Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2CCCN2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (500 mg, 1.04 mmol), methyl 3-chloro-4-(2-pyrrolidinyl)methoxybenzoate (281 mg, 1.04 mmol), Et3N (0.17 mL, 1.25 mmol) in DMF (5 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane-EtOAc (1:3, v/v) as eluent to afford methyl 3-chloro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (620 mg, 1.04 mmol) as a white crystalline solid. To a stirred solution of this compound in THF (8 mL) and H2O (2 mL) was added LiOH (74.9 mg, 3.126 mmol), and the mixture was stirred at room temp for 2 days. The mixture was diluted with CHCl3, and treated with 1N HCl. The solution was washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude solid was recrystallized from n-hexane-EtOAc—CHCl3 to afford 561.2 (98%) 29 as a white crystalline material. IR (KBr) 1676, 1599, 1487, 1267, 758, 754 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.82-2.24 (m, 4H), 2.25 (s. 3H), 3.48-3.60 (m, 4H), 3.78 (s, 3H), 4.18 (m, 2H), 4.31 (m, 1H), 6.74 (dd, J=1.5, 8.3 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.91-6.95 (m, 1H), 7.11-7.17 (m, 3H), 7.79 (dd, J=2.0, 8.3 Hz, 2H), 7.85 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 8.58 (s, 1H); MS (FAB) m/z 552 (M++1).
Reaction SMILES: CC1CC([OH:8])CC=1C.[Si:9]([O:16][CH:17]1[CH2:21][C:20]([CH2:25][CH:26]=[CH2:27])(COC)[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][CH:17]1[CH2:21][C:20]([CH2:25][CH:26]=[CH2:27])([OH:8])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC1=C(C)CC(O)C1
Reactant: C=CCC1(COC)C=CC(O[Si](C)(C)C(C)(C)C)C1
Product: C=CCC1(O)C=CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 92 %

Procedure:
From 4.50 g of (1RS,4RS)-4-allyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether was obtained by the same procedures as in (3) of the intermediate preparation example 1 (1RS,4RS)-4-allyl-4-methoxymethyl-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether in an amount of 4.88 g. Yield 92%
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:7]1=[O:19].O>CN(C=O)C.CCOCC>[N:1]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:7]1=[O:19])=[N+:2]=[N-:3]
Reactant: O=C1C(Br)CCN1c1ccc(F)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NC1CCN(c2ccc(F)c(Cl)c2)C1=O
Reaction time: 8 h
Yield: 120.6 %

Procedure:
Sodium azide (0.45 g) was added to a solution of 3-bromo-1-(3-chloro-4-fluorophenyl)-2-pyrrolidinone (2.00 g) in DMF (16 ml) and the mixture left to stand overnight. A further portion of sodium azide (0.15 g) was added and the mixture again left to stand overnight. The mixture was poured into water giving a white solid which was isolated by filtration, dissolved in ether, dried (MsSO4) and concentrated in vacuo to give the sub-title compound as an off-white solid (2.10 g) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(O)cc2c(Br)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (0.22 g, 0.61 mmol) was placed in a dry 150 mL single-necked flask fitted with a stirring bar and septa. Methylene chloride (30 mL) was added via a syringe. Boron tribromide (1.83 mL of 1.0 M methylene chloride solution) was added dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 20 hours. Then, 20 mL of water was added to quench the reaction. The mixture was extracted with 50 mL of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.10 g, 49.4% yield. MS: 334.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 10.58 (s, 1H), 9.83 (s, 1H), 8.12 (d, 1H, J=8.7 Hz), 7.71 (s, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.09 (d, 1H, J=21. Hz), 7.04 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.84 (d, 2H, J=8.7 Hz).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:26])([C:24]#[CH:25])[CH2:22][OH:23]>>[OH:26][C:21]([CH3:20])([CH2:22][OH:23])[C:24]#[C:25][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)CO
Yield: 15 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol to give the titled compound as an off-white solid (30.8 mg, 15%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:24]([NH2:25])=[CH:23][NH:22][N:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]=[C:12]1[C:20]1[C:24]([NH:25][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][NH:22][N:21]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(Cc1ccccc1)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.9 %

Procedure:
A mixture of phenylacetic acid (38 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMSO (2 ml) was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml) and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-petrol (1:2, 1:1, 2:1)] to give N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide as a brown solid (15 mg, 19%). (LC/MS: Rt 3.26, [M+H]+ 318.13).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:29]C)[C:22]=4[CH:26]([CH3:28])[CH3:27])[S:15]3(=[O:17])=[O:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([OH:29])[C:22]=4[CH:26]([CH3:27])[CH3:28])[S:15]3(=[O:16])=[O:17])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c(C(C)C)c1O)C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Reaction time: 18 h
Yield: 77 %

