Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)(=[O:12])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].O.C(O)C>[C:1]1([C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)(=[O:12])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)NC(=O)c2ccccc2)c1
Yield: 90 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(phenylcarbonylaminosulphonyl)-3-nitrobenzene (5.3 g, 17.3 mmol), 10% palladium on carbon (0.5 g, 9% (w/w)) in water (3 ml) and ethanol (100 ml), the title compound (4.3 g, 90%) was afforded as a yellow solid. mp 160°-162° C. 1H NMR (360 MHz, D6 -DMSO) δ 6.81 (1H, m), 7.07 (1H, m), 7.22 (2H, m), 7.48 (2H, m), 7.60 (1H, dd, J=7.4 and 7.4 Hz), 7.87 (2H, m).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:3]=[C:4]([CH3:20])[C:5]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: COC(=O)c1cc(I)cc(C)c1OCCN1CCCC1
Product: COC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc(C)c1OCCN1CCCC1

Procedure:
Prepared according to general working method I from methyl 5-iodo-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (150 mg, 0.39 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (112 mg, 0.53 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:19])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]#[N:37])([O-:29])=[O:28]>>[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[N:37][C:11]1[CH:12]=[C:13]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:14]=[C:9]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)([CH3:8])[CH3:7])[C:10]=1[OH:19])([O-:29])=[O:28]
Reactant: N#[N+]c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Agent: O=S(=O)([O-])O
Product: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
The title compound is prepared according to the method given in Example 12 using 45 g of 2-(4-chloro-α-cumyl)-4-tert-butylphenol prepared in Example 5 and 161 g of the diazonium salt solution (ca. 23%) prepared in Example 10. The desired compound is prepared in a yield of 70 g as a crimson viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]O>>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CO
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
After 25.0 ml (19.8 wt %) of methanol was added to 100 g of oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine at room temperature (about 25° C.), the mixture was heated to 40° C. while stirring. When the temperature of liquid reached 40° C., methanol was evaporated under reduced pressure. Oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester was again obtained. Crystals of N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester prepared in Example 1 (1.0 g) were added to the oil as seed crystals. Cooling was gradually continued to 15° C. while stirring. The precipitated crystals were immediately separated by centrifuging, and were then washed with 5 ml of previously cooled methanol. After the obtained crystals were air-dried, the crystals were further dried at 30° C. overnight under reduced pressure to give 84.3 g of N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester as crystals. The powder X-ray chart for the crystals formed in this way resembled that shown in FIG. 1 for the crystals of Example 1.
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:41][CH3:42])=[C:38]([Pb+3])[CH:39]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:41][CH3:42])=[C:36]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])[CH:35]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC12CCC(C(=O)CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.22 g, 1.22 mmol) (preparation described by H. Favre et al., Can. J. Chem. (1956), 34 1329-39) in dry chloroform (10 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is then added 4-dimethylaminopyridine (0.744 g, 6.15 mmol) and anhydrous toluene (3 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (0.673 g, 1.18 mmol) is added portionwise over 10 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (10 ml) is added, and the resulting biphasic mixture is filtered to remove any inorganic salts (washing with additional dichloromethane, 10 ml). The organic phase separated, and the aqueous phase is extracted again with dichloromethane (10 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give an orange gum. This crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.04 g, 9%) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (92 mg, 0.33 mmol) described in Example 278A. The reaction mixture was stirred at rt for 24 h. Concentration under reduced pressure gave a residue which was triturated with anhydrous diethyl ether to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (64.1 mg, 43%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 6H), 3.99 (s, 6H), 7.11 (d, J=6.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.30-7.45 (m, 5H), 7.53 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.84 (s, 1H), 8.70 (s, 1H), 8.91 (d, J=6.6 Hz, 2H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[CH2:15][CH2:14][C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]1=2>>[O:11]1[C:12]2[CH:19]=[CH:18][C:17]([CH2:20][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[CH:16][C:13]=2[CH2:14][CH2:15]1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C(O)c1ccccc1NCc1ccc2c(c1)CCO2

