Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1C2N=C(N3CC[O:63][C@@H:62]4CCC[C@@H]34)N(C[C@H]3CC[C@H](C)CC3)C=2C(C2C=NC=C(Cl)C=2)=NC=1C(=NO)N.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35]3[NH:36][C:62](=[O:63])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3:1 mixture of 4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide and 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33 mg, 0.06 mmol) in acetonitrile (2 mL) was added 1,1′-carbonyldiimidazole (19.7 mg, 0.122 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL, 0.244 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC(C-18) eluting with acetonitrile/water+0.1% TFA to afford pure 3-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31ClFNγO3 [M+H]+=568. found=568. 1H NMR (600 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.43 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.78-3.87 (m, 2H), 3.63 (dd, J=14.4, 3.6 Hz, 1H), 3.56 (d, J=12.6 Hz, 1H), 3.39 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.27 (m, 1H), 1.86 (m, 1H), 1.69 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.80 (m, 1H), 0.63-0.74 (m, 6H), 0.47 (m, 1H), 0.29-0.42 (m, 2H).
Reaction SMILES: C([SH:3])C.C(N([CH2:9][CH3:10])CC)C.[Cl:11][C:12](Cl)=[C:13]([Cl:18])[C:14]([O:16][CH3:17])=O>CO.C(S)C>[CH3:17][O:16][C:14](=[S:3])[C:13]([Cl:18])=[C:12]([Cl:11])[CH2:9][CH3:10]
Reactant: COC(=O)C(Cl)=C(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CCS
Solvent: CO
Product: CCC(Cl)=C(Cl)C(=S)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.3 %

Procedure:
A solution of 270 gms of ethanethiol and 580 ml (419 gms) of triethylamine in 1 liter of methanol was slowly added to 795 gms methyl trichloroacrylate. The addition was exothermic and cooling was required. After addition, the reaction mixture was stirred at room temperature for 18 hours. At this time, an additional 20 gms of ethanethiol was added and the system stirred for an additional 2 hours. The solvent and excess ethanethiol were removed under reduced pressure. The resulting oil was dissolved in methylene chloride. The organic solution was washed with water, dried over magnesium sulfate and filtered. The methylene chloride was removed by stripping to give 860 gms of a brown liquid. The crude product was purified by vacuum distillation to give 600 gms of the methyl-2,3-dichloro-3-ethylthioacrylate (collected at 135°-145° C. at 20 mm Hg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH3:3].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1)=[O:15].CCOCC>N1C=CC=CC=1C([O-])=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:8][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:20]=2)=[O:23])[CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CN(C)Cc1cccc(N)c1
Agent: O=C([O-])c1ccccn1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(=O)Nc2cccc(CN(C)C)c2)cc1
Yield: 73 %

Procedure:
Equimolar amounts of 3 -(N,N-dimethylaminomethyl)aniline (XVI; R=H) (Stedman, E. J. Chem. Soc. 1927, 1902) and 4-(methoxycarbonyl) benzenecarbonyl chloride (XvII; Z=H) were reacted together in pyridineat 0 ° C., to give methyl 4-[3 -(N,N-dimethylaminomethyl)phenyl]carbamoylbenzene-carboxylate (IX; R=Z=H) (73%), mp (dilsopropyl ether) 108°-109 ° C. 1H NMR (CD3SOCD3) 10.42 (s, 1 H, CONH), 8.13 (s, 4 H, H-2',H-3'), 7.75 (s, 1H, H-2), 7.70 (d, J=8.2 Hz, 1 H, H-6), 7.30 (t, J=8.2 Hz, 1 H, H-3), 7.04 (d, J=8.2 Hz, 1 H, H-4), 3.97 (s, 3H, COOCH3), 3.40 (s, 2 H, CH2), 2.18 (s , 6 H, N (CH3)2).Anal.(C18H 20 N2O3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:13]>CCCCCCC.CCOCC.N1C=CC=CC=1>[Br:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:10]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: c1ccncc1
Product: CC(Br)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 170.4 %

