Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH2:11])=[CH:2]1.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.C(N(C(C)C)C(C)C)C>CCO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:13]2[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)=[CH:2]1
Reactant: NCc1c[nH]c2ncccc12
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of (1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (intermediate A) (442 mg, 3.0 mmol), 3,5-dibromopyrazin-2-amine (758 mg, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (1160 mg, 9.0 mmol) in EtOH (70 mL) was stirred at 150° C. overnight. After being cooled to room temperature, it was concentrated and purified by chromatography to afford the title compound (70 mg) MS (m/z): 319 (M+1)+.
Reaction SMILES: [C:1](O)(=[O:13])[C@:2]1([CH2:12][CH2:11][C@@H:7]([C:8](O)=[O:9])[C:4]1([CH3:6])[CH3:5])[CH3:3]>C1COCC1.CCOCC>[OH:13][CH2:1][C:2]1([CH3:3])[CH2:12][CH2:11][CH:7]([CH2:8][OH:9])[C:4]1([CH3:6])[CH3:5]
Reactant: CC1(C)[C@H](C(=O)O)CC[C@]1(C)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(CO)CCC(CO)C1(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of (1S,3R)-camphoric acid (1) (3.0 g, 14.8 mmol) in dry THF (40 mL) and dry Et2O (30 mL) was added LiALH4 (2.0 g, 52.6 mmol) and the reaction mixture was refluxed for 5 hours. The reaction was then quenched by the addition of Na2SO4.10H2O (8.5 g) and the mixture stirred for 0.5 hour. H2O (100 mL) was added and the aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvents concentrated in vacuo to a residue which was purified over silica (n-hexane/EtOAc, 6:4) to afford 2.39 g (95% yield) of the desired intermediate (2) as crystals which were characterized as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[OH:11].[CH2:13](OB(C=C)OCCCC)[CH2:14]CC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]=[CH2:14])=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C=CB(OCCCC)OCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OC)c(O)c1

Procedure:
A solution of 2-hydroxy-4-iodo-benzoic acid methyl ester (8.01 g, 0.0288 mol) in THF (184 ml) and H2O (46 ml) is treated with vinyl-boronic acid di-butyl ester (9.53 ml, 0.0432 mol, 1.5 eq.), NaCO3 (21.37 g, 0.201 mol, 7 eq.), and dichloro-bis(triphenyl-phosphine)palladium (1.01 g, 1.44 mmol, 5 mol %). The solution is purged with N2 (g) for 5 minutes and then heated to reflux for 2 hour. The reaction is concentrated in vacuo, diluted with EtOAc, and sequentially washed with H2O and saturated aqueous NaCl. The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (5% ethyl acetate in hexanes) to afford 2-hydroxy-4-vinyl-benzoic acid methyl ester: ESMS m/z 179.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.N([O-])=O.[Na+].C(O)(=O)C.[S:20](=[O:23])(O)[OH:21].[ClH:24]>C(O)(C(F)(F)F)=O.O.Cl[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:20]([Cl:24])(=[O:23])=[O:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cl
Reactant: O=S(O)O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-Chloro-2-nitro-phenylamine (2.0 g, 11.6 mmol) (Aldrich) in TFA (30 mL) and conc. hydrochloric acid (3 mL) was cooled to −5° C., then a solution of NaNO2 in water (5 mL) was dropped into at such a rate that the temperature did not above 5° C. When the addition was complete, the mixture was stirred at 0° C. for additional 5 min, then poured into a mixture of acetic acid (40 mL), sulfurous acid (40 mL), CuCl2 (824 mg, 6.1 mmol) and CuCl (50 mg, 0.5 mmol), which was cooled to 0° C. in advance. The whole was stirred at room temperature for 40 min, diluted with water (100 mL), filtered. The filter cake was washed with water, dried in vacuo to give 1.5 g 4-Chloro-2-nitro-benzenesulfonyl chloride. MS: [M+H]+=256
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>CN(C=O)C>[C:25]([O:28][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1)(=[O:27])[CH3:26]