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde (Matrix). 13C-NMR (DMSO-d6) δ 169.9, 158.7, 150.6, 134.3, 131.6, 130.9, 127.5, 126.8, 124.0, 114.3, 111.5, 110.1, 108.6, 70.8, 45.6, 29.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].F[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COCCNCCOC
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Bis(2-methoxyethyl)amine (Aldrich B4, 820-7; 1.6 g; 12 mmol; 3 eq.) was added to a solution of 4-fluoro-3-nitrobenzoic acid (740 mg; 4 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at room temperature for 2 hours then at 70° C. for 20 hours. The solution was concentrated in vacuo and the residue was partitioned between NaOH 0.5M and Et2O. The aqueous layer was acidified to pH 2 with HCl 5M, extracted with ethyl acetate (3×) and the combined organic phase was dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallised from ethyl acetate/n-pentane to afford the title compound (1.12 g, 94%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2cccc(C(F)(F)F)c2)cn1
Yield: 45 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3-trifluoromethyl-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 22.9 mg (45%) of the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].O[NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1)=[NH:9].C([O-])([O-])=O.[K+].[K+]>O>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([C:8]3[N:7]=[C:3]([CH2:2][Br:1])[O:4][N:9]=3)=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: N=C(NO)c1ccc2c(c1)OCO2
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: BrCc1nc(-c2ccc3c(c2)OCO3)no1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
Bromoacetyl bromide (0.22 g, 1.10 mmol) was added to N-Hydroxy-benzo[1,3]dioxole-5-carboxamidine (0.40 g, 0.55 mmol) and K2CO3 (0.38 g, 0.78 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 5% EtOAc-Hexane) to get the desired product (0.05 g, 31%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:14][Cl:15])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH:3]([CH2:14][Cl:15])[O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1OC(CCl)CCl
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Temperature: -40 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
A mixture of 1-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-benzene (2) (2.0 g, 8 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.88 g, 12 mmoles) in THF at −78° C., under nitrogen, was treated dropwise over a 30 minute period with a solution of 1M potassium t-butoxide (18 ml, 18 mmoles). The reaction temperature was allowed to rise to −40° C. The reaction mixture was stirred at −40° C. for 5 hours poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant solid residue was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.4 g, 5.3 mmoles), identified by HNMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[OH:11].C(O)(=O)[CH:13]([CH2:15][C:16](O)=O)[OH:14]>>[CH2:6]1[C:5]2[CH:9]=[C:10]3[C:2](=[C:3]([OH:11])[C:4]=2[O:8][CH2:7]1)[O:1][C:13](=[O:14])[CH:15]=[CH:16]3
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Oc1ccc2c(c1O)OCC2
Product: O=c1ccc2cc3c(c(O)c2o1)OCC3

Procedure:
reacting 6,7-dihydroxy-2,3,-dihydrobenzofuran with malic acid to form 2,3-dihydroxanthotoxol,
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1>>[N:2]1([CH2:4][C@@H:5]2[CH2:6][C@H:7]([C:9]3[N:13]4[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]4=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:20]=4)[N:10]=3)[CH2:8]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: C1CCNC1
Reactant: CN(C)CC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](CN2CCCC2)C1

Procedure:
Procedures for 3-(3-Dimethylaminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine were followed, replacing dimethylamine with pyrrolidine, LC-MS (ES, Pos.): m/z 454 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10][CH2:11][CH2:12][CH2:13]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][S:10][CH3:9])=[CH:4][CH:3]=1
Reactant: CSCCCO
Reactant: Oc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-bromophenol (3.4 g) and 3-methylthio-1-propanol (2.6 g) in tetrahydrofuran (20 mL) were added tributylphosphine (7.5 mL) and 1,1′-(azodicarbonyl)dipiperidine (7.6 g), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (4.6 g, 83%) as a white crystal.
Reaction SMILES: [C:1]1(=[O:12])[N:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[CH:3]=[CH:2]1.C(O[C:17](=[O:19])[CH3:18])(=O)C>>[C:4]1(=[O:11])[N:5]([CH2:6][CH2:7][C:8]([O:10][C:8](=[O:9])[CH2:7][CH2:6][N:5]2[C:17](=[O:19])[CH:18]=[CH:3][C:4]2=[O:11])=[O:9])[C:1](=[O:12])[CH:2]=[CH:3]1
Reactant: O=C(O)CCN1C(=O)C=CC1=O
Reactant: CC(=O)OC(C)=O
Product: O=C(CCN1C(=O)C=CC1=O)OC(=O)CCN1C(=O)C=CC1=O
Temperature: 130 °C

Procedure:
3-Maleimidopropionic acid (226 mg) was covered with 5 mL of acetic anhydride and the mixture was heated at 130° C. for 3.75 hour, and then aged over night at room temperature. The solution was concentrated to an oil and the NMR spectrum (CDCl3) indicated a mixture of the homoanhydride and the mixed anhydride of acetic and maleimidopropionic acids. The starting acid shows the methylen adjacent to the carbonyl as a triplet centered at 2.68 ppm whereas in the anhydride these resonances appear at 2.81 ppm. Purification was effected by fractional sublimation, first at 70° C. and 0.2 mm and then at 120° C. and 0.2 mm. The latter fraction was removed from the sublimer by dissolving in CDCl3, affording 34 mg of pure homanhydride on evaporation of the solvent. This was recrystallized from CDCl3 and cyclohexane affording material melting at 143°-147° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]([NH2:15])=[NH:14]>C(O)C>[NH:14]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1)[C:13]([NH2:15])=[NH:12]
Reactant: N=C(N)N
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCO
Product: N=C(N)Nc1ncnc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 10 g of 4,6-dichloro-5-nitropyrimidine in ethanol is reacted at reflux for three days with a slight excess of guanidine to give 4-guanidino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1c(O[C@@H]2CCCC[C@@H]2CO)ccc2c(C(F)(F)F)noc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(O[C@H]2CCCC[C@H]2COS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 4 h

