Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([O:17][Si](C(C)(C)C)(C)C)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)/C=C/[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of 1.0 g (2.2 mmol) of the resultant compound of Example 18 in 8 ml of tetrahydrofuran was treated with 2.2 ml (2.2 mmol) of a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. After being stirred under N2 atmosphere at ambient temperature for 2 h, the solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Chromatography of the residue on silica gel using 4:1 hexane:ethyl acetate provided 0.36 g (47%) of the desired compound.
Reaction SMILES: [C:1]1(C=CC=C(O)C=1)O.COC1C=CC(C(Cl)=O)=CC=1.[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:29].CI>>[OH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:1])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:29]
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(C(=O)c2ccc(O)cc2O)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: CI
Product: COc1ccc(C(=O)c2ccc(OC)cc2O)cc1

Procedure:
Synthesized from resorcinol and 4-methoxybenzoyl chloride according to an analogous synthetic method to Preparation Example 66, (2,4-dihydroxyphenyl)(4-methoxyphenyl)methanone (9.7 g) and methyl iodide (13.1 g) were used according to an analogous synthetic method to Example 383 to provide the title compound (7.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. The reaction mixture was then partitioned between water and ethyl acetate, and the two layers were separated. The aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give 7.15 g (90%) 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:3]=1[C:4]#[N:5]>CO.O1CCOCC1.[Fe]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1c(N)cccc1Br
Temperature: 25 °C
Yield: 87.6 %

Procedure:
2-Bromo-6-nitrobenzonitrile (5 g) was dissolved in a solution of methanol (100 mL) and dioxane (65 mL) and heated to reflux. Iron powder (4.6 g) was added portion wise over 20 minutes and the mixture was heated at reflux for 4 hours. The mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated under vacuum. The residue was triturated with water and the solid was collected by filtration to give the title compound as a light brown solid (3.8 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCCNC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, a solution of N-methyl-3-buten-1-amine (6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and triethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine (207 mg) were added. A solution of benzoyl chloride (11.89 g, 84.6 mmol) in dichloromethane (60 mL) was added dropwise via addition funnel over 1 h at 0-5° C. The resulting turbid mixture was stirred 3 h at 0° C. The mixture was then washed in succession with 1 M HCl solution (3×75 mL), 5% NaHCO3 solution (3×100 mL), and water (100 mL). The organic phase was dried (Na2SO4), filtered, and concentrated on a rotary evaporator to a yellow oil (12.66 g). Vacuum distillation using a 6 in. Vigreaux column and a short path distillation apparatus afforded 8.58 g (56.3%) of a colorless oil, bp 100-103° C. at 0.1 mm Hg.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9]
Reactant: CCOCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a solution of 2-[2-(ethyloxy)ethyl]oxy-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (4.5 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.29 g) was added in one portion and the reaction heated at 90° C. for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a white solid (240 mg).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:35][CH:36]=1
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCN)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methylisothiourea hydriodide (0.39 g, 1.0 mmol) was added to a solution of 13 (0.49 g, 1.07 mmol) in THF (8 mL) containing diisopropylethylamine (0.18 mL, 2 mmol). The reaction mixture was stirred at reflux for 2.5 h and at room temperature overnight. After this time, the solvent was removed under reduced pressure. The brown residue was washed with ether (2×30 mL) and methylene chloride (2×10 mL). The residue was dissolved in a minimal volume of methanol (approx. 2 mL) and poured into water. The precipitate was collected, washed with water and dried overnight to give crude 11 (0.5 g) as a yellow solid. The compound II (0.4 g, 54%) was purified by flash chromatography on silica gel (eluent: chloroform/methanol/ammonium hydroxide=10:1:0.1) as a yellow solid. [α]D25=−20.4° (c=1.0, MeOH).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C1COCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (75 mg, 0.182 mmol) is dissolved in THF (1 mL) and added to a flask containing NaH (7.5 mg, 0.188 mmol). Stir 1 h at room temperature. Add dimethyl carbamoyl chloride (22 mg, 2.096 mmol) and stir for 16 h at room temperature. Incomplete conversion observed. Reaction is heated to 60° C. and stirred 16 h. Add additional NaH (7.5 mg, 0.188 mmol) is added and reaction quickly reaches 95% conversion. Concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (24 mg, 27%).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][N:5](C)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][CH:22]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7].ClC1C=C(C=CC=1)C(OO)=[O:42]>ClCCl>[CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][NH+:5]([O-:42])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][CH:22]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CCN(C)C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Solvent: ClCCl
Product: CN(C)CC[NH+]([O-])C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 88.3 %

Procedure:
Dissolve racemic 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide (0.097 g, 0.183 mmol) in dichloromethane (5 mL) under argon atmosphere. Add 3-chloroperoxybenzoic acid (0.045 g, 0.200 mmol) and stir at room temperature for 1 hour. Concentrate under reduced pressure and purify via flash chromatography by eluding with gradient (100%) dichloromethane to 25% methanol/75% dichloromethane to obtain 0.086 g (87%) of a white solid: MS (m/z): 546 (M+).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)C.O.[NH2:15][NH2:16]>C(O)(=O)C>[C:1]1(=[N:15][NH2:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NN=C1CCc2ccccc21
Temperature: 20 °C

