Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[O:15]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[O:15]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2/[CH:26]=[CH:27]/[C:28]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])=[CH:4][CH:3]=2)=[O:29])=[CH:16]1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccoc1
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COP(=O)(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccoc2)cc1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A mixture of dimethyl 4-aminobenzylphosphonate (258 mg), (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (218 mg), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg) and N,N-dimethylformamide (8 mL) was stirred overnight at room temperature. The reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to give dimethyl 4-{[(2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl]amino}benzylphosphonate (123 mg, yield 30%) as colorless prism crystals. melting point: 176-177° C.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1>C(Cl)(Cl)(Cl)Cl>[BrH:1].[Br:1][C:7]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]([OH:3])=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cccnc1O
Solvent: ClC(Cl)(Cl)Cl
Product: Br
Product: O=[N+]([O-])c1cc(Br)cnc1O

Procedure:
3.6 ml of bromine are added dropwise to a suspension of 10.0 g (0.071 mol) of 2-hydroxy-3-nitro-pyridine in 25 ml of carbon tetrachloride whilst cooling with ice. The reaction mixture is refluxed for 2 hours. The solvent is distilled off in vacuo, the crystalline product is suction filtered and recrystallised from water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[C:11](=[O:12])[CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:14])[C:11](=[O:12])[C:10]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:27]3[NH:28][C:29]4[C:34]([C:26]=3[CH2:25][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:23])[CH3:36])=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=4)=[C:9]2[OH:13])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)C(=O)CC1=O
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(C)(c3ccc(Cl)cc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-(4-chloro-phenyl)-2-methyl-cyclobutane-1,3-dione was reacted with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide (from Example 1.2) to give N-[2-(2-{[3-(4-chloro-phenyl)-2-hydroxy-3-methyl-4-oxo-cyclobut-1-enyl]-phenyl-methyl}-6-methyl-1H-indol-3-yl)-1,1-dimethyl-ethyl]-acetamide as a pale yellow solid. MS: 539.5 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2-Chloro-4-(trifluoromethyl)-benzeneacetic acid (3 g) [CAS Reg. No. 601513-26-2] was dissolved in DCM (30 mL) and methyl chloroformiate (1.18 g, 0.97 mL) followed by triethylamine (1.4 g, 1.93 mL) were added drop by drop. To the mixture was added DMAP (0.154 g) and the yellow mixture was allowed to stir for 1 hour at 0° C. A clear solution was obtained. The mixture was diluted with DCM (30 mL) and was poured into sat. NH4Cl solution. The layers were separated and the aqueous phase was further extracted with 2 portions of DCM. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give the title compound (3.0 g) that was used without further purification. NMR, (CDCl3): 7.6-7.4 (m, 3H); 3.84 (s, 2H); 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:26]([O:28][CH2:29][CH3:30])=[O:27])#N>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CCOC(=O)C#N
Reactant: COc1cc2c(cc1Cl)C(=O)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OC)c(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-5-methoxyindan-1-one (27.6 g, 141 mmol) in THF (630 mL) at −78° C. was added a 1.0M solution of lithium bis(trimethylsilyl)amide in THF (309 mL, 309 mmol) and then the solution was slowly warmed to ca −50° C. during 1 hour. After re -cooling to −78° C., ethyl cyanoformate (21.3 mL, 216 mmol) was introduced and the reaction mixture was allowed to warm to room temperature during 2 hours. After quenching with 300 mL of 1N HCl, most of the THF was removed by rotary evaporation under reduced pressure. The residual mixture was extracted with EtOAc and the organic layer was washed with dilute aqueous NaHCO3 and dried over Na2SO4. Filtration through a pad of silica and removal of the solvent under reduced pressure gave ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[O:22][C:21]2=[O:28].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:23]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=4)[C:5]([CH3:16])([CH3:15])[C:6]=3[CH:7]=2)=[O:27])=[C:20]([CH:19]=1)[C:21]([OH:28])=[O:22]
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (25.0 g, 0.092 mol) and 5-bromoisobenzofuran-1,3-dione (26.89 g, 0.119 mol) were placed in a reaction vessel, and added with dichloromethane (700 ml). At 0° C., aluminum chloride (18.5 g, 0.138 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 5-bromo-2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (27.9 g, yield 61%) was obtained.
Reaction SMILES: [O:1]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+].Cl>CO>[CH:19]1([N:4]2[CH2:3][CH2:2][O:1][C:9]3[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=3[O:7][CH2:6][CH2:5]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Reactant: O=C1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)OCCN(C1CCCC1)CCO2