Procedure:
To a solution of 6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (388 mg, 1.09 mmol), from this Example step 3, in CH2Cl2 (11 mL) was added Et3N (0.230 ml, 1.635 mmol) at 0° C., followed by methanesulfonyl chloride (0.093 mL, 1.2 mmol). The reaction mixture was stirred from 0° C. to room temperature for four hours. The mixture was diluted with CH2Cl2, washed with 5% HCl, followed by H2O then NaHCO3. Organic extracts were dried over NaSO4 and filtered. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:38](Cl)([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Reactant: CC[Si](Cl)(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of 6.72 g (18 mmol) 2-(1-benzyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 16) in DMF was treated with 4.03 mL (27.0 mmol) of DBU and at 0° C. then dropwise with 4.12 mL (27 mmol) TESCl. The mixture was stirred for 2 hrs at RT and the solvent was evaporated. Column chromatography on silicagel with n-heptane/EtOAc 6:1 yielded 7.7 g (88%) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, light yellow oil, MS: 489 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11]CC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[N:3]=1.C(O)C>[Pd].O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[OH:11])=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1nc(N)nc2c1ncn2O
Reaction time: 0.75 h

Procedure:
A mixture of 2-amino-9-benzyloxy-6-methoxypurine (300 mg, 1.11 mmol), 10% palladium-on-charcoal (100 mg), ethanol (10 ml) and dioxan (5 ml) was stirred under an atmosphere of hydrogen for 45 minutes. The catalyst was then removed and the filtrate evaporated to a white solid 2-amino-9-hydroxy-6-methoxypurine (190 mg, 95%). IR: νmax (KBr) 3312, 1643, 1591, 1394 cm-1 ; 1H NMR: δH [(CD3)2SO] 3.95 (3H, s, CH3), 6.45 (2H, br.s, D2O exchangeable, NH2), 7.93 (1H, s, H-8), 11.75 (1H, br.s, OH). Found: m/e 181.0594. C6H7N5O2 requires: m/e 181.0596.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([OH:41])=O.[NH2:42][CH2:43][C:44]1[C:45]([F:61])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:55]#[N:56])[C:47]([Cl:50])=[CH:48][CH:49]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([C:55]#[N:56])[CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:45]=1[F:61])=[O:41]
Reactant: O=C(O)c1[nH]c2ccc(OCCO)cc2c1Br
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(OCCO)cc4c3Br)c2F)c1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-bromo-5-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.048 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol). The solution was stirred overnight and partitioned between water and EtOAc. The organic was washed with a 15% aqueous solution of Na2CO3, dried over MgSO4 and filtered. Evaporation of the EtOAc and trituration in acetone afforded the title compound (0.049 g, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 8.49 (t, 1H), 7.77-7.89 (m, 1H), 7.51-7.57 (m, 2H), 7.43-7.51 (m, 2H), 7.37 (d, 1H), 6.96 (ddd, 1H), 6.89 (s, 1H), 4.86 (t, 1H), 4.62 (d, 2H), 4.02 (t, 1H), 3.69-3.82 (m, 1H). LCMS: m/z=592.2 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:16]([NH2:18])[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[NH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([C:26]([NH:18][CH:16]([C:6]2[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH3:17])=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: COc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: COc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (95 mg, a white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (144 mg, 0.50 mmol, Amine-22, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (70 mg, 0.50 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)#[CH:2].Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:24]=2)[N:19]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:2]#[C:1][C:3]2[CH:16]=[CH:15][CH:14]=[C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH:4]=2)[CH:27]=[CH:26]3)=[CH:33][CH:32]=1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Reactant: C#Cc1cccc(OCCN2CCCC2)c1
Product: Clc1ccc(-c2ccc3nc(C#Cc4cccc(OCCN5CCCC5)c4)ccc3c2)cc1

Procedure:
Prepared analogously to Example 18d from 1-[2-(3-ethynyl-phenoxy)-ethyl]-pyrrolidine and 2-bromo-6-(4-chloro-phenyl)-quinoline.