Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O.CC#N.CC#N.Cl[Pd]Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 10 %

Procedure:
Charge a sealed tube under a positive pressure of argon with bis(acetonitrile)palladium (II) chloride (18 mg, 0.07 mmol), 2-dicyclohexylphosphino diphenyl (73 mg, 0.21 mmol), cesium carbonate (0.557 g, 1.71 mmol) and 3-chloro-5-trifluoromethylpyridine, (prepared essentially as described in PREPARATION 7), (0.12 g, 0.66 mmol) in acetonitrile and stir at room temperature for 25 min (Angew. Chem. Int. Ed. 42, 5993-5996, (2003)). Add phenylacetylene (0.1 mL, 0.86 mmol) and stir at 100° C. for 16 h. Cool to room temperature, dilute with water, and wash twice with ethyl acetate. Combine the ethyl acetate layers, dry (sodium sulfate), and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 50:50 hexanes:dichloromethane, to obtain the title compound (30 mg, 10%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:26]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N(CC#N)[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@@H](N(CC#N)S(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1R,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (113 mg, 58%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 7.16 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 6.81 (s, 1H), 5.10 (d, 1H, J=6.6 Hz), 4.30-4.05 (m, 3H), 3.99-3.84 (m, 1H), 3.56 (t, 2H, J=5.8 Hz), 3.52-3.47 (m, 1H), 3.38 (s, 3H), 3.02-2.85 (m, 4H), 2.93 (s, 3H), 2.81-2.66 (m, 6H), 2.48-2.38 (m, 1H), 2.21-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.60-1.45 (m, 2H), 1.30-1.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36]([C:35]3[CH:34]=[N:33][C:32]([N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)=[O:37])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)nc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-morpholinonicotinic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 571.1 [M]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][NH2:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21]I>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][NH:13][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CN)CO2
Reactant: FC(F)(F)CCI
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CNCCC(F)(F)F)CO2
Temperature: 120 °C

Procedure:
A mixture of 1-[(2S)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methaneamine (0.3 g, 1.1 mmol), 1,1,1-trifluoro-3-iodopropane (0.16 ml, 1.4 mmol) K2CO3 (0.32 g, 2.3 mmol) and ACN (4 ml) was heated under microwave radiation at 120° C. for 30 min. The mixture was filtrated and evaporated to dryness and the product was purified by flash column chromatography (EtOAc). Yield: 0.12 g, 31%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 233° C. MS m/z (rel. intensity, 70 eV) 357 (M+, 1), 274 (3), 127 (5), 126 (bp), 69 (3). [α]=−53° (MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(Cl)CCl.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]([N:42]6[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]6)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: C1CNCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
A mixture of crude 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid (75 mg, 0.15 mmole), EDC (72 mg, 0.376 mmole), and DMAP (37 mg, 0.3 mmole) in dry DCM (1 mL) was stirred at RT for 0.5 hr. Piperazine (104 mg, 1.2 mmole) was added and, after 64 hr, the reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (11 mg, 13%). 1H NMR (CDCl3) δ 1.67-1.80 (m, 4H), 1.96-2.09 (m, 2H), 2.15-2.18 (m, 1H), 2.58-2.65 (m, 1H), 2.82-2.86 (m, 4H), 3.17-3.20 (m, 2H), 3.43-3.48 (m, 2H), 3.57-3.62 (m, 2H), 3.77 (s, 2H), 5.57 (s, 2H), 6.48 (d, 1H, J=2.5 Hz), 6.83-6.88 (m, 1H), 6.90-6.97 (m, 2H), 7.21-7.29 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 7.55-7.58 (m, 1H), 7.89 (s, 1H), 8.08 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 11.87 (br, 1H). MS: 568.67 (M+H+); HPLC Ret Time: 1.03 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[OH:38][CH2:39]C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[NH2:37][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:39][OH:38])=[CH:7][CH:6]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(CO)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-(hydroxymethyl)benzeneboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).
Reaction SMILES: [Na+].[Cl-].[CH:3]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH2:9]C)=[O:7])=[O:4].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:4][CH2:3][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Product: COC(=O)[C@@H](CO)Cc1ccc2c(c1)OCO2
Temperature: 37 °C
Reaction time: 18 h