Procedure:
2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5,6-dimethoxy-saccharin (0.48 g) was added with stirring at 0° C. to a solution of aluminum chloride (0.4 g) and ethanethiol (0.15 mL) in chloroform (3 mL). The temperature was allowed to rise to and remain at room temperature for 18 hours. The reaction mixture was passed through silica gel with ethyl acetate-hexane (2:3) as eluant affording as a colorless oil 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5-hydroxy-6-methoxy-saccharin, 0.3 g, 77% yield, whose structure was proven by proton and carbon-13 magnetic resonance, mass spectrometric and nuclear Overhauser enhancement analyses. The latter analysis showed 19% enhancement of the methoxy protons signal and 10% enhancement of the C-7 proton signal.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[S:11][C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]=3[C:27]([F:30])([F:29])[F:28])=[N:9][C:8]=1[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[C:21]1([C:18]2[C:17]([C:27]([F:30])([F:29])[F:28])=[C:16]([C:10]3[S:11][C:12]4[C:13]5[C:5](=[CH:4][C:3]([OH:2])=[CH:15][CH:14]=5)[CH2:6][CH2:7][C:8]=4[N:9]=3)[O:20][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.5 %

Procedure:
To a solution of 5-(7-methoxy-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (Preparation 56B, 0.448 g, 1.046 mmol) in dichloromethane (13.07 mL) was added 1M BBr3 (5.23 mL, 5.23 mmol) in dichloromethane dropwise, and the mixture was stirred at room temperature for 4.5 h. The reaction was slowly quenched with sat. NaHCO3. After stirring for 5 min, sat. NH4Cl was added. It was then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers were then washed with brine, dried over anhydrous MgSO4, concentrated and chromatographed to give the 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-ol (0.388 g, 0.936 mmol, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.63-7.69 (2H, m), 7.46-7.58 (3H, m), 7.31 (1H, d, J=8.14 Hz), 6.80 (1H, d, J=2.42 Hz), 6.76 (1H, dd, J=8.25, 2.53 Hz), 3.15-3.23 (2H, m), 3.05-3.14 (2H, m).
Reaction SMILES: [CH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.O=[O+][O-]>>[CH:1]1=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1=CCCCCCCC=C1
Agent: C1=C\CCCC/C=C/CC/1
Agent: O=[O+][O-]
Product: C1=CCCCCC=CCC1

Procedure:
The example No. I (2) was repeated (using cyclodecadiene (CDD) as cycloolefin). In this case as well, a 1:1 reaction between olefin and ozone was found.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:37])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: CN(C)CCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 442 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[N:15]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:6][C:5]=2[N:4]=1>C(O)C>[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:14]1[N:15]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Yield: 78.6 %

Procedure:
A solution of hydrochloric acid (5 mL of 1.5 M in ethanol) was added to a mixture of tert-butyl {4-[4-amino-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate (823 mg, 1.41 mmol) and ethanol. The reaction was heated at reflux for 30 minutes and became homogeneous. The solvent was removed under reduced pressure. The residue was recrystallized from methanol, isolated by filtration, washed with diethyl ether, and dried under reduced pressure to provide 534 mg of 2-(4-aminobutyl)-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH:8]2[O:14][CH2:13][CH2:12][O:9]2)=[CH:6][CH:5]=1
Reactant: OCCO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C2OCCO2)cc1
Reaction time: 2 h

Procedure:
To a mixture of 4-nitrobenzaldehyde (7.55 g, 50 mmol) and ethyleneglycol (4.65 g, 75.0 mmol) in toluene (125 ml) was added 4-toluenesulphonic acid (100 mg, 0.5 mmol) and the mixture heated under reflux using a Dean-Stark water separator for 2 h. The solution was evaporated to dryness, the residue dissolved in EtOAc (125 ml), washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was dissolved in ethanol (200 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration, the ethanol evaporated to yield the title compound which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[C:28]([Si:25]([CH3:27])([CH3:26])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CCC(CCC(O)Cc2cccc(Oc3ccccc3)c2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Yield: 74.7 %

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[3-hydroxy-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (668.3 mg, 2.05 mmol) was reacted with tert-butyldimethylsilyl chloride (341 mg, 2.26 mmol). Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (673 mg). 1H NMR (CDCl3) δ 7.32 (m, 2H), 7.22 (m, 1H), 7.09 (m, 1H), 6.99 (d, 2H), 6.89 (d, 1H), 6.83 (m, 2H), 3.85 (m, 1H), 3.58 (m, 1H), 2.76-2.62 (m, 2H), 2.32 (m, 2H), 2.23 (m, 1H), 1.73-1.34 (m, 5H), 0.84 (s, 9H), −0.03 (d, 3H), −0.16 (d, 3H); MS 440.7 (M+1).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]#[N:15])[CH:8]=[CH:7][C:6]=2[C:5]1=[O:16])=[N+:2]=[N-:3].O.[BH4-].[Na+]>C1COCC1>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]#[N:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 53.8 %