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (159 mg, 0.5 mmol) in DMF (2 mL) was treated with sodium acetate (104 mg, 1.2 mmol). The mixture was heated at 100° C. for 2 h, than it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was crystallized from EtOAc-hexane to give the title compound as colorless needles (95 mg); mp 144-147° C.; 1H NMR (CDCl3) 7.37 (s 1H), 7.33 (s, 1H), 7.19-7.24 (m, 2H), 6.97 (d, J=8.5, 1H), 6.15 (s, 2H), 6.07 (s, 2H), 5.41 (s, 2H), 2.24 (s, 3H). Anal. calcd. for C19H14N2O6: C, 62.30; H, 3.85; N, 7.65. Found: C, 62.12; H, 3.92; N, 7.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:62][CH2:63][C:64]5[CH:65]=[CH:66][C:67]6[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=6[CH:75]=5)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylic acid (10 mg, 0.023 mmol), HATU (13 mg, 0.035 mmol) and Et3N (0.02 mL, 0.11 mmol) in DMF (5 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (10 mg, 0.046 mmol). The mixture was stirred at rt overnight. EA (40 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)indolizine-8-carboxamide (4.8 mg; yield 34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (t, J=6.0 Hz, 1H), 9.04 (s, 1H), 8.55 (s, 1H), 7.84 (s, 1H), 7.66-7.68 (m, 3H), 7.46 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.28-7.30 (m, 2H), 7.05-7.12 (m, 2H), 4.54-4.63 (m, 4H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=615.7 (M+1, ESI+).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[C:2]([CH3:4])([CH3:3])[CH2:1][O:19]2)=[CH:8][CH:7]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Reactant: C=C(C)C
Product: CC1(C)COC1(Cn1cncn1)c1ccc(F)cc1
Yield: 2 %

Procedure:
Following a procedure similar to that described in Example 39, but using 2-methylpropene and 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone, the title compound, melting at 110° C., was obtained in a 2% yield.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl.[C:37]1([CH2:43][O:44][NH2:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:45][O:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (283 mg, 0.72 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.20 mL, 1.88 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (173 mg, 1.08 mmol), EDC (167 mg, 0.87 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (99 mg, 0.72 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (140 mg, 39% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([S:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:17])[CH3:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=1[S:18][C:15](=[O:17])[CH3:16])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Sc1c(C)cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Solvent: ClCCl
Product: CC(=O)Sc1c(C)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Temperature: 0 °C

Procedure:
N-Cyclopentylglycine t-butyl ester (8.3 g, 0.042 mole) and 2-acetylthio-3-methylbenzoic acid (8.9 g, 0.042 mole) were combined in 90 ml CH2Cl2. This solution was cooled to 0° C. before adding to it a solution of N,N-dicyclohexylcarbodiimide (8.6 g, 0.042 mole) in 30 ml CH2Cl2 dropwise over 15 minutes. The reaction was allowed to warm slowly to room temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[O:14]C(=O)[NH:16][C:11]=2[CH:10]=1.O>C(O)(=O)C>[C:2]1([NH:1][C:13](=[O:14])[C:12]2[C:11](=[CH:10][C:9]([F:8])=[CH:20][CH:19]=2)[NH2:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1

Procedure:
A solution of aniline (1.77 g) in acetic acid (50 ml) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (1 g) in acetic acid (100 ml) and the mixture heated at 100° for 20 minutes. It was then poured into water and the precipitate collected, dried and recrystallised from toluene to give N1 -phenyl-4-fluoroanthranilamide, m.p. 120°-122°. (Compound 4).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[CH3:15][O:16][C:17]([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:18].Cl>N1C=CC=CC=1>[CH2:1]([N:3]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:17]([O:16][CH3:15])=[O:18])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCNCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)OC
Reaction time: 1 h
Yield: 74.4 %

Procedure:
