Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.Br[C:28]1[CH:29]=[C:30]2NC(=O)N(C(OC(C)(C)C)=O)[C:31]2=[N:32][CH:33]=1.[C:45]1(C(O)C)[CH:50]=CC=[CH:47][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]1([CH:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:47]4[CH:46]=[CH:45][CH:50]=[C:31]5[C:30]=4[CH:29]=[CH:28][CH:33]=[N:32]5)[CH:3]=3)[NH:8][C:9]2=[O:19])[CH3:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)cnc21
Reactant: CC(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(Br)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate. To a solution of tert-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (See Example 166.C) (0.60 g, 1.97 mmol), 1-phenylethanol (0.289 g, 2.37 mmol) and triphenylphosphine (0.62 g, 2.37 mmol) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (0.46 mL, 2.37 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (0.30 g, 36% yield). MS (ESI) m/z 418.2 [M+1]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
The crude 3-(4-imidazol- 1 -ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (f) above was dissolved in pyridine (2 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (40.52 mg, 0.2618 mmol) and butyl chloroformate (363.5 mg, 0.339 mL) were added to the mixture. The mixture was stirred overnight under a N2 atmosphere at room temperature. Evaporation and co-evaporation with acetonitrile to remove the solvents and purification on column chromatography with 10% MeOH in chloroform as eluent gave the title compound (57.8 mg, 0.1217 mmol) in a 46.5% yield (over the last two steps).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCNCC4)c3)oc12
Yield: 21.3 %

Procedure:
2-(3-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (110 mg, 0.35 mmol) and platinum (IV) oxide monohydrate in methanol was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid. 24 mg 2-(3-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 21%. 1HNMR (400 MHz, DMSO-d6): δ 1.96 (m, 5H), 3.03 (m, 4H), 7.51 (m, 2H), 7.62 (t, 1H), 7.81 (d, J=6.4 Hz, 1H), 7.83 (brs, 1H), 7.94 (brs, 1H), 7.97 (d, J=6.4 Hz, 1H), 8.14 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 8.85 (brs, 1H), 9.02 (brs, 1H). LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl[C:11]1C=C(C)C(=O)N(C)N=1>>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[N:7]=1
Reactant: Cc1cc(Cl)nn(C)c1=O
Reactant: Cc1cc(=O)[nH]nc1Cl
Product: Cc1cc(=O)n(C)nc1Cl

Procedure:
The title intermediate was prepared from 6-chloro-5-methyl-2H-pyridazin-3-one following a procedure analogous to that described for intermediate 6-chloro-2,4-dimethyl-2H-pyridazin-3-one in Example 17*. Mass spectrum (ESI+): m/z=159/161 (CI) [M+H]+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (4.09 g, 10.0 m mole) was added to methylene dichloride (40 ml) and triethyl amine (2.02 g, 20.0 m mole), was added thereto while stirring and cooling with ice. After that, ethanesulfonyl chloride (1.29 g, 10.0 m mole)-methylene dichloride (10 ml) solution was added dropwise over 1 hour thereto. The reaction solution was allowed to stand overnight at room temperature and then washed with two 20 ml portions of hydrochloric acid, 10% aqueous sodium chloride (20 ml), two 20 ml portions of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride (20 ml) in order. A methylene dichloride layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a syrupy N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline benzylester (3.85 g).
