Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:25][C:24]=3[CH3:35])=[CH:19][CH:18]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:25][C:24]=3[CH3:35])=[CH:21][CH:22]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN(C)C
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNCCOc1cc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of N-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E1, 0.2 g, 0.41 mmole) in 1,2-dichloroethane (5 ml) was treated at room temperature with 1-chloroethyl chloroformate (0.12 ml, 1.12 mmole) followed by diisopropylethylamine (0.15 ml, 0.86 mmole). The mixture was stirred for 2 hours at room temperature. After removal of solvent in vacuo the residue was treated with methanol (8 ml) and heated under reflux for 30 minutes. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous potassium carbonate (10 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried and concentrated in vacuo. Flash column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave the title compound as a light pink solid (0.13 g, 68%) mp 97°-99° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.[Br:30][CH2:31][C:32]([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])[C:33](=[N:37][O:38][CH3:39])[C:34](Cl)=[O:35].O>C(OCC)(=O)C>[Br:30][CH2:31][C:32]([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])[C:33](=[N:37][O:38][CH3:39])[C:34]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12)=[O:35]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Yield: 100.6 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.4 g) and timethylsilylacetamide (9.8 g) in ethyl acetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyryl chloride (syn isomer) (5.0 g) at -20° C. with stirring, and the stirring was continued at -20° to 5° C. for an hour. To the reaction mixture were added ethyl acetate and water, and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (10.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:6](=[S:17])[NH:5][C:4](=[O:18])[CH:3]=1.[N:19]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:19][C:3]1[C:4](=[O:18])[NH:5][C:6](=[S:17])[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:10]=2)[C:2]=1[NH2:1]
Reactant: CC(C)c1cc(Cn2c(N)cc(=O)[nH]c2=S)on1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)c1cc(Cn2c(N)c(N)c(=O)[nH]c2=S)on1
Yield: 33.2 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(c) by using 6-amino-1-[(3-isopropylisoxazol-5-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.20 g, 0.75 mmol, obtained from Example 15(b)), sodium nitrite (0.060 g, 0.83 mmol) and sodium dithionite (0.26 g, 1.5 mmol) giving the title compound (0.070 g, 33% yield). MS (ESI) m/z 282 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[C:2]1([NH:1][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91 %

Procedure:
First, 26.2 g of aniline, 100 mL of tetrahydrofuran (THF), and 56.9 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and mixed. Then, under cooling in ice, a mixed solution of 30 g of isobutyryl chloride and 100 mL of THF was dripped through a 50 mL dropping funnel to the above mixed solution, and then the temperature was increased to room temperature and the solution was stirred for 19 hours to be reacted. After the reaction, this mixture was subjected to suction filtration to give a filtrate. The resulting filtrate was washed with water, and then saturated saline, and anhydrate magnesium sulfate was added for drying. After the drying, the mixture was subjected to gravity filtration, and the filtrate was concentrated, so that N-phenylisobutyramide was prepared (a white solid, yield: 91%). The synthetic scheme of Step 1 is shown by (a-10).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4].[CH2:18]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:26][N:27]=3)[CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNC[C@H]2C)cn1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C)cn1
Yield: 18.2 %

Procedure:
(R)-2-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (150 mg, 0.63 mmol), 1-benzyl-4-chloro-phthalazine (161.75 mg, 0.635 mmol) are added into a microwave vial followed by NMP (3.3 mL) and triethylamine (0.265 mL, 1.91 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (40-100% EtOAc in heptane). Desired product is then washed with water and lyophilized to afford the title compound (52 mg, 18% yield).
Reaction SMILES: O[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.CC1C=CC=C(C)N=1.[F:28][C:29]([F:42])([F:41])[S:30]([O:33]S(C(F)(F)F)(=O)=O)(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:28][C:29]([F:42])([F:41])[S:30]([O:33][C:3]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:2]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c3ccccc3c3ccccc3c2c1
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(Oc1cccc2c3ccccc3c3ccccc3c12)C(F)(F)F
Temperature: -78 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
Under an argon atmosphere, 12.5 g of 2-hydroxytriphenylene and 0.93 g of 4-dimethylaminopiridine were placed in a flask, 200 mL of methylene chloride was added thereto and the reaction solution was cooled to −78° C. 8.22 g of 2,6-dimethylpiridine was added to the reaction solution and then, 17.3 g of trifluoromethanesulfonic acid anhydride was dropwise added thereto. The reaction solution was stirred for 5 hours while increasing temperature of the reaction solution to room temperature. The deposited solid was collected by filtration, washed with water and methanol and then dried to obtain 17.3 g (yield: 90%) of triphenylenyl trifluoromethanesulfonate.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC1.[C-]#N.[K+]>>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: OCC1CC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 1.5 h

