Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15](OC)=[O:16].O>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:28][CH:29]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15]([NH:4][C:3]([NH2:5])=[NH:2])=[O:16]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(CCN(C)C)cc2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(Oc2cc(Cl)c(C(=O)NC(=N)N)cc2S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
268 mg of guanidine hydrochloride were dissolved in 3 ml of DMF and a solution of 286 mg of potassium t-butoxide in 3 ml of DMF is added. The mixture was stirred at RT for 3 hours, then a solution of 210 mg of methyl 2-chloro-4-(4-(2-dimethylaminoethyl)phenoxy)-5-methylsulfonylbenzoate in 4 ml of DMF was added. The mixture was stirred at RT for 3 hours and allowed to stand at RT for 18 hours. The mixture was poured onto 150 ml of water and extracted 3 times using 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. 230 mg of a glassy solid were obtained.
Reaction SMILES: C(=[C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[CH:8]=[CH:7][NH:6]1)C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:6]1[CH:5]=[CH:10][C:9]([CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C=C1C=C(CN)C=CN1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1ccncc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 2933 %

Procedure:
96 g (0.593 mol) of isobutylidene-4-aminomethylpyridine is added dropwise at 40° C. in the course of 30 minutes, with stirring, to a suspension of 2 g (0.0179 mol) of potassium tert-butylate in 100 ml of toluene. The reaction mixture becomes in the process darkish red-brown. It is stirred at 40° C. for a further 1.5 hours, and the toluene is distilled off in a water-jet vacuum. The residue is then distilled in an oil-pump vacuum to obtain 85 g (0.525 mol) of 4-pyridylmethylidene-isobutylamine as a slightly yellowish liquid, corresponding to a yield of 88.5% of theory; b.p. 62°-63° C./1.3 Pa; nD20 =1.5166.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([O:18]C)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[Li+].[OH-]>CO>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of methyl (2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylate (10 g, 37 mmol) prepared in Step D of Preparation Example A1-1 in methanol (100 ml) and water (100 ml) was added LiOH (2.5 g, 111 mmol). The solution was stirred at rt for 3 h, concentrated in vacuo, acidified with 1N HCl, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (9.5 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:22])([O:15]C3CCCCO3)[CH3:14])[C:7](=[O:23])[C:6]3([CH3:28])[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])([CH3:22])[CH3:14])[C:7](=[O:23])[C:6]3([CH3:28])[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (133 mg, 0.322 mmol) in THF (3 ml) was added 1 N HCl aqueous solution (1 ml, 1.000 mmol) and the reaction mixture was stirred for 1 h, followed by being poured into NaHCO3 aqueous solution. Extraction with EtOAc, drying over Na2SO4 and concentration in vacuo gave crude 2-chloro-5-(2-hydroxy-2-methylpropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (84.9 mg, 0.260 mmol, 81% yield) as a yellow oil which was used in the next step without further purification. MS [M+H] found 327.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O>C(O)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=CO
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-methoxy-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-(2-methoxyethyl)-undec-4-enoate (1.619 g, 2.136 mmol) was dissolved in formic acid (8.0 mL), and water (420 μL) was added. The reaction mixture was stirred at room temperature for 24 hours, and concentrated. After subsequently repeating twice the operation of dissolution in ethyl acetate and concentration, the residue was purified by diol column chromatography (dichloromethane/ethyl acetate) to obtain the target compound at a yield of 80%.
Reaction SMILES: C(=O)CC.[CH2:5]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7]CC>>[CH2:5]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH2:6][CH3:7]
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CCC=O
Product: CCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Prepared using propionaldehyde (91 μl, 1.26 mmol) and the synthetic procedure described for Intermediate 19. Purification by Biotage™ chromatography (40 g Silica column), eluted with 1:50 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (0.22 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1C=CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)OC(C)(C)C)C1C=CCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution containing 62 (6.0 g, 0.025 mol) in DCM (25 mL) at 0° C. was added Et3N (4.5 mL, 0.032 mol). After 5 min, a solution containing methanesulfonylchloride (2.33 mL, 0.03 mol) in DCM (5 mL) was added drop wise. After 2 h, TLC analysis revealed complete consumption of 62 [1:1 hexanes/EtOAc, Rf(63)=0.5, Rf(62)=0.4]. The reaction mixture was poured onto ice-water and extracted with DCM. The organic extracts were washed with water, brine, and dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.05 g (89%) of crude 63 as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ5.8-5.5 (m, 2H), 4.69 (d. J=6.15 Hz, 2H), 3.85-3.3 (m, 3H), 3.0 (s, 3H), 2.0-1.9 (m, 1H), 1.55-1.30 (m, 1H), 1.40 (s, 9H), 1.0 (d, J=6.74 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][OH:6]>ClCCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH:5]=[O:6]
Reactant: OCc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Step A A mixture of 3-chloro-4-(trifluoromethyl)benzyl alcohol (Synquest) (4.77 g, 23 mmol) and activated MnO2 (19.5 g, 230 mmol) in 1,2-dichlorethane (80 mL) was heated and stirred at 80° C. for 3 h. The mixture was cooled to room temperature and filtered through a short pad of celite. The celite was washed with dichloromethane, and ethyl acetate. The filtrates were combined, concentrated, dried under reduced pressure to give 3-chloro-4-(trifluoromethyl)benzaldehyde as a light yellow oil (2.8 g, 60%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3]1
Reactant: COC(=O)c1cncc(N2CC(O)C2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cncc(N2CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of compound 11a (250 mg, 1.20 mmol) in dry DCM (15 mL) was added Dess-Martin periodinane (1.014 g, 2.40 mmol) at 0° C. under N2 atmosphere and the solution was stirred at rt for 2 h. The resulting solution was quenched with saturated sodium bicarbonate solution and diluted with EA. The organic portion was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by CC (DCM/MeOH=150:1) to give compound 11 (140 mg, 57%) of as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1Cl
Product: Cc1nc(NC(=O)c2ccccc2Cl)sc1C(=O)NCc1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 13% yield; 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=7.8 Hz, 1H), 7.46-7.27 (m, 8H), 5.95 (s, 1H), 4.57 (d, J=4.6 Hz, 2H), 2.33 (s, 3H); MS (ES+) m/z 386.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:13]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=23)=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenol (8) (1 g, 3.55 mmol) was dissolved in 30 ml of THF and after addition of NaH (60% in mineral oil, 0.171 g, 4.27 mmol) the mixture was stirred for 20 min at rt. Then methyl 2-bromoacetate (0.382 ml, 3.91 mmol) was added and the mixture was stirred for 16 h at rt. The mixture was quenched with H2O. The mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and NaCl-solution, dried over Na2 SO4 and evaporated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][CH3:13])[C:4]=2[O:3]1.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]([CH3:13])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)[C:4]=2[O:3]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2c1OC(C)(C)C2
Agent: Cl
Product: CN(Cc1cccc2c1OC(C)(C)C2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 72.8 %

