Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[NH:24][CH:25]=[N:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 28 (42 mg, 0.16 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (37 mg, 0.16 mmol) and DIPEA (0.14 mL, 0.8 mmol) in n-butanol (1 mL) was stirred in a sealed vial for 16 h at 90° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 160 as a white solid (13 mg, 21%). LCMS: RT 3.61 min [M+H]+ 388.1. 1H NMR (DMSO, 400 MHz): δ 8.22-8.03 (2H, m), 7.80 (1H, s), 7.71-7.43 (6H, m), 7.09 (1H, t, J=9.42 Hz), 6.85 (1H, d, J=8.93 Hz), 5.38 (1H, s), 2.08-1.88 (2H, m), 0.83 (3H, t, J=7.34 Hz)
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[C:27]([C:26]1[CH:30]=[C:22]([N:21]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18][CH2:19][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:23]=[CH:24][C:25]=1[OH:31])([OH:29])=[O:28]
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2-c2ccccc2CC3)ccc1O

Procedure:
A mixture of 20.0 g. (0.076 mole) of 2-phenacyl-1-tetralone, 11.6 g. (0.076 mole) of 5-aminosalicylic acid, and 70 ml. of glacial acetic acid was heated under reflux for 4 hours, cooled diluted with 10 ml. of water and filtered. The filter cake was washed with water and dried to provide 15.5 g. of solid, m.p. 215°-218°. Recrystallization from benzene-cyclohexane gave 6.5 g. (22%) of yellow crystals, m.p. 245°-247°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:28]([CH:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=O)[CH3:29]>ClCCCl>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:31]1[CH2:32][CH2:33][C:34](=[O:35])[C:30]=1[CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1
Reactant: CCC1C(=O)CCC1=O
Solvent: ClCCCl
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1)NC1=C(CC)C(=O)CC1
Yield: 52.3 %

Procedure:
A solution of (S)-ethyl-3-[4-(3-ethyl-isoquinol-1-yl amino)phenyl]-2-aminopropionate [prepared from 1-chloro,3-ethyl-isoquinoline (from reaction of o-toluic acid with propionitrile and subsequent treatment with phosphorous oxychloride) and N-BOC-L4-aminophenylalanine ethylester] (750 mg, 2.07 mmol) and 2-ethyl-1,3-cyclopentanedione (273 mg, 2.17 mmol) in 1,2-dichloroethane (10 ml) was treated with 4 Å sieves (˜1 g) and heated at 90° for 3 days. The solution was filtered, concentrated in vacuo and the residue purified by chromatorgaphy (SiO2, 100:1 DCM/MeOH) to give the title compound as a brown solid (511 mg, 52%). δH (d6-DMSO) 9.05 (1H, s), 8.46 (1H, d, J 7.0 Hz), 7.91 (2H, d, J 8.6 Hz), 7.72 (1H, d, J 7.0 Hz), 7.64 (1H, t, J 7.0 Hz), 7.51 (1H, t, J 7.0 Hz), 7.23 (2H, d, J 8.6 Hz), 6.99 (1H, s), 4.32 (1H, m), 4.15 (2H, q, J 7.1 Hz), 3.15 (1H, dd, J 13.5, 3.5 Hz), 3.01 (1H, dd, J 13.5, 9.6 Hz), 2.69 (2H, 1, J 7.5 Hz), 2.29 (1H, m), 2.18 (1H, m), 2.06 (4H, m), 1.28 (3H, t, J 7.5 Hz), 0.91 (3H, t, J 7.4 Hz). m/z (ESI, 70V) 472 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:50][C:51]([C:53]1[C:54]2[CH:55]=[CH:56][N:57]=[CH:58][C:59]=2[CH:60]=[CH:61][CH:62]=1)=[NH:52]>CN(C)C=O>[Cl:15][C:9]1[CH:8]=[C:4]([C:5]2[O:7][N:52]=[C:51]([C:53]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:54]=3[CH:55]=[CH:56][N:57]=[CH:58]4)[N:50]=2)[CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1cccc2cnccc12
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: CCCOc1c(Cl)cc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3,5-dichloro-4-(propyloxy)benzoic acid, (Maybridge) (150 mg, 0.603 mmol), HATU (232 mg, 0.610 mmol), Hunig's base (0.263 mL, 1.506 mmol) and N,N-dimethylformamide (DMF) (1 ml) was stirred for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 94 mg, 0.502 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was left to stir for 2 hrs at room temperature and then heated to 120° C. for 2 hr in a microwave. The cooled reaction mixture was concentrated in vacuo and the residue purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound (23 mg)
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:6][CH:5]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-c2csnn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(-c2csnn2)ccc1OCC1CO1