Procedure:
Racemic 6-azido-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (28 mg, 0.13 mmol) was dissolved in THF (1253 mL) and water (66.0 mL) at 0° C. To this solution was added sodium borohydride (6.49 mg, 0.17 mmol). The resulting solution was stirred at 0° C. for 45 min. After that, the reaction was quenched by several drops of 1N HCl. The mixture was loaded to an ISCO 13 g column directly and purified by ISCO Combiflash Companion (10% ethyl acetate-hexane for 3 min then ramp to 50% ethyl acetate-hexane over 7 min then 20% ethyl acetate-hexane for 5 more min, product came out 8-10 min) to afford racemic (5S*,6R*)-6-azido-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (15.0 mg, 0.07 mmol, 53.1%) as a white solid. NMR showed that the product was a mixture of around 6:1 two diastereomers; LCMS=215.22 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[C:5]([CH3:8])=[N:6][CH:7]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:25]([CH2:9][C:4]1[C:5]([CH3:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N+:26]=[N-:27]
Reactant: Cc1ncc(Cl)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ncc(Cl)cc1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 399 mg (2.55 mmol) of (5-chloro-2-methylpyridin-3-yl)methanol in 10 mL of toluene at r.t. was added 660 μL (3.06 mmol) of DPPA (diphenylphosphoryl azide). The solution was cooled to 0° C. and 450 μL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) was added. The ice bath was removed and stirring was continued with warming to r.t. After 16 h, 1 N HCl was added to a pH=8. Water was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (45% EtOAc/hexanes) provided 3-(azidomethyl)-5-chloro-2-methylpyridine as a yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.[C:14]([C:16]1[C:21](Br)=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:15].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:21]2[C:16]([C:14]#[N:15])=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:5][N:4]=1
Reactant: N#Cc1ncccc1Br
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccnc2C#N)c(OC)n1
Yield: 79.5 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (1 g, 5.46 mmol) was dissolved in degassed n-PrOH (30 ml) and then 2-cyano-3-bromopyridine (950 mg, 5.19 mmol), Na2CO3 (1.65 g, 15.56 mmol), PPh3 (393 mg, 1.5 mmol) and Pd(OAc)2 (114 mg, 0.51 mmol) were added. The suspension was stirred at reflux for 3 hours. After cooling, the solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with iPrOH to give 1 g of the title compound as a white powder (76% yield).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:32][CH2:33][C@@H:34]([OH:36])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CCOC(C)=O>[Si:25]([O:32][CH2:33][C@@H:34]([O:36][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H]1CO1
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)CO[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
Magnesium trifluoromethanesulfonate (0.974 g, 3.02 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (1.234 g, 12.08 mmol) and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (CAS no. 113534-13-7) (2.30 g, 12.08 mmol) in EtOAc (5 mL) cooled to 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 2 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% EtOAc in isohexane to afford the product (1.336 g, 37.8%). 1H NMR (400 MHz, DMSO) δ0.00 (s, 6H), 0.83 (s, 9H), 0.98 (d, 3H), 3.34-3.53 (m, 3H), 3.55-3.64 (m, 5H), 4.11 (q, 1H), 5.39 (d, 1H)
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([OH:10])=[O:9].C1(NC2CCCCC2)CCCCC1.CCOCC>C(#N)C>[C:1]([S:3][C@@H:7]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=C(O)[C@H](Br)CC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)S[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred slurry of potassium thioacetate (1.07 g., 9.36 mmol.) in dry acetonitrile (15 ml.) at 0° C. under argon was added a solution of (R)-2-bromo-3-cyclohexylpropanoic acid (2.20 g., 9.36 mmol.) in acetonitrile (3 ml.) over 10 minutes. The reaction was warmed to room temperature and stirred 16 hours. The resulting slurry was filtered and evaporated. The residue was redissolved in ethyl acetate, washed once with 5% potassium bisulfate solution, dried (sodium sulfate) and evaporated. The oily yellow residue (2.21 g.) was dissolved in ether and treated with a solution of dicyclohexylamine (1.8 ml., 9.0 mmol.) in 5 ml. of ether. Scratching the flask surface with a glass rod provided 2.38 g. of white crystalline title product; m.p. 159°-161° C., [α]D =-41.2° (c=1.0, chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27]O)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:16]2[C:17]3[C:18]4=[C:19]([CH:23]=[CH:24][N:25]4[CH2:26][CH2:27]2)[N:20]=[CH:21][N:22]=3)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCO)c34)cc2C)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2ccc(N3CCn4ccc5ncnc3c54)cc2C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a suspension of 2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol (50 mg) and tributylphosphine (54 mg) in toluene (2.5 mL) was added 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (67 mg), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (36 mg) as a white powder.