Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([CH2:12][CH:10]4[CH2:11][N:8]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: O=C1C=COCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4CCOCC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 2H-pyran-4(3 H)-one underwent reductive amination with 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine to give 503. 517.3 (MH+)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:5][CH2:4]1
Reactant: CNCc1ccc(F)cc1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC#N
Product: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-N-(4-fluorobenzyl)amine (24 μL, 0.18 mmol) and MeCN (1 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C[O-].[Na+].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>CCOCC>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Oc1cccc(-c2nc3ncccc3o2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCOc1cccc(-c2nc3ncccc3o2)c1
Temperature: 25 °C

Procedure:
To a solution of 1.1 g. (0.005 mole) of 2-(3-hydroxyphenyl)oxazolo[4,5-b]pyridine in 15 ml. dried dimethylformamide is added 0.6 g. (0.011 mole) of sodium methoxide in portions over about 10 min. To the reddish-orange solution cooled in an ice-bath is added 0.72 g. (0.005 mole) of N,N-dimethyl-2-chloroethylamine hydrochloride in portions over 15 minutes. The resultant mixture is then stirred 10 minutes, set in an oil-bath at 75° C., and kept at 75-90° C. (bath) for 20 hours. After cooling to room temperature, 15 ml. of dried ether is added with stirring, and the resultant mixture is filtered. The filtrate is then stripped of solvent, and the residue distributed between methylene chloride and water. The organic layer is dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-[3-(2-dimethylaminoethoxy)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.Cl[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C1COCC1.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][O:1][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(CO)cn34)cn2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of compound 87d (80.0 mg, 0.164 mmol), 2-chloroquinoline (40.3 mg, 0.246 mmol) and 18-crown-6 (43.8 mg, 0.164 mmol) in 5 mL of THF at rt was added potassium tert-butoxide (0.328 mL, 0.328 mmol, 1.0M in t-BuOH). The resulting mixture was heated to 60° C. and continued to stir for 0.5 h. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with water (2×10 mL) and brine (10 mL). Removal of the solvent under reduced pressure followed by purification of the resultant residue by flash column chromatography on silica gel (0-4% MeOH/DCM) gave compound 87e as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.82 (br. s., 2H), 8.70 (br. s., 2H), 8.51 (br. s., 1H), 7.91-8.09 (m, 3H), 7.70-7.91 (m, 3H), 7.64 (t, J=7.2 Hz, 1H), 7.41 (t, J=6.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.84 (s, 2H), 3.70 (br. s., 4H), 3.60 (br. s., 4H), 1.51 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C35H34N8O3, 615.3 (M+H). found 615.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.Cl.[F:16][C:17]1([F:22])[CH2:21][CH2:20][NH:19][CH2:18]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:14][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][C:17]([F:22])([F:16])[CH2:18]2)[N:3]=1
Reactant: Clc1cc(-c2cccnc2)cc(Cl)n1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(c2cc(-c3cccnc3)cc(Cl)n2)C1
Temperature: 140 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dichloro-4-(3-pyridyl)pyridine (48 mg, 0.21327 mmol) and 3,3-difluoropyrrolidine hydrochloride (153 mg, 5.0 equiv., 1.0663 mmol) in NMP (1.0 mL, 10 mmol) in a microwave vial was added DIPEA (0.26 mL, 7.0 equiv., 1.4929 mmol), and the reaction was maintained at 140° C. for 60 min then at 150° C. for 20 min in the microwave machine, while LCMS indicated the conversion was more than 95%. The crude was used without further treatment. LCMS: m/z 296 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[C:20]([B:25]([OH:30])[OH:26])[C:21]([F:24])=[N:22][CH:23]=1
Reactant: Fc1ccc(C2OCCO2)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(C2OCCO2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Diisopropylamine (4.60 mL, 32.5 mmol) was dissolved in THF (80 mL) and cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 21.0 mL, 33.6 mmol) was added via syringe. After 30 minutes, the reaction was cooled to −78° C. and 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (3.73 g, 22.1 mmol) was added as a solution in THF (12 mL) dropwise over 5 minutes via syringe, followed by a THF (4 mL) rinse. The reaction was stirred at −78° C. under nitrogen for 1 hour, and then triisopropyl borate (Fluka 98+%, 8.0 mL, 34.9 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 4.5 hours, the reaction