Procedure:
To a solution of 0.112 g. of sodium hydroxide in 10 ml. of water is added 0.499 g. of 4-(4-hydroxyphenyl)1,2,3-thiadiazole and to the resulting solution is added dropwise, under stirring, 0.66 ml. of epibromohydrin, in a 5 minute period. The reaction mixture is stirred for 48 hours and extracted several times with ethyl acetate. The combined organic extracts are washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuo. The semisolid residue is crystallized from methylene chloride-hexane to yield the pure 4-[4(2,3-epoxypropoxy)phenyl] 1,2,3-thiadiazole.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1

Procedure:
A stirred mixture of 3-nitro-1,2-phenylenediamine (1.00 g, 6.53 mmol) and p-toluenesulfonyl chloride (1.25 g, 6.53 mmol) in pyridine (50 ml) was heated at reflux for 1 h, then concentrated to dryness in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=308 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4](OC)=[O:5].[NH3:15]>[OH-].[NH4+]>[NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4]([NH2:15])=[O:5]
Reactant: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: C[C@H](C(N)=O)[C@@H](N)c1ccccc1

Procedure:
A solution of methyl(2S,3R)-3-amino-2-methyl-3-phenylpropionate (6.3 g, 33 mmol) in 2N methanolic ammonia (20 ml) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After 4d, concentration followed by chromatography on a short column of silica gel (dichloromethane-methanol-conc. ammonium hydroxide=93:7:0.7; 90:10:0.8) provided the amide as a white solid. MS (m/z): 179.2 (M+H)+; C10H14N2 O requir. 178.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=C)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].I([O-])(=O)(=O)=[O:15].[Na+]>C(O)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCC1(C(=O)OC)CCCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1(CCC=O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 1-but-3-enyl-cyclopentanecarboxylic acid methyl ester (4.0 g, 21.5 mmol) in isopropanol (35 mL) was added a solution of sodium periodate (10.1 g, 47.3 mmol) in H2O (35 mL) followed by the addition of osmium tetroxide (16 mg, 0.065 mmol). More isopropanol (30 mL) and H2O (35 mL) were added and the resulting suspension was stirred for 24 hours and then poured onto ice/H2O (200 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (10 to 60% EtOAc/heptane) to provide 2.27 g (57 yield over two steps) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(O)C.[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[CH2:26]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: Nc1ccccc1S
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSc1ccccc1N
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Into a 2-liter 3-necked round bottomed flask equipped with condenser, stirrer and heating mantle, were placed 125.0 g (1.0 mol) of 2-aminothiophenol, 350 ml of ethanol and 40 g (1.0 mol) of sodium hydroxide dissolved in 40 ml of water. Stirring was begun and after 15 min, 249.24 g (1.0 mol) of 1-bromododecane was added. Heating was begun and the solution heated at reflux overnight. Upon cooling, solvent was removed at reduced pressure and water (500ml) and dichloromethane (500 ml) were added. The mixture was transferred to a 2-liter separatory funnel and the layers separated. The aqueous layer was discarded, the organic layer washed with 500 ml of aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The crude material was passed through a bed of silica, solvent was removed at reduced pressure, and the material distilled under vacuum to afford 220 g (75%) of 2-(dodecylthio)aniline (b.p. 180° C. at 0.25 mm).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30](O)=[O:31].[OH:34][N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.C(OCC)(=O)C>[OH:34][NH:35][C:30]([CH:3]1[C:2]([CH3:33])([CH3:1])[S:7][CH2:6][CH2:5][N:4]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:31]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
