Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]([OH:13])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A mixture of 0.70 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.79 g of WSC, 0.39 g of isonicotinic acid and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: OCC1C=C(CCCO)C=CC=1.[Si:13]([O:20][CH2:21][CH2:22][C:23]#[C:24][C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].OCC1C=C(C#CCO)C=CC=1>>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(CO)c1
Agent: OCC#Cc1cccc(CO)c1
Agent: OCCCc1cccc(CO)c1
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(CO)c1

Procedure:
Prepared by the method of Aromatic Intermediate 18, step b using (3-(4-(tert-butyldimethylsilyloxy)but-1-ynyl)phenyl)methanol [Aromatic Intermediate 19, step a] (0.79 g) in place of 3-(3-(hydroxymethyl)phenyl)prop-2-yn-1-ol. Yield 0.72 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[Li].[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]([OH:14])[C:25]2[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=2)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(SC)ncc2C(O)c2nccn2C)cc1Cl

Procedure:
A solution of 4-(3-chloro-4-methoxybenzylamino)-5-formyl-2-methylthiopyrimidine 0.5 g in tetrahydrofuran 20 ml is reacted at −78° C. with lithium salt of 1-methylimidazole 0.394 ml in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-[(hydroxy)(1-methyl-2-imidazolyl)methyl]-2-methylthiopyrimidine. Thus obtained compound is oxidized at room temperature with manganese dioxide in chloroform and then the oxidized compound is post-treated in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-(1-methyl-2-imidazolylcarbonyl-2-methylthiopyrimidine 0.5913 g. mp 158–159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][C:30]1([C:36](=[O:37])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CCCCC1
Yield: 53.5 %

Procedure:
Preparation of example 119 from the title compound of Example 7 (hydrochloride) (45 mg, 0.142 mmol), 1-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (42 mg, 0.171 mmol), triethylamine (0.059 mL, 0.426 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (65 mg, 0.171 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (38 mg, 0.076 mmol) as a yellow powder in 53% yield.
Reaction SMILES: NC1C=CC(O[C:7]2[CH:20]=[CH:19][C:10]3N[C:12](NC(=O)OC)=[N:13][C:9]=3[CH:8]=2)=CC=1.C[OH:24]>[Pd]>[C:9]1([N:13]=[C:12]=[O:24])[CH:10]=[CH:19][CH:20]=[CH:7][CH:8]=1
Reactant: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2[nH]1
Reactant: CO
Agent: [Pd]
Product: O=C=Nc1ccccc1
Yield: 17 %

Procedure:
N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide (Intermediate 7) was hydrogenated under an H2 atmosphere with Pd—C (10%) in MeOH. After the reaction was complete, the solid was filtered off, and the filtrate was evaporated to give intermediate 8 (47 mg, 17%): 1H NMR (DMSO-d6) δ 11.56 (brs, 1H) 7.51 (d, 1H), 7.32 (d, 1H), 7.05 (dd, 1H), 6.97 (d, 1H), 6.74 (dd, 1H), 6.70 (d, 1H), 5.02 (br s, 2H), 3.74 (s, 3H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 284 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH:37](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([C:21]4[O:22][CH:37]=[N:24][N:23]=4)[CH:25]=[C:26]([F:28])[CH:27]=3)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]#[N:36])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Solvent: Cc1ccccc1C
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2nnco2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A solution of 41 mg (0.081 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide and 1.5 mL triethyl orthoformate in 2 mL of xylene was stirred for 3.5 at 125° C., followed by concentration to remove solvents. The residue was purified by silica gel chromatography with hexane/ethyl acetate/ammonia in MeOH to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.23(d, 3H, J=22 Hz), 1.29(d, 3H, J=22 Hz), 2.34 (t, 1H, J=8 Hz), 2.89 (t, 1H, J=8 Hz), 2.98 (m, 1H), 3.02 (t, 1H, J=11 Hz), 3.25 (m, 1H), 3.63 (t, 1H, J =6 Hz), 4.23 (s, 1H), 7.11-7.73 (m, 11H), 8.51(s, 1H); Mass Spectrum: m/e=519 (M+1, 35Cl), 521 (M+1, 37Cl).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][C:9](=O)[N:8]([CH2:13][CH2:14][CH3:15])[CH2:7]1)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH3:15])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCOCC1CN(CCC)C(=O)CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCOCC1CN(CCC)CCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-allyloxymethyl-4-n-propylmorpholin-5-one (65 g.) in dry ether (100 ml.) is added slowly with stirring to a suspension of lithium aluminium hydride (17.5 g.) in dry ether (700 ml.). The rate of addition is adjusted so that the reaction mixture refluxes gently. When the addition is complete the reaction mixture is stirred at ambient temperature (18°-20°C.) for 18 hours and then water (90 ml.) is added very carefully dropwise to decompose the complex and excess of lithium aluminium hydride. The ethereal solution is filtered and the solid residue is washed with ether. The filtrate and ethereal washings are combined, dried (Na2SO4), filtered and the ether evaporated. The product, 2-allyloxymethyl-4-n-propylmorpholine is obtained as an oil b.p. 80°-90°C. at 1 m.m. which forms a hydrogen oxalate, m.p. 125°-127°C.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([F:37])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[C:25]3[CH2:36][CH2:35][NH:34][CH2:33][C:26]3=[N:27][C:28]=2[NH:29][CH:30]([CH3:32])[CH3:31])[CH2:19][CH2:18]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([F:37])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[C:25]3[CH2:36][CH2:35][N:34]([C:2](=[O:1])[CH3:4])[CH2:33][C:26]3=[N:27][C:28]=2[NH:29][CH:30]([CH3:32])[CH3:31])[CH2:19][CH2:18]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(N3CCC([C@H](F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1

