Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])([CH:8]=[CH2:9])[CH3:7])=[O:4].[CH2:16]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])([CH:8]=[CH2:9])[CH3:7]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CN(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 60 °C

Procedure:
Linalyl chloroacetate (5.77 g, 25 mmol, 1 eq), in toluene (50 ml), was slowly added to didodecylamine (10 g, 28.3 mmol, 1.13 eq) and sodium carbonate (5.3 g, 0.05 mol, 2 eq), in toluene (50 ml). The reaction mixture was stirred at 60° C. for two weeks after which the reaction seemed completed by 1H NMR. The sodium carbonate was filtered off, the filtrate was concentrated under vacuum and diethyl ether (200 ml) was added before storage of the solution at 4° C. for 12 hours. Then, the solution was filtered and removal of ether under vacuum yielded to the expected N,N-didodecylglycine linalyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19][Cl:20])[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][CH3:32])=[CH:25][CH:24]=1>ClC1C=CC=CC=1>[ClH:20].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19][N:31]([CH3:32])[CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CNCCc1ccc(OC)cc1
Reactant: COc1cc2c(C)nn(CCCCl)c(=O)c2cc1OC
Solvent: Clc1ccccc1
Product: COc1ccc(CCN(C)CCCn2nc(C)c3cc(OC)c(OC)cc3c2=O)cc1
Product: Cl

Procedure:
Produced analogously to Example 2 (b) by reaction of 1-[4-methyl-6,7-dimethoxy-1-(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(4-methoxy-phenylethyl)-N-methyl-amine in chlorobenzene. M. p.: 210 - 212° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:14][C:15]([C:18]([CH2:20][Br:21])=[O:19])([CH3:17])[CH3:16]>C(O)CC>[BrH:21].[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]([CH2:20][C:18](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: OCCNc1nc2ccccc2[nH]1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CCCO
Product: Br
Product: CC(C)(C)C(=O)Cn1c(NCCO)nc2ccccc21
Temperature: 25 °C

Procedure:
Heat at reflux for 3 hours a mixture of 2-(2-hydroxyethylamino)benzimidazole (1.77 g, 10 mmol) and bromopinacoline (1.35 g, 10 mmol) in 50 ml of propanol. Subsequently maintain at room temperature. The next day, the title compound is collected by filtration and washed with acetone and then with ether.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=O)[NH:29][CH2:30][C:31]1[S:32][C:33]2[C:39]([F:40])=[CH:38][C:37]([F:41])=[C:36]([F:42])[C:34]=2[N:35]=1)[CH3:16]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[S:2])[NH:29][CH2:30][C:31]1[S:32][C:33]2[C:39]([F:40])=[CH:38][C:37]([F:41])=[C:36]([F:42])[C:34]=2[N:35]=1)[CH3:16]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 115 °C
Yield: 68.2 %

Procedure:
In a flame dried flask under a nitrogen atmosphere, a suspension of phosphorus pentasulfide (2.9 g, 6.4 mmol) in pyridine (26 mL) was treated with {5-Fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (Example 54, 5.7 g, 13 mmol) and heated to 115° C. for 4 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The organic layer was washed successively with 2 N HCl (2×) and saturated NaCl, dried over MgSO4, and concentrated. The resulting brown oil was chromatographed by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) to give {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid ethyl ester (2.0 g, 34%): 1H NMR (DMSO-d6 300 MHz) δ 10.98 (br s, 1H), 7.79 (br t, J=6.0 Hz, 2H), 7.06 (br d, J=11.1 Hz, 1H), 6.90 (br t, J=9 Hz, 1H), 5.38 (br s, 2H), 4.89 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.1 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([O:7]C)=[O:6].[Li+].[OH-]>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
(I5A): A stirred solution of methyl 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (1 g, 2.74 mmol, Intermediate 4) in THF (15 mL), MeOH (3.75 mL) and water (3.75 mL) was treated with LiOH (0.263 g, 10.97 mmol). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated and the white residue was suspended in water, then neutralized with AcOH to pH˜6-7. The suspension was stirred for 30 min, then the white solid was collected by filtration and dried in air to yield 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoic acid (0.95 g).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][N:10]([CH3:37])[C:11]([C:13]1[N:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)[C:23](O)=[O:24])=[N:17][CH:18]=1)=[O:12].[CH3:38][C:39]1[N:43]=[C:42]([NH2:44])[S:41][N:40]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:37][N:10]([CH3:9])[C:11]([C:13]1[CH:18]=[N:17][C:16]([O:19][C:20]2[CH:21]=[C:22]([C:23](=[O:24])[NH:44][C:42]3[S:41][N:40]=[C:39]([CH3:38])[N:43]=3)[CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Reactant: Cc1nsc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.142 mL, 1.07 mmol) was added to a solution of 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 45) (358 mg, 0.9 mmol) in DCM (7 mL) and stirred at ambient temperature for 30 minutes. 3-Methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (206 mg, 1.8 mmol) and pyridine (0.147 mL, 1.8 mmol) were added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (10 mL) and filtered to give a solid which was washed with water and dried. The filtrate was washed with citric acid (1N, 10 mL), water (10 mL), saturated sodium bicarbonate solution (10 mL), brine (10 mL), dried (MgSO4) and evaporated. The residue was combined with the solid isolated from the filtration and purified by flash chromatography on silica eluting with a gradient of 0-3% methanol in DCM to afford the product (322 mg, 72%). 1H NMR δ (300 MHz, CDCl3) 1.93-2.06 (m, 1H), 2.45 (s, 3H), 2.55-2.66 (m, 1H), 2.80 (s, 3H), 3.03 (s, 6H), 3.19-3.53 (m, 2H), 5.14 (t, 1H), 7.30 (s, 1H), 7.63 (s, 1H), 7.72 (s, 1H), 8.43 (s, 1H), 8.58 (s, 1H), 11.9-12.8 (br s, 1H); m/z 498 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])([O-:7])=[O:6]
Reactant: CC(=N)N
Reactant: O=[N+]([O-])c1ccccc1C=CS(=O)(=O)Cl
Product: CC(=N)NS(=O)(=O)C=Cc1ccccc1[N+](=O)[O-]