Procedure:
According to the procedure of Example 35g, (2,2-dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (284 mg, 1.48 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (382 mg, 1.50 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (422 mg, 73%) as an orange solid and a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.65-10.64 (m, 1H), 8.35-8.34 (m, 1H), 8.06-8.01 (m, 1H), 7.51-7.44 (m, 1H), 7.37-7.07 (m, 2H), 6.92-6.89 (m, 1H), 6.81-6.73 (m, 1H), 4.65-4.49 (m, 2H), 3.11-2.87 (m, 7H), 2.55-2.53 (m, 2H), 1.42-1.39 (m, 6H); ESI MS m/e 392 [C23H25N3O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]([OH:49])([C:47]#[CH:48])[CH3:46]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:48]#[C:47][C:45]([OH:49])([CH3:46])[CH3:44])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)CC1COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(=O)OC)sc21
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a stirred mixture of 9-Bromo-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (90 mg, 0.22 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(PPh3)Cl2 (15 mg, 0.021 mmol), PPh3 (17.2 mg, 0.065 mmol), CuI (8.3 mg, 0.043 mmol) and 2-methylbut-3-yn-2-ol (92 mg, 1.09 mmol). The reaction mixture was degassed with N2 and heated to 80° C. in a microwave reactor for 1.5 h. Then the mixture was cooled to room temperature, EtOAc was added. The mixture was filtered through Celite. The filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (70 mg, 77%) as a light yellow solid. LC-MS (ESI & APCI): 416.7 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:48][N:47]=[N:46][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) and toluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.75 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 46%).
Reaction SMILES: Br[C:2]1[C:3]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[Cu](C#N)[C:32]#[N:33]>CN1C(=O)CCC1>[N:25]1([C:23]([C:3]2[C:2]([C:32]#[N:33])=[CH:22][C:6]3[O:7][C:8]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:9][C:5]=3[CH:4]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: O=C(c1cc2c(cc1Br)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(cc1C(=O)N1CCOCC1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 190 °C
Yield: 2583.3 %