Procedure:
A mixture of indan-1-one (10.0 g), ethanol (35 ml), hydrazine hydrate (10.0 ml) and glacial acetic acid (2.0 ml) was boiled under reflux under nitrogen for 1 hour. The mixture was cooled to 20° C. and the mixture concentrated under reduced pressure to give a solid which was collected by filtration to give indan-1-one hydrazone, m.p. 84-86° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:68]C(OC(C)(C)C)=O)[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:68][C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CCCCNC(=O)OCc3ccccc3)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
Trifluoroacetic acid (0.075 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk46) (18.6 mg, 0.019 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 40 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-(((benzyloxy)carbonyl)amino)hexanoate (Lys(Z)-pdCpA) (Compound tk47) (13.4 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1

Procedure:
1-(3-(Benzyloxy)-5-bromopyridin-2-yl)thiourea (2.00 g, 5.91 mmol), methyl 5-bromo-4-oxopentanoate (1.48 g, 7.10 mmol) (prepared according to Synthetic Communications (1994) 2557-2562), and triethylamine (1.44 mL, 10.3 mmol) were heated in methanol (50 mL) at reflux for 3 hours according to the method of Example 2, Step C, to provide methyl 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoate as a light yellow powder. 1H NMR (DMSO-d6) δ 10.26 (bs, 1H), 7.97 (s, 1H), 7.35-7.63 (m, 6H), 6.66 (bs, 1H), 5.29 (s, 2H), 3.59 (s, 3H), 2.85 (t, 2H), 2.69 (t, 2H). Mass spectrum (esi) m/z=448 (96), 450 (100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:15][C@H:14]2[C@H:12]([CH2:13]2)[N:11]1C(OC(C)(C)C)=O)=[O:9].ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2C[C@H](F)C[C@H]2C(NC2C=NC=CN=2)=O)N=1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:15][C@H:14]2[C@H:12]([CH2:13]2)[NH:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cnccn2)C[C@@H]2C[C@@H]21
Agent: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1cnccn1)[C@@H]1C[C@@H]2C[C@@H]2N1

Procedure:
Compound 121C was prepared starting from 121B using the procedure as described in 65C. LC/MS [M+H]+: 205; Ret time (Method C): 0.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH3:11])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Brc1ccc(C2CO2)cc1
Product: CNCC(O)c1ccc(Br)cc1

Procedure:
A solution of 2-(4-bromophenyl)-oxirane (0.5 g, 2.51 mmol) in methylamine (6.6 ml, 33% by volume in ethanol, 25.12 mmol) was stirred at room temperature under an atmosphere of nitrogen. After 18 hours the solvent was removed in vacuo and the residue was purified over flash silica eluting with dichloromethane: methanol: acetic acid:water (120:15:3:2) to afford the desired compound as the acetic acid salt. Further purification over a Phenomenex_Strata_SCX column eluting with methanol followed by 2N ammonia in methanol gave the desired product. LC/MS: (PS-B3) Rt 2.52 [M+H]+ 230.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum, followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (0.90 g, 100%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[OH:44][C@@H:45]1[C@@H:50]([NH3+:51])[CH2:49][CH2:48][O:47][CH2:46]1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[C:13]([NH:51][C@H:50]1[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]1[OH:44])=[O:15]
Reactant: [NH3+][C@H]1CCOC[C@@H]1O
Reactant: Nc1c(C(=O)O)cc(Br)c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C(=O)N[C@H]2CCOC[C@@H]2O)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-amino-4-bromo-2-naphthoic acid (0.644 g, 2.42 mmol) in 10 mL of acetonitrile cooled to 0° C. was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]-phosphonium hexafluorophosphate (1.82 g, 4.12 mmol), O-(7-azabenzotriazol-1yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (0.921 g, 2.42 mmol), (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-aminium chloride (0.310 g, 2.02 mmol), and triethylamine (0.84 mL, 6.1 mmol). The reaction was warmed to rt and stirred for 4 h. The mixture was diluted with ethyl acetate, washed with dilute aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 1-amino-4-bromo-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-2-naphthamide that gave a mass ion (ES+) of 366.9 (81Br) for [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([N+:30]([O-:32])=[O:31])=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1OC
Reaction time: 8 h
Yield: 88.8 %

Procedure:
5.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound B2) are dissolved in 40 ml of methylene chloride and 5.0 ml of triethylamine. A solution of 6.5 g of 3,4-dinitrobenzoyl chloride in 40 ml of methylene chloride is added dropwise at RT and the mixture is extracted with water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. 8.1 g of the title compound are obtained as a solidified oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH3:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:11])[S:25]([CH2:24][CH2:23][N:14]2[C:13](=[O:12])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:22])(=[O:26])=[O:27])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(C)C)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: CC(C)N1CCC(N(C)S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-methyl-amide was prepared by an analogous procedure as described for example 1 i) starting from 171.3 mg (1.1 mmol) (1-isopropyl-piperidin-4-yl)-methyl-amine and 300 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-methyl-amide was obtained as a light yellow foam. Yield: 385 mg MS (ES+): m/e=394.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([OH:15])[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)([O-])=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]1([OH:15])[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])CC1(O)CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCC1(O)CCC2(CC1)OCCO2
Reaction time: 120 h
Yield: 530.2 %

Procedure:
A mixture of 8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (16.0 g, 13.8 mmol) and 20% palladium hydroxide on carbon (3.2 g) in ethanol (160 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 5 d on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent and the filtrate was concentrated to give 8-(aminomethyl)-1,4-dioxaspiro[4.5]decan-8-ol as a clear oil (13.7 g, 99%) that solidified upon standing overnight.