Procedure:
Reaction of acetamidine with 2-nitrostyrylsulfonyl chloride according to the above procedure affords N-(2-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 175°-178° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:14][C:15]([N:17]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])[S:9][C:10]=1[S:11][C:12]#N)=[O:5])[CH3:2].CI>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:14][C:15]([N:17]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:16])[S:9][C:10]=1[S:11][CH3:12])=[O:5])[CH3:2].[CH:24]1([N:17]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](=[O:16])[NH:14][C:8]2[S:9][C:10]([S:11][CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Solvent: CI
Product: CCOC(=O)c1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC
Product: CSc1sc(NC(=O)N(C2CCCCC2)C2CCCCC2)nc1C(=O)O

Procedure:
2-(3,3-Dicyclohexyl-ureido)-5-methylsulfanyl-thiazole-4-carboxylic acid ethyl ester was prepared as described in general procedure (H) using 2-(3,3-dicyclohexyl-ureido)-5-thiocyanato-thiazole-4-carboxylic acid ethyl ester and methyl iodide. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([C:16](OC)=[O:17])[C:5]=3[C:4]=2[CH:3]=1.[BH4-].[Na+].CO.Cl>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:14]=[C:15]([CH2:16][OH:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(Cl)ccc1n2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c2ccc(Cl)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Yield: 93.6 %

Procedure:
A solution of 17.2 g (47 mmol) of methyl 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate, of 8.7 g (230 mmol) of sodium borohydride and of 9.4 ml (230 mmol) of methanol in 300 ml of tetrahydrofuran is heated at reflux for 4 h. The mixture is cooled and poured onto a stirred solution of 100 ml of 2N hydrochloric acid and 100 ml of dichloromethane. The precipitate is collected by filtration, washed with water and dichloromethane and dried under reduced pressure. 15 g (44 mmol) of solid are obtained.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].[OH-].[Na+].Br[CH2:54][CH:55]([OH:58])[CH2:56][OH:57]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:54][CH:55]([OH:58])[CH2:56][OH:57])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: OCC(O)CBr
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CC(O)CO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 96 h
Yield: 14 %

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)-phenyl]urea (0.25 g, 0.18 mmol) was dissolved in water (5 ml) followed by 2M aqueous NaOH (2.1 ml) and, after 5 min, bromopropane-2,3-diol (0.196 ml) was added. The solution was stirred for 4 days, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification by preparative HPLC gave 38 mg (14%) of the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C(Cl)Cl.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>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH:28]=3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (70 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (0.03 g, 0.03 mmol) in 10 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.6 mL, 1.2 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature, diluted with 100 mL DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (0.10 g) as a pale yellow solid. Found MS (ES+): 399(M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=4)[N:19]([CH3:28])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2[C:11](=[N:16][CH:15]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:13]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)nn(C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)nn(C)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
N-tert-Butyl-2-(6-ethyl-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.03 g, 0.059 mmol), ethylenediamine (1 mL, 15.0 mmol) and TBAF (1 mL, 3.45 mmol) were combined with DMF (3.0 mL) and the reaction mixture warmed to 60° C. After 3 h, the mixture was concentrated to dryness and partitioned between ethyl acetate and water. The organic phase was concentrated in vacuo then purified by chromatography to give 2-(6-ethyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (5 mg, 22%). MS: (M+H)+=377; 1H NMR (DMSO-d6) δ: 12.79 (br. s., 1H), 8.96-9.28 (m, 1H), 8.19-8.49 (m, 2H), 7.97 (s, 1H), 7.57 (s, 1H), 6.98-7.25 (m, 1H), 4.16 (s, 3H), 2.81 (q, J=7.4 Hz, 2H), 1.41-1.66 (m, 9H), 1.21-1.35 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][NH:8][CH:9]=[O:10]>[Cu]I>[CH3:7][N:8]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH:9]=[O:10]
Reactant: Brc1ccsc1
Reactant: CNC=O
Agent: [Cu]I
Product: CN(C=O)c1ccsc1
Yield: 81 %

