Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.ClCCl.[CH2:19]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34](O)[C:33]([S:40][CH3:41])=[CH:32]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1C=CC=CC=1>O.Cl>[CH2:19]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:33]([S:40][CH3:41])=[CH:32]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCc1ccc2cc(O)c(SC)cc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2cc(OS(=O)(=O)C(F)(F)F)c(SC)cc2c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 105.7 %

Procedure:
Trifluoromethanesulfonic anhydride (3 ml, 15 mmol) was added to a dichloromethane (50 ml) solution of the obtained 6-decyl-3-methylthio-2-hydroxynaphthalene (3.63 g, 10 mmol) and pyridine (2.5 ml, 30 mmol) at 0° C. This solution was stirred at room temperature for 25 minutes. Then, the mixture was diluted with water (20 ml), and hydrochloric acid (4 M, 20 ml) was added. The mixture was extracted with dichloromethane (30 ml×3). The organic phases obtained by repeating the extraction three times were collected, washed with saturated saline water (30 ml×3), dried with MgSO4, and condensed to obtain 6-decyl-3-methylthio-2-(trifluoromethanesulfonyloxy)naphthalene (compound (4)-81) (4.89 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3cnccc3C)C2=O)cc1
Yield: 71.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 1-bromo-4-methoxy-benzene (158 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.142 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.108 mg, 0.2542 mmol) and potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 172 mg of the product (72.26% yield).
Reaction SMILES: [O-]CC.[Na+].[Na].CN(C)[CH:8]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:10]=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C.C(O)(=O)C.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[N:22][C:23]([OH:24])=[N:25][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(OC(C=O)=CN(C)C)cc1
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(Oc2cnc(O)nc2)cc1
Reaction time: 2 h
Yield: 20.9 %

Procedure:
A solution of sodium ethoxide, prepared from sodium (0.80 g, 35.0 mmol), 3-dimethylamino-2-(4-methoxy-phenoxy)-propenal (3.87 g, 17.5 mmol) and urea (2.10 g, 35.0 mmol) in ethanol (25 ml) was heated at reflux for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.80 g, 21% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]2[CH2:9][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CO2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To an ice-cold stirred suspension of 4-nitrophenacyl bromide (80 g, 0.33 mol) in methanol (800 mL) was added sodium borohydride (13.64 g, 0.36 mol) in small portions. After stirring for 2 h at 0-5° C., potassium carbonate (45.20 g, 0.33 mol) was added in small portions at the same temperature. The suspension was stirred for 18 h at room temperature, diluted with brine (600 mL) and extracted with diethyl ether (600 mL, 500 mL), the combined organic layers were dried over sodium sulfate, filtered and evaporated. The title compound (54.87 g, 0.33 mmol, 100%) was obtained as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4ccc(Cl)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (100 mg, 0.559 mmol) was reacted with the product from Example 143a (224 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (mg, %). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H), 5.16 (s, 2H), 6.26 (d, J=6.99 Hz, 1H), 6.65 (d, J=8.46 Hz, 2H), 7.09-7.24 (m, 5H), 7.37-7.44 (m, 3H), 7.51 (s, 1H), 7.81 (d, J=8.82 Hz, 1H), 8.40 (d, J=6.99 Hz, 1H), 8.99 (d, J=8.82 Hz, 1H), 9.80 (s, 1H), 11.04 (s, 1H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][C:18]([CH2:22][NH2:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.ClCCl>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:12]=[CH:13][CH:14]=[CH:15]3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2.80 g, 14.4 mmol) in dioxane (20 mL) was added dropwise a solution of quinolin-6-ylmethanamine (2.28 g, 14.4 mmol) in dioxane (4 mL) and DIPEA (2.56 mL, 14.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane (20 mL) was then added to the reaction mixture. The solvent was removed in vacuo and the crude product was purified by flash chromatography over silica gel, using 50% EtOAc-hexane, gave the desired product (3.18 g, 70%) as a pale yellow solid. LCMS (APCI) m/z 316.0 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:56])([CH3:55])[CH2:11][N:12]1[CH:21]=[C:20]([S:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33]C(C)(C)C)=[O:32])[C@@H:27]([CH2:38]O)[CH2:26]2)(=[O:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:40]3[CH:45]=[C:44]([C:46](=[O:51])[NH:47][CH:48]4[CH2:50][CH2:49]4)[CH:43]=[C:42]([F:52])[C:41]=3[CH3:53])[CH:18]=2)[C:13]1=[O:54])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:48]1([NH:47][C:46](=[O:51])[C:44]2[CH:45]=[C:40]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:54])[N:12]([CH2:11][C:10]([CH3:56])([CH3:55])[CH2:9][OH:8])[CH:21]=[C:20]4[S:22]([N:25]3[CH2:30][CH2:29][N:28]4[C:31](=[O:32])[O:33][CH2:38][C@H:27]4[CH2:26]3)(=[O:24])=[O:23])[C:41]([CH3:53])=[C:42]([F:52])[CH:43]=2)[CH2:49][CH2:50]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)[C@@H](CO)C3)c2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN4C(=O)OC[C@H]4C3)c2c1