Procedure:
A mixture of (6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone, (204 mg, 0.437 mmol) and copper cyanide (102 mg, 1.139 mmol, 2.6 eq.) in N-methyl pyrrolidinone (3 mL) was heated at 190° C. during 16 h. The reaction mixture partitioned between water and ethyl acetate. The organic layer was washed with brine and evaporated in vacuo. Purification by flash chromatography afforded the title compound (4.656 g, 83 %) as an off white solid.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:35].[H][H]>[Pd].CC(O)C>[ClH:35].[NH2:11][CH2:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17]
Reactant: [H][H]
Reactant: O=C(CCC(=O)OCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCC(=O)O
Yield: 73.9 %

Procedure:
This compound was prepared from the product of 9b (0.45 g; 0.96 mmol), 12 M HCl (0.08 mL; 0.96 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.20 g (77%) product was obtained (white solid).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.Cl[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=2[N:28]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=3[N:28]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 451 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([CH:29]4[CH2:31][CH2:30]4)[N:27]=3)[N:22](COCC[Si](C)(C)C)[CH:21]=2)=[O:19])([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:16][C:13]([C:10]1([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([CH:29]4[CH2:30][CH2:31]4)[N:27]=3)[NH:22][CH:21]=2)=[O:19])[CH2:11][CH2:12][NH:8][CH2:9]1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)(C(C)(C)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C1(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 10 mL round-bottomed flask, 3-{[2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (118 mg, 0.21 mmol) was dissolved in CH2Cl2 (1 mL). Trifluoroacetic acid (0.8 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (1 mL) and ethylenediamine (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h then H2O and EtOAc were added. The aqueous layer was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was triturated with EtOAc to afford 37 mg (48%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [3-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-3-yl]-amide as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])([OH:3])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>>[C:1]([C:4]1[CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])([OH:3])=[O:2]
Reactant: Cc1cccc(C(=O)O)c1OC1CCOC1=O
Reactant: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1OC1CCOC1=O
Temperature: 0 °C

Procedure:
24.4 g. of α-[(2-Carboxy-6-methylphenyl)oxy]-γ-butyrolactone was added to 120 ml. of fuming nitric acid at a temperature not higher than -40° C. The reaction solution was poured into ice water, and the precipitating crystals were collected by filtration, washed with water and dried. The crystals were recrystallized from methanol. By the above procedure there was obtained α-[(2-carboxy-6-methyl-4-nitrophenyl)oxy]-γ-butyrolactone as pale yellow prisms, m.p. 210° C.(decomp.). Yield 20.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:17].Cl[C:19](OC(Cl)(Cl)Cl)=[O:20]>C1(C)C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]=[C:19]=[O:20])=[C:3]([F:17])[CH:4]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.9 %

Procedure:
To a solution of 6.50 g (0.0276 mole) of 4-fluorophenylmethyl 4-amino-3-fluorophenyl ether in toluene, stirring at room temperature, was slowly added 3.95 g (0.020 mole) of trichloromethyl chloroformate. During the addition a thick precipitate formed. Upon completion of addition, the reaction mixture was stirred for one hour at room temperature and then at reflux for approximately seventeen hours. The toluene was removed by distillation, leaving 7.10 g of 4-(4 -fluorophenylmethoxy)-2-fluorophenyl isocyanate.