To a solution of 0.28 g (0.56 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane. The product was triturated with ether to provide 0.024 g (8%) of N-hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a white solid. Electrospray Mass Spec: 513.4 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:16]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2COC2)c(=O)[nH]1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2COC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (44% yield). LCMS: 491.50 (M+1)+; HPLC: 98.99% (@ 254 nm) (Rt; 4.678); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.93 (t, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 6.84 (s, 1H), 6.21-6.14 (m, 1H), 5.89 (s, 1H), 5.08-5.02 (m, 4H), 4.38 (d, 2H, J=4.4 Hz), 2.42 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.24 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[C:12]2=[N:13][C:14]([Cl:18])=[C:15]([Br:17])[N:16]=[C:11]2[CH:10]=[CH:9]1)=[O:7])(C)(C)C.[CH2:19]=[O:20].[OH-].[Na+].Cl>O1CCOCC1.O>[Br:17][C:15]1[N:16]=[C:11]2[C:10]([CH2:19][OH:20])=[CH:9][N:8]([CH2:6][OH:7])[C:12]2=[N:13][C:14]=1[Cl:18]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)n1ccc2nc(Br)c(Cl)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn(CO)c2nc(Cl)c(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromo-3-chloro-pyrrolo[2,3-b]pyrazine-5-carboxylic acid tert-butyl ester (6.0 g, 18.0 mmol) in 1,4-dioxane (100 mL) was added methanal (5.4 g, 180.4 mmol) and 1 M NaOH solution (54 mL) and the reaction mixture was stirred at room temperature for 16 h. 1.2 N HCl was added into the reaction mixture until the mixture reached pH 7. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with water (50 mL) and extracted with ethyl acetate (150 mL×3). The organic layers were combined and concentrated in vacuo to give (2-bromo-3-chloro-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (4.4 g, 83%) as yellow solid. LC-MS: 292.2 (M−H). This was used directly without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:17][CH2:18][OH:19].C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OCCBr
Reactant: CCCCCCCNc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCN(CCO)c1cccc(O)c1
Yield: 54 %

Procedure:
0.1 mol of 3-(n-heptylamino)phenol in 100 ml of methanol is refluxed for 10 h with 0.11 mol of 2-bromoethanol and 0.1 mol of NaHCO3. After cooling, the mixture is filtered, the solvent is removed in vacuo, and the residue is fractionated, to give 3-[N- (n-heptyl)-N-(2-hydroxyethyl) -amino]phenol.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Solvent: CN(C)c1ccccc1
Product: CCCC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Yield: 56.7 %

Procedure:
2.12 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol--isomer A; see Example 1--were treated with a mixture of 12.1 g (0.1 M) of N,N-dimethylaniline and 5.3 g (0.05 M) of butyryl chloride as indicated in Example 3--except heating at 100° for 3 hours--to give 1.6 g (57%) of the desired ester, b.p. 120°/0.5 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:30]=[CH:29][C:15]3[N:16]=[C:17]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=4[CH3:28])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:30]=[CH:29][C:15]3[N:16]=[C:17]([C:19]4[C:20]([CH3:28])=[CH:21][C:22]([C:26]5[N:31]=[N:32][NH:33][N:27]=5)=[CH:23][C:24]=4[CH3:25])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(C#N)cc4C)[nH]c3c2)cc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(-c5nn[nH]n5)cc4C)[nH]c3c2)cc1C
Temperature: 120 °C