Procedure:
Using general procedure C with the exception that CuI (10 mg, 0.05 mmol, 5 mol %) was used, 3-bromothiophene was coupled with N-methylformamide with the reaction time of 24 h. Chromatography gave 114 mg (81%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz): δ 8.36 (s, 0.8H), 7.71 (s, 0.2H), 7.49 (dd, 0.2H, J=1.5, 5.4 Hz), 7.08 (dd, 0.2H, J=1.2, 3.0 Hz), 6.80 (dd, 0.2H, J=3.3, 5.4 Hz), 6.64 (dd, 0.8H, J=3.3, 5.1 Hz), 6.30 (dd, 0.8H, J=1.8, 5.4 Hz), 5.98 (dd, 0.8H, J=1.2, 3.0 Hz), 2.79 (s, 2.4H), 2.21 (s, 0.6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]=C)[CH:3]=1.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=[C:25]([O:32]C)C=C4)N(CC2)C1.C([OH:73])(C)(C)C.O>>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]([OH:73])([CH3:9])[CH2:25][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCc1cccc(Br)c1
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: C[C@](O)(CO)c1cccc(Br)c1
Temperature: 4 °C
Reaction time: 16 h

Procedure:
A mixture of 1-bromo-3-(2-propenyl)benzene from step 1 (2.9 g, 15 mmol) and AD-mix-β (Aldrich, 21.0 g) in t-BuOH-H2O (1:1, 150 mL) was vigorously stirred at 4° C. for 16 h. The reaction was quenched with solid Na2SO3 (5.0 g) and diluted with ethyl acetate (150 mL). The aqueous was separated and extracted with ethyl acetate. The combine organic phase was washed with brine, dried and filtered through a short path of silica gel. Removal of the solvent gave essentially pure title compound.
Reaction SMILES: [C@@H]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)O[C@H](CO)[C@@H](O)C1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N)C[NH2:35]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([NH:11][CH:10]=[N:9]2)=[C:13]([NH2:35])[N:15]=1
Reactant: NCCN
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 2′-deoxyguanosine (2 mmol), dried by coevaporation with pyridine, suspended in 40 mL of pyridine and cooled in an ice bath under an argon atmosphere, trifluoroacetic anhydride (16 mmol) is added following the procedure of Kung and Jones (Tetraheron Lett., 32, 3919, 1991). After 40 minutes, ethylenediamine (30 mmol) is added and stirred for 24 h at room temperature. The reaction mixture is concentrated and purified by silica column chromatography. The product is guanylated with reagent 5 as in Example 8 and protected at N2-position with an isobutyryl group by treating with isobutyric anhydride, 5′-dimethoxytritylated at the 5′-position and purified. The resulting compound is treated with benzoic anhydride (N6 protection) and then phosphitylated following the procedures described above to afford the 2,6-diaminopurine derivative functionalized at the 6-position (35).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.C(O)(=O)C>[OH-].[K+]>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([SH:3])[CH:10]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(S)c1
Yield: 94.8 %

Procedure:
2-Amino-6-methoxy-benzothiazole 10 g (55.6 mmol) was suspended in 25% aqueous potassium hydroxide and the mixture heated under reflux for 24 h. The pale yellow solution was cooled and acidified to pH 6 with firstly aqueous 6N HCl then acetic acid. The precipitated solid was filtered, washed with water (3×100 ml), dried (high vac.) to afford the desired material as a pale yellow powder 8.18 g, 95%.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[OH:5].Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([OH:35])=[O:34].C(N(C(C)C)CC)(C)C.C(O)(=O)[CH2:49][C:50]([CH2:55]C(O)=O)([C:52](O)=O)O>CN(C=O)C>[C:10]([NH:1][C@H:2]([C:7]([C:38]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[C:31]([C:50]([CH3:55])([CH3:52])[CH3:49])[C:30]=1[CH2:29][NH2:28])=[O:9])[CH2:3][C:4](=[O:6])[OH:5])([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11]
Reactant: NCc1cccc(C(=O)O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1c(C(=O)O)ccc(C(=O)[C@H](CC(=O)O)NC(=O)OCC2c3ccccc3-c3ccccc32)c1CN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of FmocAsp (But) OPfp (17.33 g, 30 mmol) and the compound of Step 6 (6.19 g, 33 mmol) in 50 mL DMF cooled in an ice bath was added 11.5 mL (66 mmol) diisopropylethylamine, and after stirring at room temperature for 5 h, 200 mL 5% citric acid was added and the solution was extracted with ethyl acetate twice. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a solid which was washed with ether-petroleum ether and dried. Yield 16.3 g (100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[CH2:36][CH2:37][CH3:38].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:14](=[O:15])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:44][CH2:43]1)=[O:41])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 3 h

Procedure:
To a solution of 500 mg (S)-6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid in 7 ml DMF were added at 0° C. 172 mg piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 0.14 ml N-ethylmorpholine and 357 mg TOTU. After stirring for 3 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 650 mg.