Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:16][C@@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C@H:15]2[CH2:16][O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Yield: 70 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from piperazine-1-carboxylic acid tert-butyl ester and (R)-(−)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 70% yield.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:7])C.[OH-].[Na+]>S(=O)(=O)(O)O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:6](=[O:7])[CH:5]=[CH:4]3)[CH:16]=1
Reactant: CCO/C=C/C(=O)Nc1ccc(-c2cccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccc2cc(-c3cccnc3)ccc2[nH]1
Temperature: 0 °C

Procedure:
Trans-3-[4-(3-Ethoxypropenamido)phenyl]pyridine (1.43 g) was stirred in 98% sulphuric acid (4.0 cm3) for 16 hours. The mixture was added to ice (50 g) and the resulting solution was basified to pH8 with 2.5M sodium hydroxide solution. The mixture was extracted with chloroform:methanol, 9:1 (10×100 cm3), and the combined and dried (MgSO4) extracts were concentrated in vacuo to yield a solid which was recrystallised from isopropanol to afford 6-(3-pyridyl)-2-(1H)-quinolone, m.p. 228°-230° (0.39 g).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.O>[OH:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:12]([S:13]([C:16]1[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])=[O:14])[C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid methyl ester (0.017 g, 0.04 mmol) in 0.5 mL tetrahydrofuran was added sodium hydroxide (0.004 g, 0.11 mmol) in 0.1 mL water. The reaction was stirred at room temperature for 24 hr. The reaction mixture was adjusted to a pH of 4 with 1N HCl and water was added. The aqueous solution was washed with methylene chloride and the organic layer was concentrated to afford 0.015 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid. 1H NMR (CDCl3) δ 7.05 (t, 1H, J=7.6 Hz), 7.00–6.93 (m, 2H), 6.90–6.80 (m, 4H), 6.70–6.62 (m, 2H), 6.43 (bs, 1H), 4.69 (s, 2H), 2.83 (t, 2H, J=7.2 Hz), 2.56 (t, 2H, J=7.2 Hz), 2.42 (s, 6H), 2.24 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([O:43][CH3:44])[CH:37]=1>>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][NH:33][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=2)=[CH:37][C:38]=1[O:43][CH3:44]
Reactant: COc1cc(CCN)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: COc1cc(CCNc2nccc(-c3cccc(CN(C4CCNCC4)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 30 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenol following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 512. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 2H) 7.6 (m, 2H), 7.5 (t, 1H), 7.2 (d, 1H), 6.8 (d, 1H), δ 6.7 (s, 1H), 4.5 (d, 2H), δ 3.8 (s, 3H), 3.3 (t, 2H), δ 3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), δ 2.0 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[SH:30][C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.[I-].[K+]>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:16]([C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][S:30][C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:7][CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:17]2[CH2:29][CH2:28][CH2:27][N:18]2[N:19]=1
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: Sc1ncccn1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCCSc5ncccn5)ccc24)CCC3)nc1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
7-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (0.060 g, 0.148 mmol), 2-mercaptopyrimidine (0.033 g, 0.296 mmol, 2.0 equiv) and potassium iodide (0.010 g, 0.120 mmol, 0.80 equiv) are combined in N,N-dimethylformamide (1.0 mL) and the reaction is heated at 60° C. for 72 h. The mixture is placed on a 10 g SCX resin column. The resin is washed sequentially with 9:1 dichloromethane: methanol (2×120 mL), 4:1 dichloromethane: methanol (2 N ammonia) (2×125 mL), and methanol (2 N ammonia) (125 mL). The ammonia washes are evaporated to dryness and the residue is subjected to chromatography on silica gel (20 g, 99:1 dichloromethane: methanol (2 N ammonia)) to yield 0.054 g (76%) of the desired product as a tan solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C.O>[OH:3][NH:2][C:17](=[NH:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 97.4 %

Procedure:
Hydroxylamine hydrochloride (1.9 g, 27.2 mmol) then sodium carbonate (2.2 g, 20.4 mmol) were added to a stirred solution of 4-nitro-benzonitrile (1 g, 6.8 mmol) in ethanol (20 mL) and water (8 mL). The resulting mixture was refluxed at 85° C. under an atmosphere of nitrogen for 2 hours. The volatiles were then evaporated and the residue was extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and evaporated to afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR: (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[NH:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[NH2:30]>>[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[CH3:41][NH:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:29][N:30]=[C:21]2[C:8]3[C:9](=[CH:10][CH:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[CH:7]=3)[NH:12][C:22]2=[O:27])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CNS(=O)(=O)c1ccc(NN)cc1
Agent: O=C1Nc2ccc(-n3cncn3)cc2C1=O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(-n4cncn4)cc32)cc1

