Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH3:27])[O:16][C@@H:11]([O:12]CC=C)[C@@H:10]1[O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C1COCC1.C1COCC1.O>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH3:27])[O:16][C@@H:11]([OH:12])[C@@H:10]1[O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](C)O[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
1,5-Cyclooctadiene-bis(methyldiphenylphosphine)iridium hexafluorophosphate (25 mg, 20 μmol) was dissolved THF and the resulting red solution was degassed in an argon stream. Hydrogen was then bubbled through the solution, causing the colour to change to yellow. The solution was then degassed again in an argon stream. A solution of 210(1.4 g, 3.12 mmol) in THF was degassed and added. The mixture was stirred at rt overnight, then concentrated to dryness. The residue was dissolved in a solution of I2 (1.37 g, 5.4 mmol) in 30 mL of THF/H2O (15:4). The mixture was stirred at rt for 1 h, and THF was evaporated. The resulting suspension was taken up in DCM, washed twice with water, satd aq NaHSO3, water, satd aq NaHCO3, water and said aq NaCl, successively. The organic layer was dried and concentrated. The residue was eluted from a column of silica gel with 7:3 to 6:4 Cyclohexane-EtOAc to give the corresponding hemiacetal 211 (1.3 g, 93%). 1H NMR: δ 7.40-7.30 (m, 10H, Ph), 5.40 (dq, 1H, J1,2=1.8, J2,3=3.4 Hz, H-2), 4.93 (d, 1H, J=10.8 Hz, CH2Ph), 4.78 (d, 1H, J1,2=16 Hz, H-1), 4.78 (d, 1H, J=11.2 Hz, CH2Ph), 4.63 (d, 1H, CH2Ph), 4.51 (d, 1H, CH2Ph), 3.99 (m, 1H, J3,4=9.5 Hz, H-3), 3.78 (dq, 1H, J4,5=9.5, J5,6=6.2 Hz, H-5), 3.43 (pt, 1H, H-4), 2.80 (m, 4H, Lev), 2.19 (s, 3H, Ac), 1.37 (d, 3H, H-6). Anal. Calcd for C28H34O7: C, 67.86; H, 6.83. Found: C. 67.94; H, 6.87.
Reaction SMILES: C(OO)(=O)C.[Cl:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.ClCCCC1C=C[N+:23]([O-])=[CH:22]C=1.COS([O-])(=O)=O.ClCCCC1C=C[N+](OC)=CC=1.[C-]#N.[K+]>S(OC)(OC)(=O)=O.O.[OH-].[Na+]>[Cl:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:22]#[N:23])[CH:11]=1
Reactant: ClCCCc1ccncc1
Reactant: [O-][n+]1ccc(CCCCl)cc1
Agent: CC(=O)OO
Agent: COS(=O)(=O)[O-]
Agent: CO[n+]1ccc(CCCCl)cc1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: N#Cc1cc(CCCCl)ccn1
Temperature: 0 °C

Procedure:
Peracetic acid (40%, 5.0 ml) is added to 4-(3-chloropropyl)pyridine (5.18 g) at such a rate as to keep the reaction temperature at 80°. The mixture is stirred until the temperature falls to 30°. Excess peracid is destroyed with sodium sulfite solution and the solvent is vacuum distilled. The residue is redissolved in methylene chloride (50 ml), filtered and evaporated to yield and crude 4-(3-chloropropyl)-pyridine-N-oxide which is heated to 80° in dimethyl sulfate (4.66 g) for 2 hours. The resulting 4-(3-chloropropyl)-1-methoxypyridinium methyl sulfate salt is dissolved in 10 ml of water, cooled to 0° and reacted with an ice-cold solution of potassium cyanide (6.7 g, 100 mmol) in 20 ml of 0.25N sodium hydroxide solution for 22 hours. The product is extracted with methylene chloride (3×30 ml) and dried over sodium sulfate. The solvent is evaporated and the residue filtered through 45 g of silica gel with ether to yield 4-(3-chloropropyl)-2-cyanopyridine; NMR (CDCl3) 3.56 (t, 2H), 7.40 (d, 1H), 7.57 (s, 1H), 8.60 (d, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([NH2:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:26][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])([CH3:25])[CH3:24])=[N:7][CH:6]=2)[CH:13]=1
Reactant: CC(C)(N)c1ccccc1F
Reactant: Fc1ccc(Br)cc1-c1cnc(Br)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(Nc1ncc(-c2cc(Br)ccc2F)nn1)c1ccccc1F
Yield: 67.6 %