was quenched with 1 N NaOH (75 mL). The layers were separated, and the aqueous phase was treated with 5 N HCl to lower the pH to between 6 and 7. The aqueous phase was extracted with 10:1 DCM/MeOH. 5 N HCl was added to the aqueous phase to lower the pH to about 5, and extraction was continued with 10:1 DCM/MeOH. The organic extracts were combined, concentrated and dried under high vacuum to give 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 91% purity, 61% yield over 2 steps). MS (ESI pos. ion) m/z 214 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)[C:32]#[CH:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][N:34]6[CH:38]=[CH:37][N:36]=[CH:35]6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1ccnc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(C#CCn5ccnc5)cc34)ccc21
Temperature: 80 °C
Yield: 51 %

Procedure:
Quinazoline 14 (150 mg, 0.28 mmol), 1-N-2-propynylimidazole (200 mg, 1.89 mmol), Pd(OAc)2 (4 mg, 0.016 mmol) and PPh3 (9 mg, 0.033 mmol) were mixed in NEt3 (1.25 mL) and DMF (0.5 mL). The mixture was heated at 80° C under N2 for 16 hours. Upon cooling the black suspension was concentrated under reduced pressure and the residue dissolved in MeOH. Silica gel (1 g) was added and the methanol removed in vacuo. The resulting silica gel was placed atop a silica gel (40g) column which was then eluted with 200 mL 50:1 CH2Cl2:MeOH, the 300 mL 25:1 CH2Cl2 to provide alkyne 15 (72 mg, 51%) as a yellow foam. 1H NMR (CDCl3; 400 MHz): δ: 8.95 (br, 1H, NH), 8.63 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.96 (d, 1H, J=1.7 Hz), 7.84 (m, 3H), 7.71 (m, 2H), 7.51 (m, 3H), 7.41 (m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.55 (d, 1H, J=3.5 Hz), 5.01 (s, 2H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[Br:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1.CCOC(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12]([O:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Br:27])[CH:29]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: Oc1cccc(Br)c1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Fc1cc2[nH]c(Oc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of compound 13-6 (1.53 g, 4.2 mmol) in 20 mL in pyridine was added 3-bromo-phenol (1.4 g, 8.4 mmol). The reaction mixture was heated to reflux and allowed to stir for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed three times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The crude was purified on ISCO (EtOAc/Hexanes=1/1) to yield the title compound 13-7 along with recovered starting material 13-6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].F[C:24]1C=C(C(O)C)C=C(F)C=1C1N=C(C(O)=O)C=CC=1F.[H-].[Na+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:24])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)O)cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Reaction time: 0.03 h
Yield: 63 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.
Reaction SMILES: [O:1]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:53])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)[CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:32][O:33][C:34](=[O:53])[C:35]1[CH:40]=[C:39]([O:12][C@@H:10]([CH3:11])[CH2:9][O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:38]=[C:37]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[CH:45][CH:44]=2)[CH:36]=1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After then adding 11.8 g (62.1 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 16.3 g (62.1 mmol) of triphenylphosphine to a solution of 10.0 g (31.0 mmol) of the obtained 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methyl ester in tetrahydrofuran (200 ml), 33.8 ml (77.6 mmol) of a solution of diethyl azodicarboxylate in 40% toluene was added while cooling on ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=8:2) to obtain 5-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=C[CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH:43]5[CH2:42][N:47]([CH3:46])[CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.65 (m, 5 H) 1.65-1.88 (m, 4 H) 1.88-2.01 (m, 1 H) 2.92 (dd, J=4.7, 2.4 Hz, 3 H) 3.28 (s, 3 H) 3.95 (s, 3 H) 4.01-4.25 (m, 2 H) 4.31-4.55 (m, 2 H) 4.64-4.89 (m, 2 H) 7.44-7.63 (m, 2 H) 8.21 (d, J=8.3 Hz, 1 H) 8.18 (s, 1 H) 8.97-9.09 (m, 1 H) 9.78 (br. s., 1 H). [M+H] calc'd for C26H34FN7O3, 512; found 512.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][S:9][C:5]2=[C:6](Cl)[N:7]=1.CC(O)=O.Cl.[Sn]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][S:9][C:5]2=[CH:6][N:7]=1
