Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4][C@@H:3]1[NH:26][C:27](=[O:30])[CH:28]=[CH2:29]>CCO>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4][C@H:3]1[NH:26][C:27](=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)N[C@H]1CN(c2nc(Nc3cnn(C)c3)c3ncn(C(C)C)c3n2)C[C@@H]1F
Solvent: CCO
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cnn(C)c3)c3ncn(C(C)C)c3n2)C[C@H]1F

Procedure:
N-((3S,4S)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin -2-yl)pyrrolidin-3-yl)acrylamide, 36.7 mg, 9% yield (in 3 steps), >99% ee, 95% pure. Optical rotation: [α]D22=−19.06° (c 0.08, EtOH). 1H NMR (600 MHz, DMSO-17 mm) δ ppm 9.65 (br. s., 1 H) 8.50 (d, J=6.42 Hz, 1 H) 8.00 (s, 1 H) 7.92 (s, 1 H) 7.69 (s, 1 H) 6.19-6.29 (m, 1 H) 6.11-6.18 (m, 1 H) 5.63 (d, J=11.92 Hz, 1 H) 5.08-5.22 (m, 1 H) 4.46-4.69 (m, 2 H) 3.88 (br. s., 2 H) 3.82 (s, 3 H) 3.64-3.79 (m, 2 H) 1.50 (d, J=6.79 Hz, 6 H). m/z (APCI+) for C19H24FN9O 414.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([O:15]CC)=O.[OH-].[NH4+:19]>>[C:13]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=1)(=[O:15])[NH2:19]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnc2n(c1=O)CCCCC2
Reaction time: 2 h
Yield: 97.5 %

Procedure:
11.8 g. of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate are dissolved in 40 ml. of 30% by wieght ammonium hydroxide solution and the reaction mixture is allowed to stand at room temperature for 2 hours. The precipitated crystals are filtered and washed with water. 10.1 g. (97.5%) of 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine are obtained melting at 234°-235° C.
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[C:2]=[O:3].[CH3:21][N:22]([CH3:24])[NH2:23]>O1CCCC1>[CH3:21][N:22]([CH3:24])[NH:23][C:2]([NH:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:3]
Reactant: CN(C)N
Reactant: O=C=Nc1ccccc1Oc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CN(C)NC(=O)Nc1ccccc1Oc1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
The title compound of Step C was dissolved in 100 mL of dry tetrahydrofuran and cooled to 0° C. Then 1,1-dimethylhydrazine (2.3 g, 38.2 mmol) was added at 0° C. The resultant mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted twice with methylene chloride and the combined extracts were dried (MgSO4). The organic solution was then concentrated under reduced pressure to yield the title compound of Step D as a brown solid which was carried on entirely in Step E.
Reaction SMILES: [N:1]([C@H:4]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1)[C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH2:6][CH2:7][C:8](OC)=[O:9])=[N+]=[N-].CP(C)C.[Li+].[OH-]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C@@H:5]2[C@@H:4]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)[NH:1][C:8](=[O:9])[CH2:7][CH2:6]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CC[C@H](c1cccc(Cl)c1)[C@H](N=[N+]=[N-])c1ccc(Cl)cn1
Agent: CP(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N1
Reaction time: 0.5 h

Procedure:
Crude (4R,5S)-methyl 5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate (463 g, 1.22 mol, Example 121, Step E) was dissolved in 2.5 L THF/water (4:1). Trimethyl phosphine (1 M in THF, 1.46 L, 1.46 mol, 1.2 eq) was added slowly at 0-5° C. The reaction was stirred for 30 min and then basified with 2.0 M aqueous LiOH solution to pH 12. The reaction mixture was stirred for another 30 min, and extracted to ethyl acetate (2×5 L). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@@H:29]([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:42])=[O:41])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@@H:29]([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:41])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(N)n1)C(=O)O
Yield: 44.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (23 mg, 0.036 mmol), DCM (357 μL) and TFA (165 μL, 2.14 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (7.9 mg, 36%) as a white powder. LCMS: Rt=0.40 min, m/z=489.0 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 8.69 (s, 1H), 8.18 (s, 1H), 7.20 (s, 1H), 5.54 (d, J=5.7 Hz, 1H), 4.96-4.67 (m, 4H assumed; partially obscured by solvent residual peak), 1.44 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]1([Mg]Br)[CH2:45][CH2:44]1.C(OCC)(=O)C>O1CCCC1>[CH:43]1([CH:36]([OH:37])[CH2:35][O:34][C@H:31]2[CH2:30][CH2:29][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][CH:27]=[C:19]34)[CH2:33][CH2:32]2)[CH2:45][CH2:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.57 g) in tetrahydrofuran (6 mL) was added dropwise cyclopropylmagnesium bromide (0.5M tetrahydrofuran solution, 4 mL) at 0° C., and the mixture was stirred for 1.5 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), sodium borohydride (0.04 g) was added, and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.45 g, 81%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][NH:24][CH2:25]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.CC(C)([O-])C.[Na+]>>[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][N:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:25]2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(CN2C[C@@H]3CCNC[C@@H]32)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3CCN(c4cccnc4)C[C@@H]32)cc1
Yield: 57 %