Procedure:
3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine (2.8 g, 8.4 mmol), 2-(2-fluorophenyl)propan-2-amine (2.0 g, 12.6 mmol), K2CO3 (2.3 g, 16.8 mmol) and CH3CN (20 mL) was heated to 90° C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford a yellow solid (2.3 g), m/z=406.1 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@](C(C)(C)C)=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[NH2:12][C@@H:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1)[CH2:2][NH:1][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.297 mmol) was dissolved in DCM (988 μl), followed by pyridine (71.9 μl, 0.890 mmol) and acetic anhydride (28.0 μl, 0.297 mmol). The reaction mixture was stirred at room temperature for 1 h, extracted by EtOAc, washed by water and brine, dried over Na2SO4and concentrated. The residue was dissolved in Et2O (1 mL), then HCl (4 M in dioxane) (148 μl, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the solvent was decant out, the residue solid was used in next step reaction without purification. LCMS (m/z): 275.1/277.1 (MH+), 0.41 min.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:42])([F:43])[F:44])[CH:35]=1)[CH3:33]
Reactant: CCN(C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 56 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d, 1H), 9.26 (s, 1H), 9.00 (d, 1H), 8.54 (s, 1H), 8.37 (d, 1H), 8.16 (d, 1H), 7.92 (dd, 1H), 7.82 (ddd, 1H), 7.44 (dd, 1H), 5.51 (m, 1H), 3.17 (dd, 1H), 2.99 (dd, 1H), 2.62-2.52 (q, 2H), 0.97 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
6-Amino-9-benzyl-2-ethoxypurine (143 mg, 0.53 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated and dried on sodium sulfate, filtered and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (42 mg, yield 23%).
Reaction SMILES: [I-].[K+].[C:3]([CH:5]1[CH2:14][N:13]([CH3:15])[C:12]2[N:11]=[C:10]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:9]3=[CH:8][C:7]=2[C:6]1=[O:22])#[N:4].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[C:3]([C:5]1[C:6](=[O:22])[C:7]2[CH:8]=[C:9]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:10]3=[N:11][C:12]=2[N:13]([CH3:15])[CH:14]=1)#[N:4]
Reactant: CN1CC(C#N)C(=O)c2cc3cc(F)c(F)cc3nc21
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [I-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C#N)c(=O)c2cc3cc(F)c(F)cc3nc21
Temperature: 77 °C
Yield: 93.7 %

Procedure:
A solution of 0.47 g of potassium iodide in 5 cm3 of water is added with stirring at approximately 20° C. to a suspension of 8.6 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine in 350 cm3 of ethanol. The suspension is heated to 77° C., and 4 cm3 of 33% by weight hydrogen peroxide are added in the course of 10 minutes at this temperature. The reaction mixture is kept refluxing for a further 30 minutes and is then cooled to approximately 20° C. 10 cm3 of 1N sodium thiosulphate solution are added in the course of 5 minutes at this temperature. The precipitate obtained is drained at approximately 20° C. and washed with twice 20 cm3 of water. The wet product obtained is dried under reduced pressure (20 kPa) at approximately 50° C. 8 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b]-[1,8]naphthyridine are obtained in the form of a light yellow solid, melting point 380° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]cc(Br)cc1OCc1ccccc1
Temperature: 60 °C
Yield: 38.7 %

Procedure:
To a solution of 4.4 g (23.2 mmol) 5-bromo-3-hydroxy-1H-pyridin-2-one and 1.2 g (30 mmol) NaOH in 116 mL MeOH was added benzyl bromide dropwise at room temperature. The resulting mixture was heated to 60° C. overnight. After cooling, the volatiles were removed in vacuo, 20 mL water and 40 mL EtOAc were added, and the aqueous phase was extracted 2× with 20 mL EtOAc. The combined organics were dried over Na2SO4 and evaporated. Purification by automated flash chromatography (80 g silica gel cartridge 0-100% EtAOc/hex over 30 min) afforded 2.51 g (38.7%) 3-benzyloxy-5-bromo-1H-pyridin-2-one. LCMS [M+H]+=280.1
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[NH:19]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[S:7][C:8]4[C:13]([S:14](=[O:18])(=[O:17])[C:15]=3[CH:16]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[N:2][N:21]=[N:20]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1S2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2Sc2ccc(-c3nnn[nH]3)cc21