Procedure:
To a solution of 1-(3,4-dichlorophenyl)ethanol (0.87 g, 4.55 mmol)in n-heptane (5.00 mL) and Et2O (0.500 mL) at 0° C. was added pyridine (1 drop) and phosphorous tribromide (0.214 mL, 2.277 mmol). The reaction mixture was warmed to RT and stirred for 2 h. The reaction was diluted with ether, washed with water (1×), saturated NaHCO3 (1×), and brine (1×). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-(1-bromoethyl)-1,2-dichlorobenzene (0.985 g, 3.88 mmol, 85% yield). m/z (ESI) 249.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH:18][C:19](=[O:21])[CH3:20])=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[CH2:11][Br:12])=[O:5])[CH3:2].[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Br-:12].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH:18][C:19](=[O:21])[CH3:20])=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[CH2:11][P+:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:5])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1sc(NC(C)=O)c(C(=O)OCC)c1CBr
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(NC(C)=O)c(C(=O)OCC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
22.2 G of crude 2,4-diethoxycarbonyl-3-bromomethyl-5-acetylaminothiophene, 19.7 g. (75 mmol) of triphenylphosphine and 700 ml. of toluene were refluxed for 3 hrs. The resulting precipitate was filtered from the hot solution and washed well with toluene to yield (2,4-diethoxycarbonyl-5-acetylamino-3-thenyl)triphenyl phosphonium bromide, m.p. 186°-195° C. The NMR-spectrum showed that the material contained 11% of succinimide.
Reaction SMILES: [CH2:1]([O:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:18]1[C:25]([Cl:26])=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:19]1[N:18]=[C:25]([Cl:26])[N:24]=[C:22]([N:11]2[C:10]([CH3:16])([CH3:17])[CH2:9][CH:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][C:12]2([CH3:15])[CH3:14])[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCOC1CC(C)(C)NC(C)(C)C1
Solvent: Cc1ccccc1
Product: CCCCCCOC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1

Procedure:
62.7 g of 4-hexyloxy-2,2,6,6-tetramethylpiperidine are added with stirring to a solution of 23.9 g of cyanuric chloride in 100 ml of toluene. The mixture is subsequently heated to 80° for 24 hours. A white precipitate of the piperidine hydrochloride is formed during this. After cooling, the precipitate is filtered off, and the toluene solution is washed a number of times using 2N hydrochloric acid, dried over Na2SO4 and evaporated. The residue is recrystallized from acetonitrile. The product obtained melts at 49°-51°.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[NH2:9][C:10]1[C:19]2[C:14](=[C:15](F)[C:16]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:17][CH:18]=2)[N:13]=[CH:12][N:11]=1>CN(C=O)C>[NH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:16]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:17][CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: CN(C)CCO
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(N)ncnc3c2OCCN(C)C)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
In a microwave vial with a stir bar, N,N-dimethylethanolamine (101 mg, 1.13 mmol) is dissolved in DMF (5 mL). To this solution is added sodium hydride (60% suspension in mineral oil, 45 mg, 1.136 mmol) and the mixture stirred at room temperature for 5 minutes and 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (192 mg, 0.568 mmol) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 minutes. The reaction is cooled, quenched by adding 25 mL sat. NH4Cl (aq) and extracted with CH2Cl2 (3×5 mL). The combined organics are dried with Na2SO4, concentrated and purified by silica gel chromatography by two gradient runs on the same column, the first 0% to 100% ethyl acetate in hexanes and the second 0% to 50% methanol in ethyl acetate. This gives 1-[4-Amino-8-(2-dimethylamino-ethoxy)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a yellow powder (171 mg, 74% yield) (LC/MS m/z=408 [M+H]+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][N:10]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Sodium hydride (1.289 g, 32.2 mmol) was added portion wise to a solution of methyl 6-bromo-1H-indazole-4-carboxylate (4.11 g, 16.11 mmol) in N,N-dimethylformamide (50 ml) at 0° C. The dark orange mixture was stirred at 0° C. for 10 mins, then treated with 4-methylbenzenesulfonyl chloride (3.38 g, 17.72 mmol). The resultant pale cream mixture was stirred for 30 mins at 0° C. then poured into water (1000 ml). The cream precipitate was filtered off under vacuum and dried in the vacuum oven at 50° C. for 18 h to give the title compound as a yellow solid (5.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[N:31]1[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:37]([C:35]5[CH:36]=[N:31][CH:32]=[N:33][CH:34]=5)=[O:38])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(NC(=O)c3cncnc3)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with pyrimidine-5-carboxylic acid to yield the title compound as light yellow amorphous solid. MS: 551.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=O)=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:6][CH:7]=1
Reactant: O=Cc1cccn1-c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccn3-c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-(4-chlorophenyl)-1H-pyrrole-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 436.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[N:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][N:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g. 0.87 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.5 g, 8.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.25 g, 2.1 mmol) was added and stirred for further 5 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch) then further purified through preparative TLC to provide the desired compound as yellow solid (0.05 g, 16% yield), 8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.143 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.018 g, 0.143 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.02 g, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[ClH:1].[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][OH:20])=[CH:30][CH:29]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Reactant: Nc1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OCCO)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (2.4 g), 4-(2-hydroxyethoxy)aniline (1.4 g), anhydrous potassium carbonate (2.49 g) and THF (70 ml) was stirred at ambient temperature for 3 days. The mixture was filtered and the filtrate evaporated to dryness. The residue was ground up in ether and filtered. The residue was dissolved in dichloromethane and purified by chromatography on silica. The product fractions were combined, dissolved in IMS (150 ml) and saturated with hydrogen chloride gas. The mixture was cooled in ice and diluted with ether to induce precipitation. The mixture was filtered to give ethyl 6-ethoxy-4-[4-(2-hydroxyethoxy)anilino]-1,5-naphthyridine-3-carboxylate hydrochloride, m.p. 177°-178° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:8]=2)=[CH:5][NH:4][N:3]=1.[CH:28]1([CH:33]=[CH:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:28]1([CH:33]([N:4]2[CH:5]=[C:6]([C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:8]=3)[C:2]([CH3:1])=[N:3]2)[CH2:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: N#CC=CC1CCCC1
Reactant: Cc1n[nH]cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nn(C(CC#N)C2CCCC2)cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reaction time: 8 h
Yield: 41.3 %

