A solution of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl]-6-fluoro-1H-indazole (230 mg, 0.83 mmol) in 5 ml dry DMF was added 3,4-methylenedioxyphenylisocyanate (291 mg, 1.65 mmol) in 3 ml dry DMF. The reaction was heated to 100° C. for 2 h and 16 h at 80° C. The reaction was cooled to room temperature and added a mixture of 50 ml water and 200 ml ether, filtered and separated. The ether phase was washed with water, brine and dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fractions afforded 50 mg (11%) of the title compound as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCOC3=O)cc2)CC1
Yield: 61 %

Procedure:
To a mixture of (4-bromophenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.6 g) described in Preparation Example 30, oxazolidin-2-one (348 mg), potassium carbonate (1.1 g) and copper (I) iodide (152 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (200 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (991 mg).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH:15]([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:22].[Na+]>CO>[NH2:22][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH:15]1[CH3:20]
Reactant: [BH3-]C#N
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (178.3 g, 2.31 mol) was charged to a solution of 1-benzyl-3-methyl-4-piperidone (47 g, 0.232 mol) in 500 ml methanol. The suspension was stirred for 4 hours at room temperature. Sodium cyanoborohydride (7.3 g, 0.16 mol) was added in lots at 10° C. and it was stirred for 1 hour.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:21][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: COc1cccc(C(N)=O)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(C(=O)Nc2ccc3c(=O)[nH]nc(Cl)c3c2)c1

Procedure:
A mixture of 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.39 mmol), 3-methoxy-benzamide (64 mg, 0.42 mmol), Pd2(dba)3 (36 mg, 0.039 mmol), xantphos (68 mg, 0.12 mmol) and Cs2CO3 (607 mg, 0.98 mmol) in dioxane (5 mL) was purged with nitrogen for 10 min. The mixture was place in a microwave reactor for 5 min. After this time the mixture was filtered and purified by preparative HPLC to yield the title compound hydroformate. m/z (M+H)=329.96, 1H-NMR (DMSO-d6) δ: 12.75 (s, 1H), 10.85 (s, 1H), 8.63 (s, 1H), 8.25 (m, 2H), 7.60 (d, 1H), 7.56 (s, 1H), 7.45 (t, 1H), 7.20 (dd, 1H), 3.85 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[Cl-].[Li+].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[C:30]([O:29][C:27](=[O:28])[NH:26][C@@H:4]([CH2:3][OH:2])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:31])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of ethanol/tetrahydrofuran (50/50) (2.16 mL), (R)-2-tert-Butoxycarbonylamino-3-[4-(4-phenoxy-phenoxy)-phenyl]-propionic acid methyl ester (0.125 g, 0.324 mmol) was added. Then lithium chloride (0.046 g, 1.296 mmol) and sodium borohydride (0.041 g, 1.296 mmol) dissolved in ethanol/tetrahydrofuran (50/50) (2.16 mL) were added to the reaction mixture. The resulting mixture was stirred starting at 0° C. and warming to room temperature over 18 hours. Reaction was stopped with 1N HCl (1.0 mL) and then extracted with EtOAc (20 mL) and water (15 mL). The organic layer was separated. Organic layer was washed with each and separated for the next wash, 1N HCl (15 mL), sodium bicarbonate (15 mL), and brine (15 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to obtain a crude mixture, which was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.1 g, 71%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 2.75-2.82 (m, 2H), 3.56-3.70 (m, 2H), 3.85 (s, 1H), 4.73 (s, 1H), 6.94 (d, 2H, J=8.8 Hz), 6.99-7.01 (m, 5H), 7.08 (t, 1H, J=7.2 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.31-7.35 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:33])[N:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([N:37](C(C)C)CC)(C)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CCOC(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:33])[N:25]([CH2:29][C:30]([NH2:37])=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(CC(=O)O)c3=O)cc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(CC(N)=O)c3=O)cc1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To 501 (0.150 g, 0.324 mmol) in THF (4 mL) was added diisopropylethylamine (0.33 mL, 1.94 mmol), ammonium chloride (0.069 g, 1.29 mmol), and HATU (0.184 g, 0.485 mmol). The resulting mixture was stirred 24 h at room temperature. The reaction mixture was diluted with EtOAc. The solution was washed sequentially with saturated sodium bicarbonate, water, and brine, before drying over MgSO4 and concentrating under reduced pressure to 50 mL of EtOAc. The solids were collected by filtration to give 504 (0.101 g, 68%). 1H NMR (500 MHz, DMSO) δ 9.10 (d, J=2.3, 1H), 8.08 (s, 1H), 7.70 (dd, J=7.0, 1.9, 1H), 7.61 (ddd, J=10.8, 7.6, 2.1, 2H), 7.07 (d, J=8.4, 1H), 6.34 (t, J=6.9, 1H), 5.94 (dt, J=13.1, 6.6, 1H), 4.60 (s, 2H), 4.40 (t, J=4.9, 2H), 3.45 (t, J=4.9, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 463.1 (M+H)
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:3]([NH:6][C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([CH3:5])[CH3:4].O1CCCC1.[ClH:33]>O>[ClH:33].[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][NH:6][C:3]([CH:2]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[OH:1])([CH3:5])[CH3:4])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1cccc(C(O)C(C)(C)NC(=O)Cc2ccc(OC)c(OC)c2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(O)C(C)(C)NCCc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 45 g. (0.12 mole) of N-(β-hydroxy-3-methoxy-α,α-dimethylphenethyl)-3,4-dimethoxybenzeneacetamide in 500 ml. dry tetrahydrofuran is added 200 ml. 1 M (0.2 mole) of BH3 /THF solution over 30 minutes at 0° C. with stirring. After addition, the reaction is allowed to stir overnight at room temperature. Water is added dropwise with caution until effervescence ceases, then 50 ml. more water is added all at once. Aqueous HCl (10%) is added to pH 1.0. Then the acidic reaction mixture is heated at 65° C. for 1 hour to remove most of the tetrahydrofuran and destroy excess BH3. Next, the mixture is cooled with ice and basicified with NH4OH. The mixture is extracted twice with 1 l. ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated to dryness in vacuo. The crude hydrochloride is made by dissolving the residue in 250 ml. ethyl acetate and adding a solution of ethyl acetate saturated with dry HCl to pH 2.0. On standing, 25 g. of crude solid is obtained, which is recrystallized from 300 ml. hot isopropanol to give 18.5 g. (39% yield) of α-(1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-1-methylethyl)-3-methoxybenzenemethanol hydrochloride as a white crystalline solid of analytical purity; m.p. 185°-186° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3C[C@H](NC(=O)CO)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)C3C=CC=CC=3)[N:8]=2)[CH:6]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H:56]([NH:58][C:59]([CH2:61][O:62]C(=O)C)=[O:60])[C@@H:55](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH2:56]([NH:58][C:59]([C@@H:61]1[C@@H:18]([OH:26])[C@@H:17]([OH:27])[C@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:5]2[CH:6]=[C:2]([NH2:1])[N:3]=[CH:4]2)=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:62]1)=[O:60])[CH3:55]
Reactant: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc(N)c4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU), by substituting (2S,3S,4R,5R)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide (Intermediate ZY) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in step ZU1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:26]1[CH2:30][CH2:29][N:28]([N:31]=[CH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]1=[O:39])([C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[CH3:40][O:41][C:42]1[CH:60]=[CH:59][C:45]([CH2:46][O:47][C:48](SC2N=C(C)C=C(C)N=2)=[O:49])=[CH:44][CH:43]=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:32](=[N:31][N:28]1[CH2:29][CH2:30][N:26]([C@@:5]2([C:10]([O:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[NH:1][C:48]([O:47][CH2:46][C:45]3[CH:59]=[CH:60][C:42]([O:41][CH3:40])=[CH:43][CH:44]=3)=[O:49])[CH2:6]2)[C:27]1=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OC(c3ccccc3)c3ccccc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H]2C(=O)N3C[C@@](C(=O)OC(c4ccccc4)c4ccccc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
In 80 ml of methylene chloride was dissolved 7.50 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazoldin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 5 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine. The mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with 80 ml of water, and the resulting mixture was adjusted to pH 7.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/acetone=1/0 to 25/1) to obtain 8.36 g (yield: 85.2%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(p-methoxybenzyloxycarbonylamino)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 10 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and toluene (60 ml) was heated to reflux while stirring for 10 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.6 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[S:29][N:28]=1.Cl[C:40]1[N:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=2)[N:41]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:40]3[N:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:52][CH:51]=4)[N:41]=3)=[CH:34][CH:33]=2)[S:29][N:28]=1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1nsc(-c2ccc(N)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nsc(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)n1
Yield: 27.6 %