Procedure:
The product from Example 33E and 3-bromopyridine were processed according to the procedure of Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used. The residue was purified by chromatography (SiO2, hexanes:ethyl acetate, 20:80, Rf 0.2) to provide the title compound (0.16 g, 57% yield). 1H NMR (CD3OD, 300 MHz) δ 2.04 (m, 2H), 2.56 (m, 1H), 3.00 (m, 2H), 3.22 (m, 2H), 3.55 (m, 1H), 3.60 (d, J=12.5 Hz, 1H), 3.70 (d, J=12.5 Hz, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 7.04 (ddd, J=8.8, 3.0, 1.3 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.24 (m, 5H), 7.80 (dd, J=4.7, 1.3 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 280 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([OH:18])[C:5]([NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]2[O:18][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][C:5]2=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1
Reactant: CC(C)(C)C(=O)Nc1c(C(=O)O)cc(Br)c([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1nc2c(C(=O)O)cc(Br)c([N+](=O)[O-])c2o1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
5-Bromo-2-(2,2-dimethylpropionylamino)-3-hydroxy-4-nitrobenzoic acid (I-221) (1.90 g, 5.26 mmol) was dissolved in benzene (38 ml), then p-toluenesulfonic acid monohydrate (1.00 g, 5.26 mmol) was added at room temperature. Under nitrogen atmosphere, the reaction liquid was heated under reflux for 21 hours, then cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, ethyl acetate:methanol=4:1) to obtain the entitled compound (1.80 g, 98%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1.[S:28]([NH2:32])([CH3:31])(=[O:30])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:32][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:26])([CH3:27])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(Cl)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2O1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)C=C(c2ccc(Cl)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Yield: 57.6 %

Procedure:
A mixture of [4-(4-chlorophenyl)-2,2-dimethyl-2H-chromen-7-yl]trifluoromethanesulfonate (100 mg), mesylamine (27 mg), cesium carbonate (117 mg), tris(dibenzylideneacetone)dipalladium (10 mg, 10% wt), 9,9-dimethyl-4,5-bis(diphenylphosphino)-9H-xanthen (Xantphos, 20 mg, 20% wt) and dioxane (2 mL) was heated under reflux for 10 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=100/1) to give the titled compound (50 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11](O)=[O:12])=[O:5].C(Cl)CCl.C1C=CC2N(O)N=[N:40]C=2C=1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11]([NH2:40])=[O:12])=[O:5]
Reactant: Cc1cccc(-c2ccc3c(C(=O)O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(-c2ccc3c(C(N)=O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-m-tolyl-benzofuran-3-carboxylic acid from step 6 (61.2 mg, 0.14 mmol, 1 eq) in anhydrous THF (3 mL) solution were added EDC (60.0 mg, 0.31 mmol, 2.2 eq) and HOBt (50.0 mg, 0.37 mmol, 2.6 eq). The reaction mixture was stirred at rt for 1 h. A 30% aq. NH4OH solution (0.5 mL) was added to the reaction mixture and stirring was continued for 15 h. The reaction mixture was poured into EtOAc (10 mL). The organic layer were washed with 1N NaOH (5 mL), 1N HCl (5 mL), brine (5 mL). The organic layer was dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by pre-TLC (10% Acetone/DCM) to afford an yellow solid (46.2 mg, 78%) as product. 1H-NMR (CDCl3): δ 9.39 (broad, NH, 1H), 8.58 (d, J=8.3 Hz, 1H), 7.68 (dd, J=1.5, 8.3 Hz, 1H), 7.63 (s, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.43-7.40 (m, 3H), 7.32 (t, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.01 (broad, NH, 1H), 2.42 (s, 3H); LC-MS (MH+=424/426).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.[C:12](=[O:14])=[O:13]>>[CH3:9][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([C:12]([OH:14])=[O:13])=[CH:3][C:4]=2[CH:8]=1
Reactant: Cc1cc2cc(Br)ccc2s1
Reactant: O=C=O
Product: Cc1cc2cc(C(=O)O)ccc2s1