Procedure:
Recombinant Escherichia coli HB101 (PNTCRG) (Accession Number: FERM BP-6898) was inoculated in 50 ml of 2×YT medium (containing 1.6% of tripeptone, 1.0% of yeast extract, and 0.5% of NaCl, pH=7.0) sterilized in a 500-ml Sakaguchi Flask and incubated while shaking at 37° C. for 18 hours. To 50 ml of the resultant culture solution, 1.89 g of the methyl 2-formyl-3-(3,4-methylenedioxyphenyl)-propionate obtained in Example 1, 2.5 mg of NADP, and 1.9 g of glucose were added and the reaction mixture was stirred at 30° C. for 24 hours. After completion of the reaction, the reaction solution was extracted with toluene and the extract was concentrated to obtain 1.82 g of a blown oily substance. The chemical purity and optical purity of the product were analyzed in the same manner as in Example 9. The chemical purity was 96.8% and the optical purity was 98.0% ee. The product had an (R) configuration.
Reaction SMILES: C(NC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(N)=O)CCC.[CH2:26]([C:33]1[C:48]([S:49](=[O:52])(=[O:51])[NH2:50])=[CH:47][C:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O)=[CH:35][C:34]=1[O:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[C:48]([S:49](=[O:51])(=[O:52])[NH2:50])=[CH:47][C:36]([CH2:37][NH:39][CH2:40][CH2:41][N:42]([CH2:43][CH3:44])[CH2:45][CH3:46])=[CH:35][C:34]=1[O:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCOc1cc(C(=O)NCCN(CC)CC)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCOc1cc(CNCCN(CC)CC)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide with an equimolar amount of 4-benzyl-3-n-butoxy-5-sulfamyl-N-(2'-diethylaminoethyl)-benzamide and following the procedure described, (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)-2-diethylaminoethylamine is obtained as a dihydrate with a melting point of 89°-93° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=S(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)(Cl)Cl>[N:19]([CH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:14])=[N+:20]=[N-:21]
Reactant: OCc1cc2cccc(Cl)c2nc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of (2,8-dichloroquinolin-3-yl)methanol (228 mg, 1 mmol) in CHCl3 (4 mL) was treated with SOCl2 (0.36 mL, 5 eq) dropwise, and the reaction was stirred at rt for 2 h before removal of solvents and the residue was partitioned between EtOAc and NaHCO3. The organic was separated and dried over Na2SO4. Solvents were removed under reduced pressure and the residue was dried under vacuum. The residue was dissolved in DMSO (2 mL) and treated with NaN3 (72 mg, 1.1 eq) at rt. LCMS showed completion after 4 h. The reaction mixture was partitioned between EtOAc (2 mL) and water (1 mL), and the water layer was extracted with EtOAc (5 mL) once and combined organics were washed with water, brine, dried over Na2SO4 and concentrated to give a pale yellow solid as 3-(azidomethyl)-2,8-dichloroquinoline (215 mg, 85%, 2 steps). This solid (50 mg, 0.2 mmol) in DCM (2 mL) was treated with piperidine (143 μL eq) in EtOH (2 ML) at reflux over night. The reaction was worked up and the residue was purified by column chromatography on silica gel (eluent: EtOAc/hexane, ⅕) to give a yellow solid (30 mg, 50%). 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1 H, s), 7.62 (1 H, t, J=8.0 Hz), 7.53 (1 H, d, J=8.0 Hz), 7.49 (1 H, d, J=8.0 Hz), 4.02 (2 H, s), 3.26-3.23 (m, 4H), 1.74-1.58 (m, 6H). Mass Spectrum (ESI) m/e=302 (M+1).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ccccc2s1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nc3ccccc3s2)cc1
Yield: 68.2 %

Procedure:
A solution of 28.1 g (0.2 mol) of benzyl chloride in 50 ml of ethanol is added slowly, with stirring, to a solution of 33.4 g (0.2 mol) of 2-mercaptobenzothiazole and 8 g (0.2 mol) of NaOH in 150 ml of ethanol and 25 ml of water. The resulting solution is refluxed for 2.5 h. After cooling, it is filtered and evaporated to leave 35.1 g of a yellowish solid melting at 39°-40° C. 1H NMR (CDCl3): δ4.41 (2H), δ6.98-7.8 (9H) ppm.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1)[CH3:2]
Reactant: CCOCCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CCOCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of 2-ethoxyethanamine (4.07 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (4.05 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.90 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10](=O)[NH:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[NH2:20])C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][CH3:10])[C:13]([NH2:20])=[C:14]([CH3:19])[CH:15]=1
Reactant: CCOC(=O)Nc1cc(Br)cc(C)c1N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred suspension of lithium aluminum hydride (400 mg) in THF (25 ml) was added a solution of ethyl(2-amino-5-bromo-3-methylphenyl)carbamate (1 g) in THF (10 ml) at 0° C. The mixture was then warmed to room temperature, followed by heating at reflux for 1 h. The reaction mixture was cooled to 0° C., diluted with THF (45 ml) and a saturated Na2SO4 solution was added dropwise thereto. The mixture was further stirred for 30 min and solids were filtered over Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (550 mg) as a brownish liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([NH:18][C:19]([NH:24][CH2:23][CH2:22][NH2:25])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCN
Reactant: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate (0.42 g) in methylene chloride (50 mL) is added dropwise over 15 minutes to 1,2-ethylenediamine (0.45 mL) in solution in methylene chloride (100 mL). The mixture is stirred for 10 minutes at room temperature, then rotary evaporated. The residue is triturated for 30 minutes with ether (100 mL). The resulting white suspension is filtered and the solid is dried in vacuo overnight.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:8]=[C:9]([C:14]3[N:22]=[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]4[N:15]=3)[C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[N:22]1[C:14]([C:9]2[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:4]3[CH2:3][CH2:2][N:1]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:6][CH:5]=3)[N:8]=2)=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccn2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccn4n3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(1,2,3,6-tetrahydropyridin-4-yl)-3-([1,2,4]triazolo[1,5-a]pyridin-2-yl)pyrazin-2-amine (82 mg, 0.1291 mmol) was dissolved in DCM (4 mL) and treated with triethylamine (78.38 mg, 108.0 μL, 0.7746 mmol) followed by ethanesulfonyl chloride (18.26 mg, 13.46 μL, 0.1420 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour when analysis showed SM remaining. The mixture was treated with further ethanesulfonyl chloride (16.60 mg, 12.23 μL, 0.1291 mmol) and stirred for a further hour. The reaction was diluted with DCM, washed with water and the aqueous layer extracted further with dichloromethane (2×). The combined organics were washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-2.5% MeOH/DCM) to afford the title compound which was freeze-dried to give a yellow solid (9 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.4 Hz, 3H), 2.71 (br s, 2H), 3.14 (q, J=7.3 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.98 (d, J=2.9 Hz, 2H), 6.62 (br s, 1H), 7.30-7.33 (m, 1H), 7.72 (br s, 2H), 7.75-7.79 (m, 1H), 7.98 (d, J=8.8 Hz, 1H), 8.40 (s, 1H) and 9.11 (d, J=6.7 Hz, 1H) ppm; MS (ES+) 386.0
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][NH:6][CH:5]([CH:8]2[NH:13][C:12](=[O:14])[CH:11]([CH:15]3[CH2:20][CH2:19][CH:18]([Cl:21])[CH2:17][NH:16]3)[NH:10][C:9]2=[O:22])[CH2:4][CH2:3]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([N:6]1[CH2:7][CH:2]([Cl:1])[CH2:3][CH2:4][CH:5]1[CH:8]1[NH:13][C:12](=[O:14])[CH:11]([CH:15]2[CH2:20][CH2:19][CH:18]([Cl:21])[CH2:17][N:16]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:10][C:9]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(C2CCC(Cl)CN2)C(=O)NC1C1CCC(Cl)CN1
Solvent: CC(C)=O
Product: O=C1NC(C2CCC(Cl)CN2Cc2ccccc2)C(=O)NC1C1CCC(Cl)CN1Cc1ccccc1
Reaction time: 24 h