Procedure:
To methanol add N-(3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonin-9-yl)methanesulfonamide, cyclopentanone, and NaBH3CN. Adjust the pH to six with concentrated HCl. Monitor the progress of the reaction by thin-layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Partition the reaction mixture between EtOAc and water. Add 1N aqueous NaOH until the solution is basic. Separate and dry the organic layer over Na2SO4. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][NH2:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH2:14][NH:30][CH3:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added methylamine (2.0 M in THF, 0.52 mmol) and NaBH(OAc)3 (0.82 g, 0.39 mmol). The reaction was stirred for 3 hours, quenched with water, and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting crude imine was dissolved in MeOH (5 ml) and NaBH4 (0.06 g, 0.4 mmol) was added. The reaction was stirred for 10 min, quenched with aq. Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse phase column chromatography (5-35% ACN) to give the title compound (0.05 g, 48%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.38 (m, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.02-6.98 (m, 2H), 6.00-5.52 (br s, 1H), 5.05 (s, 1H), 3.63 (s, 2H), 2.37 (s, 3H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.9 Hz, 3H), 0.93-0.91 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 398. Found: [M+H]+399.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[CH2:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].[CH:32]1([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:32]1([CH2:38][NH:39][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:11][O:12][C:13]5[CH:21]=[C:17]6[C:16](=[CH:15][C:14]4=5)[CH2:20][CH2:19][O:18]6)[C:2]3=[O:1])[CH:24]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: NCC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Yield: 108.1 %

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS ) [1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g, 12.0 mmol) in CH2Cl2 (40 ml) at 0° C. under an argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluoride etherate (8.8 ml, 71 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl (50 ml). The mixture was extracted with EtOAc (150 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to provide the title compound (4.2 g, 95%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [SH2:1].C([CH2:4][C:5]([O:7][CH3:8])=[O:6])#N.[N:9]1C=CC=[CH:11][CH:10]=1.C(N(CC)CC)C>>[C:10]([NH:9][CH2:4][C:5]([O:7][CH3:8])=[O:6])(=[S:1])[CH3:11]
Reactant: COC(=O)CC#N
Reactant: S
Reactant: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(C)=S

Procedure:
A stream of H2S is bubbled into a mixture of methyl cyanoacetate (70 g, 710 mmol), pyridine (70 ml, 710 mmol) and triethylamine (49.6 ml, 350 mmol). The exothermic reaction, which is cooled with an ice bath, is followed by TLC. When the reaction is complete, the reaction mixture is washed with a dilute solution of acid and extracted with ether. After drying over magnesium sulfate and concentration under vacuum, an orange oil is obtained which crystallizes. The yellow solid obtained is washed with ether and then filtered off to give 83.3 g of methyl thioacetamidoacetate melting at 78°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]2[C:65]=1[C:66](=[O:84])[C:67]([C:77]1[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=1)=[C:68]([CH:74](O)[CH3:75])[O:69]2>C1COCC1.O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:74]([C:68]3[O:69][C:70]4[C:65]([C:66](=[O:84])[C:67]=3[C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=3)=[C:64]([F:63])[CH:73]=[CH:72][CH:71]=4)[CH3:75])[N:15]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)=[C:2]([F:1])[CH:3]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(N4CCOCC4)c(F)c3)c12
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N3CCOCC3)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
This example is also described in Example 59 of WO 2012/151525. To a solution of 3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.254 mmol) in THF (2 ml), tris(4-methoxyphenyl)phosphine (0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol) is added and stirred at room temperature (RT) for 10 minutes. To this mixture (−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.077 g, 0.254 mmol) is added and stirred for 12 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid. MP: 242-245° C. Enantiomeric excess: 96.21% Mass: 599.1 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[CH:5]=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)[CH:5]=[CH:4][C:3]=2[C:28]([F:31])([F:30])[F:29])=[CH:48][CH:47]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(Cl)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(-c4ccc(OC)cc4)n3)ccc21
Temperature: 80 °C