Procedure:
3-Cyanothianthrene-5,5-dioxide (0.55 g), sodium azide (0.36 g), ammonium cloride (0.30 g) and dimethylformamide (15 ml) were heated together at 130°-135° C. for 3 hr. The mixture was cooled, poured into dilute hydrochloric acid, and the oily precipitated product extracted into chloroform and washed with water. On standing, 3-(5-tetrazolyl)thianthrene-5,5-dioxide crystallised out, m.p. 233° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([OH:36])=O)[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C1C=CC2N(O)N=[N:50]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C=O)C.O.CCN(CC)CC>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([NH2:50])=[O:36])[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Reaction time: 2 h
Yield: 90.8 %

Procedure:
5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (200 mg, 0.33 mmol), HOBT (50 mg, 0.37 mmol) and EDCI (140 mg, 0.73 mmol) were dissolved in dry DMF (5 mL). The resulting solution was stirred for 2 hours. And then NH4Cl (100 mg, 1.87 mmol) and Et3N (0.5 mL) were added to the mixture. The mixture was stirred at room temperature overnight. Then H2O was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (dichloromethane:MeOH=40:1) to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.98˜8.03 (m, 2H), 7.69 (s, 1H), 7.48˜7.54 (m, 2H), 7.19˜7.24 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 6.83˜6.88 (m, 1H), 6.01 (s, 2H), 5.70˜5.86 (m, 2H), 3.39 (s, 3H), 2.74 (s, 3H). MS (M+H)+: 601.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:24][Mg]Cl>O1CCOCC1>[CH3:1][C:2]([C@@H:3]1[C@@:20]2([CH3:21])[CH2:19][CH2:18][C@@H:17]3[C@@:15]4([CH3:16])[CH2:14][CH2:13][C@:12]([OH:22])([CH3:24])[CH2:11][C@@H:10]4[CH2:9][CH2:8][C@H:7]3[C@@H:6]2[CH2:5][CH2:4]1)=[O:23]
Reactant: C[Mg]Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
5α-Pregnane 3,20-dione (10 g) is reacted with a reagent obtained by reacting FeCl3 (5.2 g) and MeMgCl (4 equiv, based on FeCl3) in dioxane (anhydrous, 200 mL) at −25° C. for 5 h. The reaction is quenched with acetic acid (32 ml). The reaction mixture is concentrated in vacuo and the residue is stirred with 3N HCl for 6 h. The solid is collected by filtration, washed with water and dried at 50° C. under vacuum to obtain crude ganaxolone. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is added with water (45 mL) to obtain a suspension, which is collected by filtration, washed with water and dried. The dried product is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h. The suspension is cooled to 0° C. and filtered, washed with cold ethyl acetate. The ethyl acetate slurry step is repeated one more time to obtain purified ganaxolone.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[O:4][N:3]=1.Cl.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C@H:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[NH2:31])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:31][C@H:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:33])([F:17])[F:32])=[CH:24][N:23]=2)=[O:11])[O:4][N:3]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1

Procedure:
A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 57.4 mg, 0.28 mmol), (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol), HATU (146 mg, 0.38 mmol) and triethylamine (107 μl, 0.77 mmol) in dry DMF (852 μl) was stirred at room temperature for 72 hours. The reaction was diluted with DMSO and filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:28].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]I.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:26]=[C:27](/[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)\[CH3:28])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccncc1
Temperature: 90 °C