Procedure:
One mole of 3,6-bis(5-chloro-2piperidinyl)-2,5-piperazinedione is stirred in 150 parts of acetone and 2.2 moles of benzyl bromide is added. The mixture is stirred 24 hours and refluxed 24 hours. The solvent is removed in vacuo and treated as in the preparation of 3,6-bis-(1-methyl-5-chloro-2-piperidinyl)-2,5-piperazinedone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[O:28]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2ncnc(Oc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Example 5, Alternative Preparation, Step 1: A sample of 4-chloro-6-(trifluoromethyl)quinazoline (3.25 g, 13.97 mmol) was dissolved in acetonitrile (60 mL) under N2 atmosphere. The resultant cloudy solution was charged with Cs2CO3 (6.83 g, 20.96 mmol) and phenol (1.578 g, 16.77 mmol) and stirred at room temperature. After ˜65 hours, the reaction was filtered to remove the solids. The organic phase was concentrated in vacuo to yield an orange solid. The material was purified by automated flash chromatography (80 g silica gel) using 1:3 EtOAc/Hexanes as the eluant to afford the desired 4-phenoxy-6-(trifluoromethyl)quinazoline as a crystalline solid. LC/MS found (M+H)+=291.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)CC1
Yield: 98.1 %

Procedure:
Next, 3′,6′-Dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (9.0 g) was hydrogenated using 10% Pd/C dry (900 mg) at 60 psi at room temperature for 1.5 hr to give 8.9 g (99%) of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.58 (m, 2H), 1.81 (m, 2H), 2.85 (m, 3H), 4.06 (m, 2H), 7.20 (dd, 1H), 7.28 (d, J=9 Hz, 1H), 7.70 (m, 1H), 8.48 (m, 1H).
Reaction SMILES: Cl.[Na].[CH2:3]([OH:15])[C@H:4]([OH:14])[C@@H:5](O)[C@H:6]([OH:12])[C:7]([C:9]([O-:11])=[O:10])=[O:8]>>[O:10]=[C:9]1[O:11][C@H:5]([C@H:4]([CH2:3][OH:15])[OH:14])[C:6]([OH:12])=[C:7]1[OH:8]
Reactant: O=C([O-])C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: [Na]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
L-ascorbic acid is prepared from sodium 2-keto-L-gulonate by introducing gaseous hydrogen chloride in a molar ratio of about 1.5-2.0 to the sodium-2-keto-L-gulonate into a mixture composed of the sodium 2-keto-L-gulonate, ethanol and acetone at a ratio of 1:0.25-1.00:0.5-2.5 by weight at a temperature of about 25°-75° C. until precipitation of sodium chloride ends, removing the precipitated sodium chloride before L-ascorbic acid begins to crystalize out, maintaining the filtrate or supernatant at a temperature of about 25°-75° C. for a period of 5-100 hours and cooling it to yield crystals of L-ascorbic acid as a final product. A solvent inert to the L-ascorbic acid and 2-keto-L-gulonate may be added to the filtrate or supernatant with a favorable result in obtaining purer intended product.