10 g of N-ethyl-tryptamine (i.e., 3-(2-ethylaminoethyl)-indole) were dissolved in 80 ml of pyridine, and 9.62 g of 4-methoxycarbonylbutyryl chloride were added dropwise thereto at 10° C. The mixture was stirred for one hour. After the reaction was completed, the mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and water, successively. The washed extract was dried and evaporated under reduced pressure to remove solvent. The oily residue thus obtained was recrystallized from a mixture of ethanol and petroleum ether. 12.5 g of N-ethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-ethyl-4-methoxycarbonylbutanamido)ethyl]-indole]were thereby obtained as yellow crystals. M.p. 73°-75° C. Yield: 74.4%
Reaction SMILES: C(O)C.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][C:14]#N)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[CH2:28](I)[CH:29](C)[CH3:30]>O>[CH2:14]([S:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2)[CH:29]([CH3:30])[CH3:28]
Reactant: N#CSc1ccc2c(c1)CCN2
Reactant: CC(C)CI
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: CC(C)CSc1ccc2c(c1)CCN2
Temperature: 50 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
An ethanol (14 mL) solution of indolin-5-yl thiocyanate (compound described in the document J. Med. Chem., 1998, vol. 41, p. 1598; 1.33 g, 7.55 mmol) was added to a solution of sodium sulfide nonahydrate (1.84 g, 7.66 mmol) in water (2.8 mL), and the mixture was stirred at 50° C. for 2 hours. To the reaction solution, an ethanol (2.4 mL) solution of isobutyl iodide (1.2 mL, 10.4 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. To the reaction solution, water was added, followed by extraction with ether three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-80:20-55:45, V/V) to obtain the title compound as brown oil (0.65 g, yield: 41%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[CH2:16]1>C(Cl)Cl.O>[CH3:1][S:2]([O:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[CH2:16]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC(CO)C2(CC2)N1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.40 g, 1.0 mmol) and triethylamine (0.22 mL, 1.6 mmol) were added to a solution of 7-(hydroxymethyl)-4-azaspiro[2.4]heptan-5-one (0.11 g, 0.78 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL×3). The organic layers were combined and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (neat ethyl acetate, Rf=0.6) to afford (5-oxo-4-azaspiro[2.4]hept-7-yl)methyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 5.87 (br s, 1H), 4.35-4.01 (m, 2H), 2.95 (s, 3H), 2.87-2.54 (m, 2H), 2.41-2.35 (m, 1H), 1.05-0.72 (m, 4H).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)CCN(C)C.[Li]CCCC.[I:27]I>C1COCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:27])=[O:6]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to −78° C. While maintaining the temperature between −78° C. and −65° C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to −10° C. for 2 h, and then cooled back down to −78° C. Iodine (6.73 g, 26.5 mmol) dissolved in dry THF (20 mL) was added slowly. After stirring for 2 h at −78° C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1H NMR (DMSO-d6 300 MHz) δ 9.24 (s, 1 H), 8.35 (s, 1 H), 8.04 (d, 1 H), 7.95 (d, 1 H), 1.26 (s, 9 H). MS (ES+)=305.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([NH:20][CH2:21][CH2:22][OH:23])[N:13]=1)[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27].[CH3:30][NH2:31]>C(O)(C)C>[Cl:1][C:2]1[C:3]([NH:31][CH3:30])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([NH:20][CH2:21][CH2:22][OH:23])[N:13]=1)[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27]
Reactant: O=C(O)c1cn(-c2nc(NCCO)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN
Solvent: CC(C)O
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(NCCO)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