Reaction SMILES: [F:1]C(F)(N(CC)CC)C(F)C(F)(F)F.[CH3:15][N:16]([CH3:32])[C:17]([C@@H:19]1[CH2:23][C@H:22](O)[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18].[F-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:15][N:16]([CH3:32])[C:17]([C@@H:19]1[CH2:23][C@@H:22]([F:1])[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
8.85 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 2 minutes under ice cooling to a suspension of 8.54 g of the compound obtained in step 1-1b and 1.67 g of sodium fluoride in 90 mL of dichloromethane, after which the reaction mixture was stirred for 15 hours at room temperature. 200 mL of a saturated sodium hydrogencarbonate aqueous solution was added dropwise to the reaction solution over a period of 3 minutes, and the reaction mixture was stirred for 1 hour. After liquid separation, the aqueous layer was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 7.54 g of the titled compound (pale yellow solid).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:5]=[CH:4][CH:3]=1.[OH-:13].[Na+].C[OH:16]>C(OCC)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]([OH:16])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: CC(C)(C#N)c1cccc(Br)n1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)c1cccc(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (Example 367, Step 1) (50 mg, 0.22 mmol) in methanol (2 mL) was added 1 N aqueous sodium hydroxide (2 mL) and the mixture was heated to 80° C. overnight. The reaction was then cooled to ambient temperature, diluted with ethyl acetate (15 mL) and water (15 mL), and the layers were separated. The aqueous layer was acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[C:36]1[N:37]=[C:38]([CH2:64][CH3:65])[C:39]([NH:44][C@H:45]2[C@@H:49]([O:50][CH2:51][CH2:52][F:53])[CH2:48][N:47](C(OCC3C=CC=CC=3)=O)[CH2:46]2)=[N:40][C:41]=1[CH2:42][CH3:43]>>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[C:36]1[N:37]=[C:38]([CH2:64][CH3:65])[C:39]([NH:44][C@H:45]2[C@@H:49]([O:50][CH2:51][CH2:52][F:53])[CH2:48][NH:47][CH2:46]2)=[N:40][C:41]=1[CH2:42][CH3:43]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.35–7.26, 5.38, 4.68–4.53, 4.11, 3.88, 3.80, 3.74, 3.46, 3.24–3.16, 2.93, 2.70, 2.62, 2.29, 2.00, 1.33–1.24, 1.15; IR (liq.) 2971 (s), 2936 (s), 2874, 2359 (w), 2342 (w), 1566 (s), 1552 (s), 1500 (s), 1470 (s), 1396 (s), 1200 (s), 1129 (s), 1102 (s), 1046 (s), 868, cm−1; HRMS (FAB) calcd for C20H25Cl2FN4O+H 427.1468, found 427.1474.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: CNCCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CNCCCC(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
4-(Methylamino)butanoic acid hydrochloride (22.1 g, 144 mmol) was dissolved in methanol (560 mL), thionyl chloride (42 mL) was added under ice cooling, and then the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resulting white solid was washed with a mixed solvent of dichloromethane (30 mL) and hexane (300 mL) to give the title compound (21.2 g; yield, 88%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(OCCCCl)cc1

Procedure:
1-(4-hydroxyphenyl)ethanone, 1-bromo-3-chloropropane and potassium carbonate were processed as described in Example 67B to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:14]([NH:16][CH2:17][C@H:18]3CC[C@H](C(O)=O)C[CH2:19]3)=[O:15])[C:11]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:38][P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH2:71]([O:73][C:74](=[O:87])[C:75]([O:78][C:79]1C=CC(N)=[C:81]([F:86])[CH:80]=1)([CH3:77])[CH3:76])[CH3:72]>CN(C)C=O.C(OCC)(=O)C>[CH2:71]([O:73][C:74](=[O:87])[C:75]([O:78][C:79]1[CH:19]=[CH:18][C:17]([NH:16][C:14](=[O:15])[CH:13]([N:12]2[C:11]3[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:81]([F:86])[CH:80]=1)([CH3:77])[CH3:76])[CH3:72]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Yield: 39 %

Procedure:
To the solution of 0.2 g (0.49 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c)) in 3 ml N,N-dimethylformamide, 0.21 g (0.55 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.42 ml (0.32 g, 2.5 mmol) N-ethyldiisopropylamine and 0.13 g (0.54 mmol) 2-(4-amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester were added. After 18 h the reaction mixture was poured on water and ethyl acetate, the phases were separated, the organic layer was washed twice with water followed by brine and dried over magnesium sulfate. After filtration the residue was purified by column chromatography on silica gel to give 0.12 g (40%) of the desired compound as light yellow foam.