Procedure:
A mixture of 2-(4-Cyano-2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide (40 mg), NaN3 (65 mg) and NH4Cl (54 mg) in DMF (1 mL) was heated at 120° C. under microwave radiation for 60 min. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (C18, H2O:CH3CN=100:0 to 70:30) to give 2-[2,6-dimethyl-4-(2H-tetrazol-5-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide as a white solid: MS (m/z) 438 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:21])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[C:12](OCC)=[O:13])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:24])=O>>[CH2:1]([O:5][C:6]1[C:7](=[O:21])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[C:12]([Cl:24])=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1ccn(CC(C)C)c(=O)c1OCC(C)C
Product: CC(C)COc1c(C(=O)Cl)ccn(CC(C)C)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of ethyl 3-isobutoxy-1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (Intermediate 8) (100 mg, 0.339 mmol) was added thionyl chloride (24.71 μL, 0.3390 mmol). The reaction mixture was stirred at 80° C. for 3 h. The solvent was evaporated under reduced pressure to give Example 52A which was used without further purification (90 mg, 0.315 mmol, 93% yield). LCMS RT=1.89 min [M+MeO+1]=282 {(MeOH/H2O/TFA) Phenom. Luna C18; 50×4.6 mm; 4 min Grad}.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O.Cl>O1CCCC1>[Br:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH2:16])[CH:20]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(OCC)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of commercially available 1-bromo-4-ethoxy-benzene [588-96-5] (0.1 g, 25 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added dropwise a solution of n-butyllithium (1.6 M solution in hexane, 14.0 mL, 0.9 eq) at −78° C. After stirring 30 min at −78° C. 3-bromoacetophenone (3.7 mL, 1.1 eq) in tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in acetic acid (50 mL) and sulfuric acid (10 mL) and the mixture was warmed to 75° C. for 30 min, cooled to room temperature and 1 N NaOH was added up to pH=7. The aqueous phase was extracted with dichloromethane (3×10 mL), dried (sodium sulfate) the solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (2.3 g, 30%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCCl
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of 2-methoxy-4-nitro-phenol (2.50 g, 14.8 mmol), 1-bromo-2-chloro-ethane (1.35 mL, 16.3 mmol) and potassium carbonate (4.08 g, 29.6 mmol) in DMF (50 mL) in a sealed tube was heated at 90° C. for 18 h. The reaction was cooled and filtered, washing with ethyl acetate. The filtrate was washed with sodium bicarbonate, water (4 times) and brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes provided 1-(2-chloro-ethoxy)-2-methoxy-4-nitro-benzene (1.93 g, 56% yield) as an off-white solid. 1H-NMR (DMSO-d6, 500 MHz) 7.89 (dd, 1H), 7.76 (d, 1H), 7.21 (d, 1H), 4.41 (t, 2H), 4.00 (t, 2H), 3.90 (s, 3H) ppm; HPLC (Method A) 3.781 min.
Reaction SMILES: C(OC([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)(C)(C)C.CC1C=CC(S(O[C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][CH2:41][CH2:40]4)[C:34]=3[N:33]=[C:32]([NH2:44])[N:31]=2)(=O)=O)=CC=1>>[NH2:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][N:12]([C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][CH2:41][CH2:40]4)[C:34]=3[N:33]=[C:32]([NH2:44])[N:31]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Product: COC(=O)C1(N)CCN(c2nc(N)nc3c2CCCC32CCCC2)CC1

Procedure:
The title product was prepared using the procedures outlined in Examples 1G and 1H, substituting methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (CAS# 115655-44-2) for the product from Example 1D. 1H NMR (300 MHz, CDCl3) δ 4.50 (s, 2 H), 3.74 (s, 3 H), 3.30-3.36 (m, 4 H), 2.45 (t, J=4.58 Hz, 2 H), 2.04-2.21 (m, 4 H), 1.79-1.92 (m, J=4.07 Hz, 2 H), 1.49-1.73 (m, 10 H). MS (DCI+) m/z 360 (M+H).