Procedure:
tert-Butyl (2R)-4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)-2-(hydroxymethyl)piperazine-1-carboxylate (Example 49c, 0.537 g) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (3 mL). The reaction mixture was diluted with toluene (5 mL) and evaporated under reduced pressure.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[N:37]1([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C1COCCN1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Yield: 30.1 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (60 mg, 0.13 mmol) and morpholine (56.63 mg, 0.65 mmol) were allowed to react in the presence of K2CO3 (77 mg, 0.56 mmol) and NaI (Cat. 2.13 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (20 mg, 30%).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH:9]=O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH2:9][NH:2][CH3:1]
Reactant: CN
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
Under N2, a solution of methylamine (2.9 mL, 5.8 mmol, 2.0 M solution in CH3OH) in 20 mL of ethanol was treated with titanium (IV) isopropoxide (1.7 mL, 5.8 mmol) at room temperature. After 5 min., a suspension of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (1.0 g, 2.9 mmol, the title compound of Preparation 1) in 20 mL of ethanol was added and stirred for 16 hr at room temperature. Sodium borohydride (0.165 g, 4.4 mmol) was then added and stirring was continued for an additional 24 hr, at which time the reaction was quenched by the addition of 5 mL of 6 N HCl and 5 mL of water, stirred for 30 min and made basic by the addition of saturated aqueous Na2CO3. The resulting mixture was extracted with EtOAc, and the organic extracts were clarified by filtration throught diatomaceous earth (d.e.), washed with saturated NaCl, dried over Na2CO3and concentrated in vacuo to a clear oil, 0.987 mg.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>[Fe].O1CCCC1.CO.O>[I:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(I)c(-c3ccccc3)oc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c(I)c(-c3ccccc3)oc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
In a round bottom flask were combined 3-iodo-6-nitro-2-phenylbenzofuran (3.65 g, 10.0 mmol), ammonium chloride (0.802 g, 15.00 mmol) and iron powder (2.79 g, 50.0 mmol). To this was added a mixture of tetrahydrofuran/methanol/water (1:1:2 v-v, 100 mL). The mixture was heated to reflux for a total of four hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) filtered and concentrated to give the title compound 3.35 gm (100%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C1(C)C=CC=CC=1.[CH3:13][O:14][C:15]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:16]=1[C:17]([C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N+:22]([O-])=[CH:21][C:20]=1[O:30][CH3:31])=[O:18]>CN(C)C=O>[CH3:13][O:14][C:15]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:16]=1[C:17]([C:19]1[C:20]([O:30][CH3:31])=[CH:21][N:22]=[C:23]([Cl:3])[C:24]=1[C:25]([F:28])([F:27])[F:26])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
1.8 ml (19 mmol) of phosphorus oxychloride was added at 0° C. to 4 ml of toluene and 8 ml of dimethylformamide, followed by stirring for 10 minutes, and then 4.0 g (10 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide was added, followed by stirring for 20 minutes. After stirring at room temperature for 2 hours, the reaction solution was charged into ice water to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.57 g (yield: 85%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine (melting point 117 to 119° C.).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14](OC)=[O:15])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[BH4-].[Na+].[Li+].[Cl-]>CCO>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][OH:15])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Cc2ccccc2)ccn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cc(Cc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
To a solution of methyl 4-benzyl-picolinate (5.80 g, 26.0 mmol) in EtOH (100 mL)/THF (66 mL) was added a mixture of NaBH4 (1.90 g, 51.0 mmol) and LiCl (2.16 g, 51.0 mmol). The resulting mixture was stirred at 25° C. for 4 h then concentrated under reduced pressure, diluted with brine (200 mL) and extracted with EtOAc (2×200 mL). The collected organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a pale yellow oil (4.4 g, 80%). 1H NMR (CDCl3) δ3.8 (bs, 1H), 3.97 (s, 2H), 4.70 (s, 2H), 7.03 (d, J=4.5 Hz, 1H), 7.06 (s, 1H), 7.17 (d, J=6.9 Hz, 2H), 7.20-7.40 (m, 3H), 8.43 (d, J=4.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:17][C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1>CN(C=O)C.O>[Cl:17][C:18]1[S:19][C:20]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCc1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Br)cc2)s1
Temperature: 90 °C
Reaction time: 6 h
Yield: 69.4 %