Procedure:
A mixture of 12 g (31 mmol) of ethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 60 ml (750 mmol) of hydroxymethyl-cyclopropane and 500 mg of powdered potassium cyanide is stirred at 135° for 1.5 hours, the alcohol being simultaneously distilled off over a Hickmann headpiece and a 15 cm Vigreux column. The mixture is evaporated to dryness, the residue is taken up in chloroform, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 135°-136°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[NH:21][CH:20]=3)[CH:16]=[C:15]([Cl:30])[N:14]=2)[CH2:8][CH2:7]1)=[O:4].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C=O)C>[Cl:30][C:15]1[N:14]=[C:13]([NH:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:7][CH2:8]2)[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][CH:20]=2)[CH:16]=1
Reactant: NC1CCCCC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)CCl)CC4)c3)c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)CNC5CCCCC5)CC4)c3)c2c1

Procedure:
A mixture of Example 251a (50.0 mg, 0.112 mmol), cyclohexanamine (0.038 mL, 0.335 mmol) and triethylamine (0.054 mL, 0.39 mmol) in DMF (1.0 mL) was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated and purified by reverse-phase HPLC as described in Example 56 to give the title compound (44.6 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.20-1.53 (m, 9H), 1.72 (m, 1H), 1.83-1.95 (m, 2H), 1.98-2.25 (m, 6H), 3.07 (m, 1H), 3.67-3.84 (m, 4H), 3.96 (s, 3H), 6.80 (d, J=1.53 Hz, 1H), 6.89 (d, J=1.22 Hz, 1H), 7.87-7.94 (m, 2H), 8.08 (d, J=2.44 Hz, 1H). MS (DCI+) m/z 511.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[K+]>CCO.O>[CH2:1]([CH:5]([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 8.34 g (38.6 mmol) of diethyl isobutylmalonate in 35 mL of 95% EtOH was added a solution of 9.0 g (161 mmol) of KOH in 110 mL of 95% EtOH. The mixture was stirred at 25° C. for 16 hours and then at reflux for 1 hour. The mixture was cooled, diluted with water and extracted with CH3Cl. The aqueous layer was cooled to 0° C. and acidified to pH<1 with 30 mL of concentrated HCl, then it was extracted with CHCl3. The aqueous layer was further continuously extracted with CHCl3 overnight. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford 5.44 g (33.9 mmol, 88%) of isobutylmalonic acid as a solid which was essentially pure according to 1H NMR and which was used without further purification. Characteristic analytical data are as follows: mp 108°-110° C.; 1H NMR (300 MHz, CDCl3) δ3.52 (t, J=8 Hz, 1H), 1.84 (t, J=8 Hz, 2H), 1.66 (m, 1H), 0.94 (d, J-7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ175.6 (C=O), 49.7 (CH), 37.1 (CH2), 25.7 (CH), 21.7 (CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=O.[Na+].[ClH:26]>O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:26])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cl
Reactant: Nc1ccc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cnc(-n2ncc3cc(Cl)ccc32)c(Cl)c1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-aminoindazole [Compound No. 7] (3.0 g) in conc. hydrochloric acid (30 g), the solution of sodium nitrite (0.6 g) in water (1 ml) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature. After 30 minutes, cuprous chloride (CuCl) (3 g) was added thereto, and the resultant mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-chloroindazole (2.0 g).
Reaction SMILES: [CH2:1]([CH:3]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:4](Cl)=[O:5])[CH3:2].S(Cl)(Cl)=O.[NH2:15][C:16]([NH2:18])=[O:17]>C(#N)C>[CH2:1]([CH:3]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:4]([NH:15][C:16]([NH2:18])=[O:17])=[O:5])[CH3:2]
Reactant: CCC(C)C(CC)C(=O)Cl
Reactant: NC(N)=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCC(C)C(CC)C(=O)NC(N)=O

Procedure:
2-Ethyl-3-methyl-pentanoylchloride (0.057 mol), was prepared using thionylchloride according to a published method [24], and dissolved in dry acetonitrile (50 ml). The 2-ethyl-3-methyl-pentanoylchloride solution was slowly added to a boiling solution of urea (0.14 moles) in dry acetonitrile (100 ml) and was allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in 100 ml ethyl acetate and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The product was purified by crystallization from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(CC(=O)O)on1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)on1