Procedure:
4-(4-(5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0690 g, 0.191 mmol), 3-cyclopentylacrylonitrile (Table 1, compound g; 0.0696 g, 0.574 mmol) and DBU 0.0661 mL, 0.479 mmol) were suspended in DMF (3 mL) and stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5-2% (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(3-methyl-4-(7-(4-morpholinophenyl) imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.0380 g, 0.078905 mmol, 41.2% yield). MS (apci) m/z=482.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:4]=[N:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O>>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2cncnc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cncnc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Pyrimidin-5-yl-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1
Reactant: COc1cccc([Mg]Br)c1
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 3-methoxyphenylmagnesium bromide (1M in THF, 61 ml, 61 mmol, 1 equiv) at 0° C. was slowly added cyclohexanone (6 g, 61 mmol, 1 equiv) in Et2O (30 ml). The resulting mixture was stirred at room temperature for 4 h then poured in H2O at 0° C. The two layers were separated and the aqueous phase was extracted three times with Et2O. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-[3-(methyloxy)phenyl]cyclohexanol (D314) (12.4 g, 100%) as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])[CH3:3].[C:22]([OH:27])(=[O:26])[CH:23]([CH3:25])[CH3:24].CN1CCOCC1.CCCCCC>C(OCC)C>[C:22]([O:27][CH:2]([O:4][C:5]([NH:7][CH2:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])[CH3:3])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)Cl)CCCCC1
Reactant: CC(C)C(=O)O
Solvent: CCCCCC
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound (14) (38 g, 0.12 mol) in isobutyric acid (55 mL, 52.5 g, 0.6 mol) was added to a mixture of isobutyric acid (55 mL, 52.5 g, 0.6 mol) in N-methylmorpholine (65 mL, 60 g, 0.59 mol) at 0° C. over a period of 30 min. The resulting turbid solution was stirred for 16 h at room temperature. The reaction mixture was diluted with diethyl ether (500 mL) and washed with water (3×200 mL) followed by 10% potassium bicarbonate (4×200 mL) and brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield a viscous liquid. This crude product was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate:hexane to give the desired compound (15) as a clear, viscous liquid (37 g, 84% yield). 1H NMR (CDCl3, 400 MHz): δ 1.15 (d, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, 2H), 4.56 (d, 2H), 5.24 (dd, 1H), 5.32 (dd, 1H), 5.35 (br. s, 1H), 5.84-5.94 (m, 1H), 6.78 (q, 1H). MS (ESI) m/z 392.24 (M+H+).
Reaction SMILES: O[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)Cl>[I:41][CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@@H](CO)CN1C(=O)COc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](CI)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
A reaction flask was charged with (R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.71 g, 7.77 mmol), triphenylphosphine (4.50 g, 17.2 mmol), imidazole (1.27, 18.7 mmol), and iodine (5.54 g, 21.8 mmol) in CH2Cl2 (20 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (2.25 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC1CCCC1Oc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Product: CC1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 97.8 %

Procedure:
2-Fluoro-4-chloro-5- (2-methylcyclopentyl) oxyaniline (660 mg, 2.71 mmol), 3,4,5,6-tetrahydrophthalic anhydride (503 mg, 3.31 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 5 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into ice-water (100 ml). The mixture was extracted with ethyl acetate (30 ml×3), and the organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, the solvent was distilled off under reduced pressure, and the resulting pale brown oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol, 98% yield)