Procedure:
A solution of (S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (56.0 mg, 0.105 mmol) in DCM (1.05 mL) at 0° C. was treated with acetic anhydride (19.8 μL, 0.210 mmol) and pyridine (25.5 μL, 0.315 mmol). The reaction mixture was concentrated under reduced pressure, taken up in MeOH, filtered, and purified by HPLC Method B. Fractions containing product were concentrated under reduced pressure. The material was repurified by HPLC Method A to give the title compound, as a TFA salt, as a pale yellow solid (5.4 mg, 8.9%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.31 (m, 6H), 1.45 (d, J=11.7 Hz, 1H), 1.67 (m, 2H), 2.00 (m, 1H), 2.11 (m, 1H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.80 (m, 4H), 3.53 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (t, J=5.9 Hz, 0.7H), 4.11 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+ 462.5.
Reaction SMILES: C[O:2]C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(O)=O)N=2)CC1)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[O:54][CH:55]=[C:56]([C:58]([O:60]C)=[O:59])[N:57]=2)[CH2:48][CH2:47]1)=[O:43]>>[OH2:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[O:54][CH:55]=[C:56]([C:58]([OH:60])=[O:59])[N:57]=2)[CH2:48][CH2:47]1)=[O:43]
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4nc(C(=O)O)cs4)CC3)c2c1
Reactant: COC(=O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4nc(C(=O)O)co4)CC3)c2c1
Product: O

Procedure:
2-{[4-({[(5-Methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}-1,3-oxazole-4-carboxylic acid hydrate 10 was prepared, according to the procedure described for compound 8, starting from compound 9. Yield: 238 mg, 82%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:22]
Reactant: C=C(F)C(=O)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(F)C(=O)Oc1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
27.5 g (0.169 mol) of 3-trifluoromethylphenol were dissolved in 100 ml of anhydrous methylene dichloride, and 17.1 g (0.169 mol) of triethylamine were added in portions to the solution; 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 30 ml of methylene dichloride. The mixture of filtrate and wash solution was distilled, after adding 0.01 g of hydroquinone monomethyl ether. 27 g (68% of theory) of 3-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 78° to 79° C. (under 4 mbar).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[CH3:16]N(C=O)C>CO>[CH3:2][NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: Cl
Solvent: CO
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
HCl was bubbled through a mixture of 4-methylamino-3-nitrobenzoic acid (7.41 g, 37.8 mmol), DMF (60 mL) and MeOH (250 mL) at reflux for 10 h. The mixture was allowed to cool, filtered and concentrated. NaHCO3 (aq, sat) was added to the residue which was extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to give the sub-title compound.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.CN1CCOCC1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([OH:55])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:53](=[O:55])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1ccccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 131.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (209 mg, 0.39 mmol) in dry DMF (1 mL) was added N-methylmorpholine (0.5 mL, 4.45 mmol), picolinic acid (64 mg, 0.52 mmol), 1-hydroxybenzotriazole (57 mg, 0.42 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.44 mmol). The reaction mixture was allowed to stir at room temperature for further 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL) and washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and evaporated. Purification of the crude material by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired amide (237 mg, 94%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCOc1cccnc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (3.50 g, 36.8 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was then cooled to 0-5° C., and 1-chloro-4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 6.89 g (quantitative yield) of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH3:14][NH:15][CH2:16][CH2:17][NH2:18]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:18][CH2:17][CH2:16][NH:15][CH3:14])=[O:12])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CNCCN
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Solvent: C1CCOC1
Product: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of 20 g (99.0 mmol) of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (see U.S. Pat. No. 4,029,816 for an example of how to obtain this material) and 17 g (230.0 mmol) of N-methylethylenediamine was heated at reflux under an inert atmosphere for 30 hours. The rection mixture was cooled to ambient temperature and the solid was dissolved in 100 ml of tetrahydrofuran. The solution was filtered and evaporated. The residue was crystallized from 2-propanol. There was obtained 15.0 g (61.2 mmol, 61%) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide; mp 142.5°-143° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][C:8]=1[OH:17])=[O:6].CO.[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([O:15][CH3:16])[CH:9]=[C:8]2[C:7]=1[C:5](=[O:6])[C:4]([I:21])=[CH:3][O:17]2
Reactant: II
Reactant: COc1cc(O)c(C(=O)C=CN(C)C)c(OC)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)c(I)coc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To an eggplant type flask (500 ml), 3-dimethylamino-4',6'-dimethoxy-2'-hydroxyacrylophenone (5.026 g) prepared in Example 15 and methyl alcohol (200 ml) were added. The mixture was dissolvedby heating at 80° C. for 10 minutes with stirring. After the solution was cooled, iodine (10.152 g) was slowly added. After 15 minutes, the disappearance of the starting material was confirmed by thin layer chromatography. To the reaction mixture, methylene chloride (700 ml) and then 5% aqueous solution of sodium thiosulfate (200 ml) were added to reduce iodine. The organic layer was separated, and washed with distilled water (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1 to 1/2), and recrystallized from ether to give the titled compound (3.43 g; yield=34.5%) as colorless crystals. Melting point: 158°-160° C. 1H-NMR(CDCl3, δ ppm): 3.88 (s, 3H, OMe), 3.93 (s, 3H, OMe), 6.38 (s, 1H, ArH), 6.42 (s, 1H, ArH), 8.06 (s, 1H, H2).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@H:4]2[O:3]1.[CH2:13]([Mg]Br)[CH3:14]>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:11])[CH2:13][CH3:14])[CH2:9][C@H:4]2[O:3]1
Reactant: CC[Mg]Br
Reactant: CC1(C)O[C@H]2O[C@H](C=O)C[C@H]2O1
Solvent: C1CCOC1
Product: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: -20 °C
Reaction time: 20 h