Procedure:
Following General Procedure BI above, and using (3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][OH:24])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[C:25]1([CH2:31]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[O:3]1[C:7]2([CH2:8][CH2:9][CH:10]([C:13]3[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][O:24][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[O:6][CH2:5][CH2:4]1
Reactant: BrCc1ccccc1
Reactant: OCc1cccc(C(F)(F)F)c1C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(COCc2ccccc2)c1C1CCC2(CC1)OCCO2

Procedure:
A suspension of 3.3 grams (0.084 mole) of sodium hydride (60% in mineral oil) in 20 mL of toluene is stirred, and a solution of 24.3 grams (0.080 mole) of [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methanol in 65 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about one hour. After this time a solution of 13.7 grams (0.080 mole) of phenylmethyl bromide in 45 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux where it is stirred for about 4 hours. The reaction mixture is then cooled and shaken with water. The organic layer is separated and dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:6][CH:7]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Fc1ccc(I)cn1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Fc1ccc(C23CCCN2CCC3)cn1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 40.4 %

Procedure:
2-Fluoro-5-iodopyridine (200 μL, 0.90 mmol) was dissolved in Et2O and cooled to -78° C. A solution of 2.5M t-BuLi (1.2 mL, 1.98 mmol) in pentane was added, and the reaction was stirred for 2 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (375 mg, 1.80 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes at -78° C. then allowed to warm to -20° C. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2 Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (75 mg, 40%). 1H NMR (CDCl3, 300 MHz) δ1.58-1.73 (m, 2H), 1.79-2.05 (m, 6H), 2.64-2.73 (m, 2H), 3.12-3.19 (m, 2H), 6.82 (dd, J=8.4, 2.7 Hz, 1H), 7.90 (m, 1H), 8.30 (dd, J=1.4, 0.7 Hz, 1H); MS (CI/NH3) m/z: 207 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[CH:5]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Sodium hydride (2.13 g, 53.3 mmol, 60% dispersion in mineral oil) was added to 3-bromo-1H-pyrrolo[2,3-b]pyridine (7.5 g, 38.1 mmol) in DMF (190 mL) at 0° C. This mixture was stirred at 0° C. for 30 minutes, and benzene sulfonyl chloride (7.40 g, 41.87 mmol) was then added by syringe. After 30 minutes at 0° C., TLC indicated most of the starting material had been consumed. Benzene sulfonyl chloride (0.5 mL) was added, and the mixture was stirred for another 15 minutes at 0° C. The mixture was then quenched with saturated ammonium chloride solution (100 mL) followed by water (200 mL). A precipitate had formed. The solids were collected by filtration and dried under high vacuum for 16 hours to give 3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.2 g, 87%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.46-8.49 (m, 1H), 8.19-8.22 (m, 2H), 7.79-7.83 (m, 2H), 7.57-7.62 (m, 1H), 7.47-7.53 (m, 2H), 7.25-7.29 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5](=[N:16][OH:17])[O:7][CH3:8]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=NO)c1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate (5.0 g, 25.9 mmol), hydroxylamine hydrochloride (8.55 g, 133 mmol), and sodium acetate (10.25 g, 125 mmol) in ethanol/water (200 mL, 1/1). Heat to 50° C. After 1 hour, pour the reaction mixture onto ice to give a solid. Collect the solid by filtration to give methyl 2-methoxy-5-formylbenzoate oxime: Rf =0.76 (silica gel, 9/1 dichloromethane/methanol).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.[I:20]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:20][CH2:11][C:10]1([CH3:12])[O:1][CH2:2][C@@H:3]2[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][N:8]2[CH2:9]1
Reactant: C=C(C)CN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2CC(C)(CI)OC[C@@H]2C1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a round bottom flask charged with (S)-tert-butyl 3-(hydroxymethyl)-4-(2-methylallyl)piperazine-1-carboxylate (0.1 g, 0.370 mmol) in acetonitrile (3.70 ml) was added N-iodosuccinimide (0.125 g, 0.555 mmol) and potassium carbonate (0.077 g, 0.555 mmol). The reaction mixture was stirred at rt ON. The reaction mixture was quenched with 20% sodium thiosulfate solution and stirred 30 min. The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (9aS)-tert-butyl 3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.156 g) was isolated as a yellow oil. Material used crude in subsequent chemistry.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(Nc2ncc(Br)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Yield: 41.7 %

Procedure:
5,8-dibromoimidazo[1,2-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CHCl3 (3×40 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10%-20% DCM/MeOH to afford the title compound as a pale yellow solid (200 mg, 0.43 mmol).