Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:12]2[N:13]=[C:14]([O:16][CH2:17][C:18]([F:20])([F:21])[F:19])[N:15]=[C:10]([NH:9][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]3)[N:11]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)CC1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)NCCCCN)cc3)nc(OCC(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) in DMF (5 mL) was added tert-butyl 4-aminobutylcarbamate (64.0 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (109 mg) and iPr2NEt (0.119 mL). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2 mL of TFA. The mixture was stirred at r.t. for 3 hours. All solvents were removed under vacuum and the residue was purified by prep. HPLC to give ethyl 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylate (80 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][OH:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:21]=1.[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(Br)C=CC1C=CC=CC=1>[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[N:21]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
Sodium hydride (0.41 g, 10.24 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (10 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (2.9 g, 9.752 mmol) from Part G of Example 7 in N,N-dimethylformamide (15 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of cinnamyl bromide (2.11 g, 10.73 mmol) in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60% in mineral oil) and then cinnamyl bromide (0.1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 9% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid, which contained about 6% starting material by HPLC analysis. The white solid was passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. The isolated product was triturated with diethyl ether, filtered off, and dried to provide 2.9 g of product with no starting material. This was carried on to the next step.
Reaction SMILES: [NH3:1].O=[C:3]([CH3:11])[CH2:4][C:5]([O:7][CH2:8][CH2:9][OH:10])=[O:6]>C(O)C>[NH2:1]/[C:3](/[CH3:11])=[CH:4]\[C:5]([O:7][CH2:8][CH2:9][OH:10])=[O:6]
Reactant: CC(=O)CC(=O)OCCO
Reactant: N
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Anhydrous ammonia gas was bubbled through a solution of 2-hydroxyethyl 3-oxo-butyrate (25 g, 0.17 moles) (ref 5) and ethanol (250 mL) for 20 minutes. This solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the resulting oil was chromatographed on silica gel (250 g) using ethyl acetate-hexane 60:40 as eluant. The enriched fractions were combined and the solvent removed in vacuo to give the product; H' NMR CDCl3 4.33 (t, 2H) 3.85 (t, 2H) 3.55 (s, 1H) 2.85 (broad singlet, 1H) 2.31 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1.[H-].[Na+]>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[N:16]=[C:15]([C:20]([F:22])([F:23])[F:21])[N:14]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Temperature: 0 °C
Reaction time: 60 h
Yield: 68.7 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (3.64 g, 23.0 mmol, Acros Organics) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (5.00 g, 23.0 mmol SynChem, Inc.) were dissolved in tetrahydrofuran (41 mL) in a vial and cooled to 0° C. A 60% mixture of sodium hydride in oil (1.10 g, 27.5 mmol, Aldrich) was added. The reaction was stirred for 30 minutes at 0° C. and at 25° C. for 60 hours at which time TLC analysis showed that most of the starting material had been consumed. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was purified by silica gel chromatography using 10-20% ethyl acetate (EtOAc)/hexanes to give the product 4-113 chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine as a white solid (5.35 g). 1H NMR (400 MHz, CDCl3) δ: 6.90 (s, 1H), 5.35 (m, 1H), 3.95 (s, 4H), 1.60-2.05 (m, 8H).
Reaction SMILES: C(O[C:4](=[O:8])/[CH:5]=[CH:6]\[O-])C.[Na+].Cl.[CH:11]1([C:14](=[NH:16])[NH2:15])[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[N:16]=[C:4]([OH:8])[CH:5]=[CH:6][N:15]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)/C=C\[O-]
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccnc(C2CC2)n1
Reaction time: 72 h

Procedure:
Sodium (1Z)-3-ethoxy-3-oxoprop-1-en-1-olate (6.60 g, 47.8 mmol) was dissolved in water (1.5 mL) and in a second flask cyclopropanecarboximidamide hydrochloride (3 g, 24.88 mmol) was dissolved in water (2 mL) and the contents of the second flask were added to the first flask. The reaction was allowed to stir for 72 hours. The reaction was then transferred to a separatory funnel and extracted with chloroform and a small amount of methanol. The water layer was extracted again and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to a pale yellow solid. Diethyl ether was then added to precipitate product. The mixture was filtered and the solid was collected and dried to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]2.C1COCC1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]3)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.65 g, 19.8 mmol) and 6-bromomethyl-2-chloroquinoline (5.40 g, 21.0 mmol) in 80 mL of a 3:1 mixture of THF:DMF at 0° C. is added sodium hydride (0.81 g, 20.2 mmol, 60% mineral oil dispersion). The resulting mixture is stirred for 1 hour at 0° C. then at room temperature for 18 hours. The reaction mixture is quenched with saturated NH4Cl solution, then diluted with EtOAc. The organic layer is washed sequentially with 1N HCl, water, saturated NaHCO3 and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is triturated in Et2O/hexanes/EtOAc and filtered to afford the title compound (6.96 g, 17.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.00 (d, 1H), 7.69 (s, 1H), 7,63 (dd, 1H), 7.41 (d, 1H), 7.35 (s, 5H), 5.15 (s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.70 (m, 2H), 3.32 (bs, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11].[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]4[CH:34]=[C:33]([OH:35])[NH:32][N:31]=4)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:14]1[C:18]2([CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:34]=[C:33]([O:35][CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[O:9][C:10]([F:13])([F:12])[F:11])[NH:32][N:31]=4)=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[O:17][CH2:16][CH2:15]1