Procedure:
To a solution of (3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 1d, 296 mg, 2 mmol) in THF (20 mL) was added ethyl magnesium bromide (2M in THF, 2 mL, 2 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution and extracted with EtOAc (30 mL) three times. The combined organic layers were concentrated in vacuo to afford the crude product of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e), which was used in next step without further purification. MS obsd. (ESI+) [(M+NH4)+]: 316.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[C:32](F)=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ncccc2F)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
Dissolve (3-{[3-(3-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester (260 mg, 0.56 mmol) in N,N-dimethylformamide (5 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.34 mL, 0.67 mmol) and stir for 15 min. at ambient temperature. Quench the dark mixture with water and follow by the adding solid sodium chloride. Extract with ethyl acetate and wash with water and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane to give 131 mg (53%) of the desired product. MS(ES): (M+1)+ 447.2, 448.2 m/z.
Reaction SMILES: CCCP(=O)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=O)=[C:10]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]([CH:26]([CH3:28])[CH3:27])[C:19]=3[CH:18]2[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:9]=1.CCN(CC)CC>CCOC(C)=O>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]#[N:14])=[C:10]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]([CH:26]([CH3:28])[CH3:27])[C:19]=3[CH:18]2[C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:9]=1
Reactant: CC(C)n1ccc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C(N)=O)C2=O
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1ccc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of propylphosphonic anhydride (T3P/PPA) (50% in EtOAc) (7.13 mmol) was added dropwise to a solution of 4-chloro-2-[6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]benzamide (Step AB2) (3.10 mmol) and Et3N (3.41 mmol) in EtOAc (25 mL) at 45° C. After 23 h, the reaction mixture was cooled to rt and partitioned between EtOAc and H2O. The organice phase was successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 4.97 min (HPLC 1); ESI-MS: tR=1.19 min, [M+H]+ 410/412/414 (LC-MS 1); TLC: Rf=0.16 (1:3 EtOAc/heptanes).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])[CH3:3].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([CH3:4])[CH3:3]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nccs1
Temperature: 85 °C
Yield: 23.3 %

Procedure:
To a solution of (3-bromopropyl)-carbamic acid 1,1-dimethylethyl ester (1.2 g, 5.0 mmol) and 2-aminothiazole (1.0 g, 10 mmol, 2 equiv.) in DMF 20 (mL) was added Cs2CO3 (2.5 g, 7.7 mmol, 1.5 equiv.). The resulting mixture was heated at 85° C. under N2 overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), and brine (200 mL). The organic phase was dried over Na2SO4, then concentrated in vacuo to afford an oil. The crude product was purified by chromatography (SiO2) using hexane/ethyl acetate to afford the title compound as a light yellow solid (300 mg).