Procedure:
5-[1,2,4]Triazol-1-yl-1H-indole-2,3-dione was prepared from 4-[1,2,4]-triazol-1-yl-phenylamine according to Procedure A in 6% yield: 1H NMR (DMSO-d6): δ 7.04 (d, J=8.4 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 8.01 (dd, J=2.2, 8.4 Hz, 1H), 8.20 (s, 1H), 9.26 (s, 1H), 11.19 (bs, 1H); APCI-MS m/z 215 (M+1)+. Condensation of 5-[1,2,4]triazol-1-yl-1H-indole-2,3-dione with 4-hydrazino-N-methyl-phenylsulfonamide according to Procedure G gave the title compound in 86% yield: 1H NMR (DMSO-d6): δ 2.38 (d, J=5.0 Hz, 3H), 7.05 (d, J=8.4 Hz, 1H), 7.30 (q, J=5.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz, 3H), 8.01 (s, 1H), 8.20 (s, 1H), 9.23 (s, 1H), 11.27 (s, 1H), 12.80 (s, 1H); Anal. Calcd for C16H15N7O3S.1.3H2O: C, 48.52, H, 4.22; N, 23.30; S, 7.62. Found C, 48.53, H, 4.25; N, 23.17; S, 7.55.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)#[N:36]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CN)cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CNC(=O)c3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a suspension of {4-[3-(4-aminomethyl-phenoxy)-propoxy]-benzyl}-carbamic acid tert-butyl ester prepared in Example 78 (3.00 g,7.76 mmol) in THF (30 mL) was added a 10% aqueous solution of potassium carbonate (53.90 mL, 38.81 mmol). 4-Cyanobenzoyl chloride (1.29 g, 7.76 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc (150 mL), washed with 1N aqueous HCl (2×150 mL), dried over MgSO4, and concentrated to provide the desired compound as a yellow solid (2.41 g, 60% yield) which did not require any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:16]([B-](F)(F)F)=[CH2:17].[K+].C(Cl)Cl.CCN(CC)CC>CC(O)C.O.CCOC(C)=O>[CH:16]([C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[CH2:17]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=Cc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A stirred solution of dimethyl 5-bromoisophthalate (273 mg, 1.0 mmol), potassium vinyltrifluoroborate (134 mg, 1.0 mmol) PdCl2(dppf).CH2Cl2 (16.3 mg, 0.02 mmol) and Et3N (0.42 mL, 3.0 mmol) in i-PrOH (6 mL) and H2O (3 mL) was heated to reflux for 3 h. The solution was cooled to room temperature and diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (8% EtOAc in hexanes) to provide dimethyl 5-vinylisophthalate (153.6 mg, 70%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([O:18]C)=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCCCc1cc(C(=O)OC)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCc1cc(C(=O)O)c2ccccc2c1

Procedure:
Methyl 3-[3-(methyloxy)propyl]-1-naphthalenecarboxylate (1 eq.) from the previous step was taken up in a 2:1 (v/v) mixture of MeOH:THF (0.08 M). To this solution was then added LiOH (2.0 M aq. solution, 3 eq.) and the resulting cloudy solution was vigorously stirred at RT for 24 h. The volatiles were then removed in vacuo and the pH of the residue was carefully adjusted to ˜2 with 1 N aq. HCl before it was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]2=[N:33][CH:34]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.C(=O)(O)O.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21]([NH:28][C:29]3[CH:30]=[C:31]4[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]4=[N:33][CH:34]=3)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C(=O)O
Reactant: COC(=O)c1cc2cc(N)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NC(=O)c3cc(NC(=O)c4ccc(CN5CCN(C)CC5)cc4)ccc3C)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
A reactor is charged successively with 150 mg (0.4 mmol) of the solid obtained in step 3, 15 ml of anhydrous dichloromethane, 90 mg (0.4 mmol) of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 0.12 g (0.49 mmol) of triethylamine and 93 mg (0.61 mmol) of hydroxybenzotriazole. The mixture is stirred at room temperature for 15 min and then 90 mg (0.49 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrogen carbonate (EDCl) is added. The mixture is stirred for 16 hours. The solvent is then evaporated under reduced pressure and the residue is taken off in 100 ml of water. The aqueous phase is extracted by 6*50 ml dichloromethane. The aqueous phases are combined, dried on sodium sulphate and then evaporated under reduced pressure. The raw product obtained is purified by preparative HPLC and 18 mg (8%) of a solid is obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:1][C@H:2]1[CH2:3][C@@H:4]([NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])[CH2:5]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1