Reactant: Oc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)Oc1ccccc1COc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1
Temperature: 50 °C

Procedure:
1-(bromomethyl)-2-(trifluoromethoxy)benzene (0.4 g, 1.57 mmol) was added dropwise to a stirred solution of Example 93D (0.43 g, 1.42 mmol) and potassium carbonate (0.16 g, 1.13 mmol) in refluxing dry acetone (7 mL). The resulting solution was heated (50° C.) for another 1 hour before the solvent was evaporated and the residue was partitioned using brine and ethyl acetate. The organic phase was dried (magnesium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography using 0 to 100% ethyl acetate in hexanes to provide the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8]Cl.[NH4+:19].[OH-].CCO.C(O)(=O)/C=C\C(O)=O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][NH2:19]
Reactant: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(O)/C=C\C(=O)O
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCC[C@@H](Oc1cccc(F)c1)c1ccccc1

Procedure:
A solution of (R)-3-(3-fluorophenoxy)-3-phenylpropyl chloride (0.971 g, 3.96 mmol), conc. NH4OH (30 mL), and EtOH (20 mL) were shaken at 90° C. on a Parr' apparatus (50-90 psig) for 18 h. The mixture was then evaporated under vacuum and the residue was dissolved in Et2O (100 mL) and washed with H2O (2×25 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated under vacuum to provide a yellow oil. This material was then dissolved in EtOAc (50 mL) and filtered. A solution of maleic acid (0.272 g, 2.6 mmol, 0.93 equiv) dissolved in hot EtOAc (5 mL) was added to precipitate the maleate salt (519 mg, 53.5%) as a white solid: TLC Rf 0.25 (1% MeOH-CHCl3); GC, tr 7.37 min; MS, m/z 245 (M+). The synthesis of Compound 187 was accomplished as follows.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[NH2:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:23]([O:27][C:28]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Yield: 96.5 %

Procedure:
A solution of 391 mg of 4-chloro-2-(4-chlorostyryl)-6-methoxyquinazoline, 379 mg of cis-2-(tert-butoxycarbonyl)aminocyclohexylamine, and 358 mg of triethylamine in 20 mL of toluene was combined with a catalytic amount of 4-dimethylaminopyridine, and heated under reflux for 20 hours. After distilling the reaction solution off, the residue was combined with water, extracted with chloroform, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain 580 mg of the desirable compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[NH2:40][C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])=[CH:9][C:10]=3[F:32])[CH:21]=2)=[CH:29][CH:28]=1)[C:47]([OH:49])=[O:48]
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: N[C@@H](CCCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)O
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a suspension of 321 (0.26 g, 0.58 mmol) and N-Boc-lysine (1.1 g, 4.6 mmol) in dichloromethane (75 mL) and was added acetic acid (0.066 mL, 1.2 mmol). The reaction mixture was stirred for 1 h, then sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added and the resulting mixture stirred for 18 h. The mixture was then partitioned between water and dichloromethane, and the solid precipitate removed by suction filtration through celite. The product was mostly in the solid filter cake, so this was solubilized by washing with 1:1 dichloromethane/methanol. This solution was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield BOC-protected product. This was dissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield title compound 324 (44 mg, 69% yield). 1H NMR (DMSO-d6) δ (ppm) 1H: 9.02 (s, 1H); 8.66 (s, 1H); 8.53 (d, J=5.3, 1H); 8.35 (s, 1H); 8.28 (d, j=8.4, 1H); 7.98 (d, J=6.3, 1H); 7.72 (dd, J=13.5, 2.3, 1H); 7.37 (t, J=9.0, 1H); 7.21 (d, J=10.0, 1H); 6.89 (s, 1H); 6.68 (d, J=5.3, 1H); 4.00 (s, 2H); 2.75-2.70 (m, 2H); 2.55-2.52 (m, 1H); 2.45 (m, 1H); 1.70-1.30 (m, 6H); 0.67-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: 579.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (1.0 g, 4.21 mmol) in THF (20 mL) was dropwise added LHMDS solution (5.1 mL, 5.1 mmol, in 1 M THF) at −78° C. After stirring at −78° C. for 30 min, a solution of 2,4,6-trifluoronitrobenzene (0.747 g, 4.21 mmol) in THF (5 mL) was added dropwise into the reaction mixture, which was slowly warmed to room temperature and stirred for 16 h. After completion (as indicated by TLC), the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was triturated with hexane to yield 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (1.1 g). 1H-NMR (400 MHz, CDCl3): δ 6.42-6.47 (2H, m), 7.08 (1H, t, J=8.0 Hz), 7.52-7.58 (2H, m), 8.60 (1H, s).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[O:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:57])=[C:52]([CH:54]=[CH:55][CH:56]=2)[NH2:53])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[O:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:57])=[C:52]([NH:53][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:54]=[CH:55][CH:56]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)o1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluoroaniline (150 mg, 0.433 mmol) and 2,6-difluorobenzenesulfonyl chloride (184 mg, 0.865 mmol), the title compound was obtained as a white solid (135 mg, 59%). MS (ES): 522 [M+H]+.