8-Chloro-6,7-difluoro-1-[3,5-difluoro-6-(2-hydroxyethylamino)pyridin-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (250 mg) and an aqueous solution (about 40%; 3 g) of methylamine were added to isopropyl alcohol (4 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (175 mg) as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1([CH3:51])[O:48][C@@H:47]([CH2:49]O)[CH2:46][O:45]1.C1(C)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1COCC1>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16](=[O:17])[C:4]4[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:49][C@H:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[CH:21][C:5]=4[C:6]([CH3:20])([CH3:19])[C:7]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CC1(C)c2cc(O)c(Br)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Under nitrogen atmosphere, 9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-4, 76 mg, 0.2 mmol) and triphenylphosphine (69 mg, 1.3 eq.) were added with THF (2 ml), and ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (35 mg, 1.3 eq.) and 2.19 N toluene solution (118 μL, 1.3 eq.) of diethyl azodicarboxylic acid were added dropwise thereto, followed by stirring at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to give a solid, which was then washed with dichloromethane to obtain the title compound (brown powder, 53 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:16])/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>C1COCC1.CCOCC>[Si:17]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][O:16][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Reactant: CCCCCCCCCC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC/C=C\COCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with 60 mg of a 60% dispersion of NaH in oil. The dispersion was washed with three 2-mL portions of THF. The NaH was suspended in 5 mL of THF and cooled to 0° C. A solution Of cis-2-tridecen-1-ol (206 mg, 1.1 mmol, 1.1 equiv) in THF (1 mL) was slowly added to the mixture. After 25 minutes the cold bath was removed and stirring was continued for an additional 10 minutes. At this time a solution of (40) (361 mg, 1 mmol) in THF (1 mL) was added and stirring was continued for 12 hours. The mixture was poured into water (20 mL) and ether (25 mL). The organic layer was separated and washed with three 10-mL portions of water. The ether extract was dried (MgSO4) filtered and concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (95:05 petroleum ether/EtOAc) afforded 341 mg (85%) of the coupled produced (41) as a clear colorless oil: Rf 0.80 (9:1 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.20 (s, 4 H), 5.61 (m, 2H), 4.76 (s, 2H), 4.52 (s, 2H), 4.08 (d, J=4.8 Hz, 2H), 2.05 (m, 2H), 1.29 (m, 16 H), 0.97 (s, 9 H), 0.91 (t, J=6.9 Hz, 3 H), 0.12 (s, 6 H); 13C NMR (CDCl3) δ 140.76, 137.04, 127.71, 126.04, 125.98, 71.86, 65.58, 64.80, 31.92, 29.62, 29.56, 29.52, 29.24, 29.36, 27.61, 25.94, 22.69, 18.57, 14.12, -5.25. ##STR8##
Reaction SMILES: FC(F)(F)C(O)=O.Cl.C(O[C:12]([C:14]1[N:15]([NH2:24])[CH:16]=[CH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:13])C.[CH2:25]([N:27](CC)CC)[CH3:26]>CC#N>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[CH:16][N:15]2[C:14]=1[C:12](=[O:13])[NH:27][C:25]([CH3:26])=[N:24]2)=[O:20])[CH3:23]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccn(N)c1C(=O)OCC
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccn2nc(C)[nH]c(=O)c12
Temperature: 85 °C
Yield: 54 %

Procedure:
Trifluoroacetic acid (0.45 ml, 5.85 mmol) was added to a solution of 1-amino-1H-pyrrole-2,3-dicarboxylic acid diethyl ester, hydrochloride salt in CH3CN (20 ml) and heated to 85° C. for 12 h. The reaction mixture was concentrated in vacuo, diluted with CH3CN (20 ml), treated with triethylamine (1.36 ml, 11.9 mmol), and heated to 85° C. for 6 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and the organic layer washed with 1 N HCl (1×50 ml), saturated NaHCO3 (3×50 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a solid (0.20 g, 54%): 1H NMR (CDCl3) δ 7.27–7.32 (m, 1H), 7.01–7.02 (m, 1H), 4.32–4.38 (m, 2H), 2.41 (s, 3H), 1.90 (br m, 1H), 1.35–1.40 (m, 3H); MS (ESI+) 222 (M++H).