Procedure:
tert-Butyl (cis-3-hydroxycyclobutyl)carbamate (1.00 g, 5.34 mmol, Synthonix) was treated with triethylamine (1.5 mL, 11 mmol) and methanesulfonyl chloride (0.50 mL, 6.4 mmol, Aldrich) in DCM (10 mL) at 0° C. for 2 hours. Water was added and the product was extracted with EtOAc three times. The combined extracts were dried over sodium sulfate, filtered, and concentrated to afford cis-3-[(tert-butoxycarbonyl)amino]cyclobutyl methanesulfonate. Yield: (1.4 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(OC)c1N
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(OC)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of compound 53 (22.4 g, 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30](F)[CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([O:15][C:30]2[CH:29]=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[C:26]([F:25])[CH:31]=2)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a 0° C. solution of (2S,4R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (1 equiv) in DMF (0.5 M) was added NaH (1.3 equiv) as a solid. After stirring for 30 minutes at 0° C., 3,5-difluoronitrobenzene (1.2 equiv) was added by syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of water, and the mixture was diluted with EtOAc. The organic layer was washed four times with water and once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (10-20% EtOAc/Hexanes) provided the title compound in 66% yield.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1.CO.[CH3:29]S(O)(=O)=O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:29][O:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 60 °C
Yield: 87 %

Procedure:
To a flask charged with 7-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (340 mg, 0.821 mmol) was added methanol (9962 μL, 246 mmol) and methane sulfonic acid (533 μL, 8.21 mmol). The flask was sealed and heated at 60° C. for 3 hours. The reaction was diluted with saturated sodium bicarbonate (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a tan solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-methoxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (306 mg, 0.714 mmol, 87% yield) as a tan solid. MS m/z=428.0 [M+H]+. Calc'd for C20H19BrN3O3: 428.1.
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[CH2:13]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:17]=1[CH2:18][OH:19])[CH3:14].CCOCC>ClCCl>[CH2:13]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:17]=1[CH:18]=[O:19])[CH3:14]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1CO
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Yield: 83.2 %

Procedure:
To a 250 mL round bottom flask fitted with a reflux condenser, was added pyridinium chloro chromate (PCC) (16.1 g, 75 mmol) in anhydrous dichloromethane (100 mL). 2-Ethoxy-6-pentadecyl-benzyl alcohol (18.1 g, 50 mmol) in dichloromethane (10 mL) was added in one portion to the magnetically stirred solution. After 1.5 hr dry ether (100 mL) was added and the supernatant decanted from the black gum. The insoluble residue was washed thoroughly with diethyl ether (3×25 mL), where upon it became black granular solid. The organic solution was passed through a short pad of celite, and the solvent was removed by distillation to obtain brownish low melting solid (Yield: 15 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:18][NH:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([C:30]3[C:35]([Cl:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=3)[S:27][C:26]=2[CH:38]=1)=[O:21].C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>O1CCOCC1.ClCCl>[CH3:18][NH:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([C:30]3[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:17][CH2:16][CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:31]=3)[S:27][C:26]=2[CH:38]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1
Agent: CC[SiH](CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc2cc(-c3nc(NCCCC4CCNCC4)ncc3Cl)sc2c1
Reaction time: 2 h

Procedure:
4-(3-Aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 3.0 mmol) is added to a stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (0.40 g, 1.2 mmol) and diisopropylethylamine (0.38 g, 3.0 mmol) in anhydrous 1,4-dioxane (15 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 90° C. for 12 hours. At room temperature, the mixture is concentrated and the resultant solid is washed with diethyl ether (20 mL) to give a yellow solid. The solid is suspended in dichloromethane (5 mL), followed by the successive addition of triethylsilane (0.7 mL) and TFA (4 mL). The resultant yellow solution is stirred for 2 hours. After concentration to dryness, the crude product is dissolved in MeOH (20 mL)/dichloromethane (10 mL) and the solution is treated in portions with 2N LiOH (4.2 mL) to form a suspension. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-10%, the title compound is obtained as a yellow solid (0.26 g, yield 49%). ES+(m/z) 444 (35Cl) and 446 (37Cl) [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=CC=C[N:5]2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.NO>CCO>[CH3:1][C:2]1[N:3]=[C:4]([NH2:9])[NH:5][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Agent: NO
Solvent: CCO
Product: Cc1nc(N)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 95 %

Procedure:
Stir a mixture of 2-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine (180 g, 649.2 mmol, 1 equiv) in EtOH (1.4 L) and hydroxylamine (159 ml, 2.596 mol, 4 equiv) at an internal temperature of 82° C. for 48 hours. Cool the mixture, and concentrate to dryness. Dilute the residue with DCM (1.5 L), and wash sequentially with water (2×500 ml) and brine (500 ml). Dry the organic phase over MgSO4; filter; collect the filtrate and; and remove the solvent in vacuo to give a yellow gum. Purify the resulting material by flash chromatography on silica gel (2 kg), eluting with a gradient of 4:1:0.02 DCM/MeOH/NH3 to obtain the title compound as a yellow foam (95% yield). MS (m/z) 242 (M+1).