Procedure:
Conversion of 5-bromo-2-methylbenzo[b]thiophene to the Grignard reagent followed by reaction with carbon dioxide by the method of Example 3(i) gave 2-methylbenzo[b]thiophene-5-carboxylic acid, m.p. 220°-222° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]3[CH:37]=[CH:36][NH:35][C:29]=3[N:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39]>CN1CCCC1=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]4[CH:37]=[CH:36][NH:35][C:29]=4[N:30]=[C:31]([C:33]#[N:34])[N:32]=3)=[CH:23][C:22]=2[C:38]([F:39])([F:40])[F:41])[CH2:4][CH2:3]1
Reactant: N#Cc1nc(-c2ccc(F)c(C(F)(F)F)c2)c2cc[nH]c2n1
Reactant: CN1CCC(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCC(CCNc2ccc(-c3nc(C#N)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
2-(1-Methylpiperidin-4-yl)ethanamine (93 mg) and N,N-diisopropylethylamine (0.22 mL) were added to a mixture of 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and N-methylpyrrolidone (2 mL), and the mixture was stirred at 140° C. for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, the reaction mixture was purified by silica gel column chromatography (CHCl3:MeOH=98:2 to 85:15), whereby 4-[4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (66 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[C@@H:25]([C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CC(O)C>[C:1]([O:5][C:6]([NH:8][N:9]([CH2:24][CH:25]([OH:23])[CH:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccn2)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccc(-c2ccccn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 66 %

Procedure:
Into a 100 mL flask was placed (5) (1.0 g, 3.34 mmol), (6) (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane (2.78 g, 10.5 mmol, 3.16 equivalents), and 2-propanol (15 mL). The reaction was heated to reflux. After approximately 61 hours of refluxing, the heat was removed, and the mixture cooled to room temperature. To the cooled mixture was added water/ice (50 mL). To the aqueous mixture was added dichloromethane (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and then dried over sodium sulfate. The dried organic solution was filtered, and the filtrate was concentrated under reduced pressure, and then dried under high vacuum overnight. The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV) to give 1.24 g (66%) of (7) as a white solid. TLC Rf (hexane/ethyl acetate, 1:2)=0.45; 1H NMR (CD3OD) δ 8.60 (d, 1H), 7.88 (m 4H), 7.50 (d, 2H), 7.36 (m, 1H), 7.25 (m, 4H), 7.18 (m, 1H), 3.93 (m, 2H), 3.70 (m, 2H), 3.0-2.6 (m, 4H), 1.33 (s, 9H), 1.30 (s, 9H); MS (M)+=563; HPLC tR 9.6 minutes.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:54][C:55]4[NH:61][C:60](=[O:62])[CH2:59][CH2:58][NH:57][C:56]=4[N:63]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:54][C:55]4[NH:61][C:60](=[O:62])[CH2:59][CH2:58][NH:57][C:56]=4[N:63]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Yield: 108.4 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (27 mg, 0.06 mmol) was reacted to afford the title compound (25 mg, 73%). LCMS (Method D): RT=0.644 min, M+1=385. 1H NMR (500 MHz, MeOD): 7.47-7.43 (5H, m), 7.27-7.25 (3H, m), 7.16-7.14 (2H, m), 3.78-3.76 (2H, m), 2.90-2.88 (2H, m), 2.79-2.73 (2H, m), 2.62-2.56 (2H, m), 2.26-2.22 (1H, m), 1.99-1.95 (1H, m).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[C:15](C1C=CC(C(N)=O)=CC=1)#[N:16].O.NN.CCOCC>CN(C(OC)OC)C>[NH:12]1[CH:13]=[N:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:15]#[N:16])=[CH:5][CH:6]=2)=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-c2nc[nH]n2)cc1
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: COC(OC)N(C)C
Agent: NN
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(-c2nc[nH]n2)cc1

Procedure:
The general procedure outlined by Lin et al. (J. Org. Chem. 1979, 44, 4163) for preparation of 3-(4-nitrophenyl)-1H-[1,2,4]triazole was used. 4-Cyanobenzamide (21.63 g, 0.148 mol) was dissolved in DMF-DMA (100 mL) and was stirred at reflux under N2 for 8 h. The mixture was concentrated to dryness and suspended in AcOH (50 mL). The vessel was then charged with hydrazine monohydrate (7.18 mL, 0.148 mmol) and stirred at reflux for 1 h before concentration. The desired 4-(1H-[1,2,4]triazol-3-yl)-benzonitrile was obtained in 98% purity by trituration with Et2O followed by filtration (12.17 g, 0.072 mol, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10](=[N:13][N+:14]([O-:16])=[O:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10]([NH:19][CH3:18])=[N:13][N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CSC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A mixture of 0.82 g of 1-(6-chloro-3-pyridylmethyl)-1,2-dimethyl-3-nitroisothiourea, 0.464 g of 40% methylamine aqueous solution and 10 ml of acetonitrile was stirred for 2 hours at 70° C., and concentrated. The residue was purified by a column chromatography [developing solution: dichloromethane-methanol [10:1]) to afford 0.56 g of 1-(6-chloro-3-pyridylmethyl)-1,3 -dimethyl-2-nitroguanidine (Compound No. 8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:24][CH:25]=[N:26]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜1 g, quant.): LCMS (ES) m/z=209 (M+H)+.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH:40]12[N:46]([C:47](=O)[CH2:48]Br)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>>[CH:40]12[N:46]([CH2:47][CH2:48][O:10][C:8]3[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=4[CH:14]4[CH2:23][CH2:22][C:21]5[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=5[CH2:15]4)=[CH:35][CH:34]=3)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1cc(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 17.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.