Reaction SMILES: NC(N)=O.C=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12]([OH:15])(=[O:14])[CH3:13]>>[NH:7]([CH2:13][C:12]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(=O)O
Reactant: NCC(=O)O
Agent: C=O
Agent: NC(N)=O
Product: O=C(O)CNCC(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A 2 L autoclave was charged with urea (V)(60 g, 1.0 mole), Co(OAc)2 ·4H2 (66 g, 0.26 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately one hour, rapid gas uptake was observed. The reaction mass was cooled to 85° C. and the feed gas was changed to a CO:H2 (90:10) composition. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 16 mL/min. The reaction was stirred at 85° C. for 90 min. after the formalin addition was complete. Then the reaction was cooled to 250° C., removed from the autoclave, and concentrated to an oil under reduced pressure. The oil was treated with 2 L of 10% HCl at 100° C. for two hours. This resulted in a 13% yield of (XIV) and 5% glycine.
Reaction SMILES: C[O-].[Na+].[C:4]1([N:10]=[N:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]([NH2:32])=[NH:31])=[N:22]1>>[F:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]2[N:32]=[C:13]([NH2:14])[C:12](/[N:11]=[N:10]/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[C:15]([NH2:16])[N:31]=2)=[N:22]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: N#CC(C#N)N=Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1/N=N/c1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
3.87 g of sodium methanolate and then 12.2 g (71.7 mmol) of phenylazomalononitrile (L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533) are added to a stirred solution of 21.92 g (71.7 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine in N,N-dimethylformamide from Example 6A. The mixture is stirred at 110° C. overnight and allowed to cool. The solid which precipitates is filtered off with suction and washed with ethanol. Drying results in 23 g (73% of theory) of the target compound.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
mixture of 2.0 g of ethyl mercaptoacetate, 3.13 g of 1-bromo-3-chloropropane, 2.29 g of anhyrous potassium carbonate and 10 ml of dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide and water in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure The residue was applied to silica gel column chromatography and eluted with a mixture of hexane-ethyl acetate (15:1) to obtain 2.65 g of oily ethyl [(3-chloropropyl)thio]acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].C(O)C.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Into a three-necked flask of one liter, 25g (0.145 mol) of o-bromophenol, 8.7 g (0.217 mol) of sodium hydroxide and 300 ml of ethanol were charged and refluxed for two hours. Then, 49.4 g (0,289 mol) of benzyl bromide was added dropwise and the mixture was refluxed further for four hours. After the mixture was cooled to room temperature, 600 ml of diethyl ether was added. The mixture was charged into a separatory funnel. Separated organic layer was washed successively with, 100 ml of 2N-hydrochloric acid cooled with ice, 300 ml of saturated sodium thiosulfate, and water until the washings were neutral. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrate was distilled under reduced pressure to obtain 35.6 g (0.135 mol) of o-benzyloxyphenylbromide.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:10])[CH3:9].[Cl:11][C:12](Cl)=[CH:13][N+:14]([O-:16])=[O:15].Cl.[Cl-].[Na+]>CO>[Cl:11][C:12]([S:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:13][N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])C=C(Cl)Cl
Reactant: CC(=O)NCCCS
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCCCSC(Cl)=C[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A solution of 0.12 g of sodium hydroxide in 5 ml of methanol was added over 10 minutes to a solution of 0.40 g of 1 in 5 ml of methanol. Then a solution of 0.95 g of 1,1-dichloro-2-nitroethene (13A) in 5 ml of methanol was added over 20 minutes, at 0° C. The mixture then was stirred for 20 minutes and poured into 2% hydrochloric acid saturated with sodium chloride. The resulting mixture was extracted with methylene chloride, the solvent was evaporated and the residue was purified over silica gel to give 13, as an oil.