Reaction SMILES: [H-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][C@H:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:19][O:18]1)[CH3:16].O.[CH3:29][N:30](C)C=O>C(OCC)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]([OH:18])([C@@H:15]([O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH3:16])[CH2:19][N:5]1[CH:6]=[N:30][CH:29]=[N:4]1
Reactant: C[C@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
In dimethylformamide (5 ml) was dispersed 60% sodium hydride in oil (0.23 g), to which was added triazole (0.59 g) under ice-cooling, followed by stirring for 15 minutes. To the resultant mixture was added a dimethylformamide solution (1 ml) of 2-[(1S)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (0.40 g), which was heated for three hours at 80° C. The reaction mixture was cooled, after which were added cold water (1.0 ml) and ethyl aceate (50 ml), and the mixture was shaken. The aqueous layer was subjected to extraction with ethyl acetate twice. Ethyl acetate layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel chromatography (eluent, dichloromethane:ethyl acetate:acetone=6:1:1). The resultant waxy product was further subjected to reprecipitation twice from ethyl acetate-hexane to afford (3S)-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.22 g) as a colorless waxy product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[C:29](=O)[C:30](=[O:34])[C:31]=1[O:32]C>CO>[CH3:26][O:27][C:28]1[C:31](=[O:32])[C:30](=[O:34])[C:29]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 81.2 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2-phenylethylamino)methyl]phenylamine (1.74 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (776 mg) were reacted, to afford the title compound (1.88 g) as yellow foamy solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].C(O)(=O)C.[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH2:19][N:29]3[CH2:30][CH2:31][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a 250 ml round bottomed flask 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate B37) (780 mg, 2.60 mmol) was dissolved in 30 ml of DCM then acetic acid (0.446 ml, 7.79 mmol) and benzyl piperazine-1-carboxylate (1.503 ml, 7.79 mmol) were added. After few minutes sodium triacetoxyhydroborate (2.75 g, 12.99 mmol) was added and the mixture was stirred at r.t. The mixture was poured into 100 ml of DCM and 100 NaHCO3 sat. sol. then phases were separated and the organic one was concentrated to dryness to leave a brown oil that was immediately purified by chromatography eluting with Hexane\EtOAc mixtures to leave the title compound (903 mg, 1.790 mmol, 68.9% yield) as a yellow oil.
Reaction SMILES: F[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)[C:7]([F:20])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH2:39])[CH3:38])=[N:35][CH:36]=1>CCCCO.O>[F:20][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[N:9][C:2]([NH:39][C@H:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=2)[CH3:38])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(C#N)cc2F)n[nH]1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2,5-difluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Method 42, 0.30 g, 1.07 mmol), DIEA (0.16 g, 1.29 mmol), and (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.22 g, 1.6 mmol) in n-BuOH (3 ml) was heated to 130° C. for 18 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexanes-EtOAc=3:1) to give the title compound (0.25 g, 58%). 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.56-7.55 (m, 2H), 7.45 (d, J=10.5 Hz, 1H), 5.42 (s, 1H), 5.25-5.22 (m, 1H), 4.63 (br s, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.34 (d, J=6.1 Hz, 6H). MS: Calcd.: 399. Found: [M+H]+ 400.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][NH:23][CH2:24]2)=[CH:19][CH:18]=1.CN1CCOCC1.O>CN1CCCC1=O>[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)[N:5]=[C:4]([NH2:15])[N:3]=3)[CH2:24]2)=[CH:19][CH:18]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: O
Product: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (500.0 mg, 2.196 mmol), 7-bromo-1,2,3,4-tetrahydroisoquinoline (512.3 mg, 2.416 mmol, Alfa Aesar, Cat. No. B25712) and 4-methylmorpholine (289.7 μL, 2.635 mmol) in N-methylpyrrolidinone (10 mL) was heated at 180° C. overnight. The reaction mixture was cooled to r.t., poured into water, extracted with AcOEt, washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 10% MeOH in CH2Cl2 (include 1% NH3) as eluent to afford the desired compound 695 mg (yield 78.5%). LCMS (M+H)+: m/z=403.2.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:23][O:24][C:25]1[CH:44]=[CH:43][C:28]([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][O:21][C:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml of dry pyridine, stirred in an ice bath under nitrogen, was added in a steady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150 ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for 30 minutes, then at room temperature for 2 hours, then refrigerated at 0° C. overnight. The mixture was concentrated to remove the volatile solvents. The residual solution was dissolved in 400 ml of chloroform, washed twice with 200 ml portions of 10% aqueous sodium bicarbonate and twice with 200 ml portions of water, dried and evaporated. The residue was evaporated twice from toluene, taken up in ether, chilled and filtered. The filtrate was taken to dryness, giving a syrup. A 30 g portion of this syrup was dissolved in petroleum ether and chromatographed on a silica gel column eluting with 20% ether in petroleum ether. The product fractions 6-20 (200 ml each) were combined and evaporated, giving 21 g of the desired compound.