Reactant: Clc1cc2ccsc2c(Cl)n1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1cc2ccsc2cn1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 5,7-dichlorothieno[2,3-c]pyridine (1.86 g, 8.20 mmol), AcOH (9.42 mL, 164 mmol), and concentrated HCl (3.16 mL, 38.4 mmol) was treated with tin powder (3.04 g, 24.6 mmol) at 60° C. After 3 h heating, another portion of concentrated HCl (3.16 mL) was added followed by another portion of tin powder (3.04 g). After 2 h heating, another portion of concentrated HCl (3.16 mL) was added followed by tin powder (1.03 g). After 2 h, the heating was stopped, and the reaction mixture was cooled and diluted with water (50 mL). After filtration, the residue was washed with water. The combined filtrates were extracted with EtOAc (4×100 mL). The combined extracts were washed with aqueous 1 N NaOH until the pH was >9, followed by brine (100 mL), dried over MgSO4, and concentrated in vacuo. Purification by ISCO chromatography (0 to 30% EtOAc:heptane) afforded 980 mg (70%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.93 (d, J=0.4 Hz, 1 H), 7.79 (d, J=6.4 Hz, 1 H), 7.75 (d, J=1.2 Hz, 1 H), 7.33 (dd, J=5.6, 0.8 Hz, 1 H); MS (ESI): 169.98, 171.98 [M+H]+; HPLC tR=1.29 min (TOF: polar—3 min).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: CC[C@@H](O)C(=O)OC
Product: CC[C@H](Oc1cc(C)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCC(F)(F)F)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 29.8 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenyl-pyrrolo[3,2-d]pyrimidine (Example-1(e)) (55.9 mg, 0.23 mmol) and 2,2,2-trifluoroethylamine (Aldrich Chemical Company) (95 μL, 1.15 mmol) was added a solution of K2CO3 (0.13 g, 0.92 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated aqueous NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was washed with CH2Cl2 until all the color was removed. The remaining solid was recrystallized from hot MeOH to provide 21 mg (29%) of the title compound as a white solid. Mp: >310° C. MS m/z 307 (M+1), 294, 281, 226. 1H NMR (DMSO-d6; 400 MHz): δ 2.31 (s, 3), 2.52 (s, 2), 6.74 (s, 1), 7.33 (t, 1, J=7.3), 7.43 (t, 2, J=7.8), 7.92 (d, 2, J=7.3), 11.74 (s, 1), 12.22 (s, 1). HRMS: Calcd for M+H, C15H13F3N4: 307.1168. Found: 307.1160.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH:8]=2)=[O:14])[CH2:43][CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred mixture of 6-hydroxy-2-napthoic acid (100 mg, 0.531 mmol) in anhydrous dimethylormamide (5 mL) was added triethylamine (163 μl, 1.168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg, 0.584 mmol), and 1-benzyl-piperidine-4-amine (100 μl, 0.531 mmol). The mixture was allowed to stir at room temperature overnight, then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield N-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide as a light brown solid (0.191 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[N+:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][C:36](=[O:37])[NH:1][C:2]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[CH3:23])=[O:7])=[CH:44][CH:43]=1)([O-:47])=[O:46]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of (2R, 5S)-2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.150 g, 0.37 mmol) in dichloromethane (7 ml) was added pyridine (0.066 ml, 0.82 mmol) followed by 4-nitrophenyl chloroformate (0.075 g, 0.41 mmol). The reaction was stirred at ambient temperature for 3½ hours. The reaction mixture was concentrated followed by chromatography on silica gel to give the title compound (0.153 g, 74% yield).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])#[N:2].CO.[ClH:13].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(Cl)Cl>[ClH:13].[CH2:15]1[CH2:16][CH:14]1[CH2:17][NH:18][C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])=[NH:2]
Reactant: N#CCCN1CCOC1=O
Reactant: NCC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N=C(CCN1CCOC1=O)NCC1CC1
Temperature: -15 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A solution of N-(cyanoethyl)oxazolidinone 18 (30 g, 0.21 mol) in dry methanol (10.9 g, 0.34 mol) and dry CH2Cl2 (60 mL) was saturated with dry HCl at -15° to 0° C. The mixture was then stirred for 6 h at 0°-20° C. The mixture was evaporated and dried in vacuo for 1 h. The crystalline imidoester hydrochloride was dissolved in dry methanol (120 mL) and cooled to -15° C. To the stirred solution cyclopropylmethylamine (31.2 g, 0.44 mol) was added in drops over a period of 20 min while maintaining the temperature at -15 to 0° C. The mixture was then stirred at -10° C. for 45 min and evaporated. The residue was dissolved in methanol, treated with ether until turbid and was refrigerated for 6 days. The colorless crystalline material was collected and dried to give 59 (28.7 g, 55%), mp 86°-88° C. 1H NMR (DMSO--d6) δ 0.28 (m, 2, --CH--CH2), 0.55 (m, 2, --CH--CH2), 1.05 (m, 1, --CH), 2.68 [t, 2, --CH2 --C(N=)], 3.07 (d, 2, --NH--CH2), 3.54 [t, 2, --CH2 --CH2 --C(N=)], 3.67 (t, 2, --O--CH2 --CH2). 4.30 (t, 2, --OCH2).