Procedure:
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (117 mg, 0.5 mmol) and potassium phosphate tribasic (212 mg, 1 mmol) in DMF was purged with nitrogen and heated at 90° C. 4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol) in DMF were charged in a separate flask. This mixture was purged with nitrogen and heated at 90° C. for 5 min. Both reaction mixtures were combined and heated at 90° C. overnight. The reaction mixture was poured into water to obtain a precipitate. The precipitate was filtered and purified with silica column chromatography (100-200 mesh) by neutralizing the silica gel with 2-3 drops of aq. NH3 and using 0-2% MeOH:DCM as eluant. Compound was further purified by reverse phase HPLC to obtain the product. 1HNMR (CD3OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 7.70 (d, 1H), 7.58 (d, 1H), 7.20 (s, 2H), 3.70 (m, 2H), 3.40 (m, 2H), 3.30 (m, 4H), 3.05 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[OH-].[Na+]>C(O)C.O>[NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])(=[O:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(O)CN)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
0.5 g of ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is dissolved in 5 ml of ethanol and this solution is added to a solution of 0.14 g of sodium hydroxide in 2 ml of water. This mixture is then heated to 60° for a period of 3 hours, cooled to room temperature and the solvent evaporated under reduced pressure. The oily residue is passed downan Ion Exchange Resin (DOWEX® 50W-X8 H+) using de-ionised water aseluant. Ninhydrin-positive fractions are combined and evaporated to give 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinic acid, m.p. 214°-215° (dec.), 31P-NMR : δ=+30.9 ppm (D2O).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:21]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>CO.ClCCl>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[C:31]2[CH2:32][CH2:33][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH:30]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: C1=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CCN(Cc2ccccc2)C1

Procedure:
A slurry of 5-benzyloxyindole (6.85 g, 30.7 mmol) in methanol (50 mL) was added to a 25 wgt % solution of sodium methoxide in methanol (115 mL) at 5° C. under argon. 1-Benzyl-4-piperidone (5.8 g, 30.7 mmol) was added in one portion and the suspension heated at reflux for 16 h, cooled and diluted with a mixture of dichloromethane (100 mL) and methanol (150 mL). The solution was acidified to pH 5 with glacial acetic acid, concentrated to 100 mL, diluted with water (750 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and dried (Na2SO4). Filtration and concentration in vacuo gave the title compound as a yellowrange solid (10.6 g, 87%). MS(ES) m/e 395.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:25][CH:26]([CH3:41])[CH2:27][CH2:28][CH2:29][N:30]3C(=O)C4=CC=CC=C4C3=O)[CH:8]=[C:9]([O:23][CH3:24])[C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=[CH:4][CH:3]=1.O.NN.[C:45]([OH:52])(=[O:51])[CH2:46][CH2:47][C:48]([OH:50])=[O:49].CO>C(O)C.CCOCC>[C:45]([OH:52])(=[O:51])[CH2:46][CH2:47][C:48]([OH:50])=[O:49].[NH2:30][CH2:29][CH2:28][CH2:27][CH:26]([NH:25][C:7]1[CH:8]=[C:9]([O:23][CH3:24])[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[CH3:1])[CH3:41]
Reactant: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: NN
Agent: O=C(O)CCC(=O)O
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(NC(C)CCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A solution of the phthalimide VIII (4.9 g, 8.7 mmol) in ethanol (110 mL) containing hydrazine hydrate (75%, 1.48 mL) was heated at reflux for 6 hours. The ethanol was removed under reduced pressure and the residue was shaken with ether and 10% aqueous potassium hydroxide. The ether layer was washed with water (×2) and dried (K2CO3). To the dried ether solution of 1 as the free base, was added a solution of succinic acid (1.03 g, 1 mol equiv) in ether (100 mL) containing methanol (4 mL) to solubilize the succinic acid. After standing overnight, the solid was filtered to yield 4.5 g (94%) of the target compound (1), mp 102°-103° (eff).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc2occc2c1
Yield: 17.7 %

Procedure:
A suspension of 2,3-dihydrobenzofuran-5-sulfonamide (19.9 g, 100 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (56.7 g, 250 mmol) in dioxane (500 ml) was heated at reflux under nitrogen for 111 hours. The reaction mixture was reduced in volume by evaporation under vacuum and purified by silica gel flash chromatography (EtOAc/hexanes) to provide benzofuran-5-sulfonamide (3.5 g, 18% ) . This was combined with another lot of benzofuran-5-sulfonamide (1.0 g), slurried in ether, collected and vacuum dried at 45° C. overnight to give 4.5 g of benzofuran-5-sulfonamide.