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-chloro-5-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 303, 0.06 g, 0.14 mmol) in a mixture of toluene (3.75 mL), 1,4-dioxane (0.75 mL), and water (0.88 mL) were added Na2CO3 (0.15 g, 1.38 mmol), 4-methoxyphenyl boronic acid (0.08 g, 0.55 mmol), and PdCl2(dppf)CH2Cl2 (0.02 g, 0.03 mmol). The mixture was heated at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.11 g, 94%) was purified by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, 1H), 7.39 (t, 1H), 7.33 (d, 2H), 7.04 (d, 1H), 6.94 (dd, 2H), 6.74 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 4.08 (q, 2H), 3.97 (t, 2H), 3.79 (s, 3H), 3.45-3.30 (m, 3H), 2.76-2.68 (m, 3H), 2.35 (dd, 1H), 2.30-2.20 (m, 1H), 1.95 (qt, 2H), 1.70-1.58 (m, 1H), 1.19 (t, 3H).
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=O.[C:8]1([CH2:14][C:15]([O:17]CC)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1.Cl>O.O1CCCC1>[OH:17][C:15]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:27]=[CH:28][C:29]([S:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)=[C:21]2[N:20]=[CH:3][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1c(-c2ccccc2)cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To tetrahydrofuran suspension of 480 mg of 60% sodium hydride, 2 ml of ethyl formate and 1.64 g of ethyl phenylacetate were added in nitrogen atmosphere, and stirred for 19 hours at room temperature. Adding 1.0 g of 3-amino-4-(4-phenylthiophenyl)pyrazole, the mixture was stirred for 4 hours under reflux. After allowing to cool, water and 10% hydrochloric acid was added. The solution obtained was extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was dissolved in 5 ml of acetic acid, and the mixture was heated and stirred for 2 to 20 hours at 120° C. After allowing to cool, ethyl acetate was added, and the precipitate was filtered. The filtrate was washed with ethyl acetate and ether and dried, and the title compound was obtained (270 mg, 18%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CC(C)=O.Cl[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: O=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(CSc2ccc([N+](=O)[O-])cn2)cc1
Yield: 93.3 %

Procedure:
To 40 mg of 2-mercapto-5-nitropyridine was added 200 mL of acetone, and the solution was stirred while cooled with water. To this reaction solution were added 43.6 of 4-chloromethylbenzaldehyde and 45 g of potassium carbonate, to conduct reaction. After the completion of the reaction, 1 L of water was added to the solution. The precipitated crystal was collected by filtration, washed with water, washed with methanol, and dried (yield amount 65.5 g, and yield 93.3%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]OS(=O)(=O)OC.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:20]([CH3:23])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc(COCCCc2nc3cccnc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(CCCOCc2ccccc2)nc2cccnc21

Procedure:
Under an argon atmosphere, to a solution of 2-[3-(benzyloxy)propyl]-3H-imidazo[4,5-b]pyridine (2 g) in DMF (40 mL) was added 60% sodium hydride (0.299 g), and the mixture was stirred under ice-cooling for 30 min. Then, dimethylsulfuric acid (0.75 mL) was added, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added methanol (5 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.2 g).