Procedure:
In DMF (75 ml) was dissolved 4-bromophenol (7.5 g). To the mixture were added at room temperature potassium carbonate (7.2 g) and sodium iodide (6.5 g) and then was added dropwise 2-chloro-5-chloromethyl thiophene (6.5 g), and the mixture was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 4-bromophenyl (5-chloro-2-thienyl)methyl ether (8.2 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:9]2[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Nc1nnc(C2CCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclobutyl-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:30][C:31](=[O:33])O.[NH:51]([CH2:54][CH3:55])[CH2:52][CH3:53].Cl.CCN(C(C)C)C(C)C>C(Cl)Cl.CCCCCC.CCOC(C)=O>[NH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:30][C:31]([N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])=[O:33]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 89 %

Procedure:
BOP (2.20 g, 5.0 mmol) was added under N2 to a cooled (0°) solution of Boc-Asp-OBzl (1.90 g, 4.6 mmol) in CH2Cl2 (50 ml). After 3 min NHEt2.HCl (0.55 g, 5.0 mmol) and DIPEA (2.4 ml, 1.38 mmol) were added. The resultant solution was stirred at 20-22° for 18 h. The solution was washed with 10% aqueous citric acid (2×), 10% aqueous NaHCO3 (2×) and brine (2×). The organic layer was dried (MgSO4) and concentrated to give an oil. After SiO2 chromatography of the oil using hexane-EtOAc (7:3) as the eluent, Boc-Asp(NEt2)-OBzl (1.55 g, 89%) was obtained as an oil. Under a N2 atmosphere, a solution of the latter compound (1.55 g, 4.09 mmol) in MeOH (100 ml) was mixed with 5% Pd/C (155 mg). The mixture was shaken on a Parr apparatus under H2 (50 psi) for 90 min. The mixture was filtered through a 45 m membrane and the filtrate concentrated to give Boc-Asp(NEt2)—OH (1.15 g, 98%) as an oil. The structure of the product was confirmed by NMR.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:31]=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:37](=[O:38])[CH2:36][C:32]6[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccnc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine tri-HCl (137 mg, 0.300 mmol), 3-pyridinylacetic acid-HCl (78.1 mg, 0.450 mmol), and EDC (115 mg, 0.600 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.261 mL, 1.50 mmol). The mixture became a clear solution after being stirred for a few minutes and was stirred overnight. The products, which precipitated from the solution during the reaction, were collected by filtration, washed with dichloromethane (2×1 mL), and dried in vacuo to afford the title compound as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ=2.73 (s, 2H), 2.89 (s, 2H), 3.78 (dt, J=4.0, 18.8 Hz, 2H), 3.86 (d, J=20 Hz, 2H), 4.19 (s, 1H), 4.33 (s, 1H), 6.45 (d, J=5.2 Hz, 1H), 6.84 (d, J=16.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.87 (dt, J=2.0, 8.0 Hz, 1H), 7.95 (s, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.34 (d, J=3.6 Hz, 1H), 8.44-8.48 (m, 1H), 8.92 (s, 1H), 9.24 (s, 1H), 9.62 (d, J=7.6 Hz, 1H). MS (ES+): m/z 467.94 [MH+]. HPLC: tR=1.98 min (ZQ2000, polar—5 min).
Reaction SMILES: C([BH3-])#N.[Na+].C(OC([N:12]1[CH2:17][CH2:16][C:15](=O)[CH:14]([CH2:19][CH3:20])[CH2:13]1)=O)(C)(C)C.Cl.[CH3:22][NH:23][CH3:24].[OH-].[K+]>CO>[CH3:22][N:23]([CH3:24])[CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]1[CH2:19][CH3:20]
Reactant: CNC
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CCC1CNCCC1N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (3.2 g, 50.8 mmol) was added to the stirred suspension of N-tert.-butoxycarbonyl-3-ethyl-4-piperidone (8 g, 35 mmol), N,N-dimethylamine hydrochloride (14 g, 172 mmol) and KOH (9.6 g, 172 mmol) in methanol (50 ml) at 0° C. The resulting mixture was stirred for 4 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to give 4-dimethylamino-3-ethylpiperidine. Yield 2.3 g (37%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>CN(C=O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14]
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (4 mL) was added sodium hydride (0.032 g, 0.81 mmol, 60% in mineral oil). After stirring for 10 minutes, 1-(bromomethyl)-3-methoxybenzene (0.038 mL, 0.27 mmol, Aldrich) was added and the reaction was stirred for 45 minutes and was quenched by the addition of water and diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.04 g, 50%).