Procedure:
Palladium(II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.032 mmol) were stirred in dioxane (1 mL) for 10 minutes at room temperature under an atmosphere of nitrogen. Sodium tert.-butylate (29 mg, 0.3 mmol), 4-(3-methyl-[1,2,4]-thiadiazol-5-yl)-phenylamine (38 mg, 0.20 mmol) and) 2-[2-chloro-6-(4-trifluoromethyl-phenyl)pyrimidine-4-yl]-propan-2-ol (70 mg, 0.22 mmol) dissolved in dioxane (1 mL) were added. The reaction was heated for 30 minutes to 130° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (1:1 v/v) as eluent to yield the title compound as a yellow solid (26 mg, 28%). MS ISP (m/e): 472.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.97 (d, 2H), 7.85 (d, 2H), 7.79 (d, 2H), 7.45 (br s, 1H, NH), 7.39 (s, 1H), 3.72 (s, 1H, OH), 2.73 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1.[C:21](OCC)(OCC)(OCC)[CH3:22].C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>CO>[Cl:1][C:2]1[C:7]2[N:8]=[C:21]([CH3:22])[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(C)n(CCOc3ccccc3)c2c1C

Procedure:
2-Chloro-5,6-dimethyl-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.41 g), triethyl orthoacetate (1.60 ml), toluene (20 ml), and a catalytic amount of pyridine HCl were combined and heated to reflux for 2 hours. Methanol (15 ml) was then added and the reaction mixture was allowed to cool. The resulting white needles were filtered and dried. NMR analysis of the dried solid indicated a pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:25]2[O:24][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccco1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccco2)c1
Yield: 32.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(furan-2-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.080 g; 0.230 mmol), furan-2-ylboronic acid (0.027 g; 0.241 mmol), tetrakis(triphenylphosphine)palladium (0.027 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.028 g (32%) of the title compound as a white solid.