Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:22]2(O)[CH2:25][O:24][CH2:23]2)=[CH:9][C:10]=1[F:21].C(N(S(F)(F)[F:34])CC)C>C(Cl)Cl>[F:21][C:10]1[C:11]2[O:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:6]=2[CH:7]=[C:8]([C:22]2([F:34])[CH2:25][O:24][CH2:23]2)[CH:9]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(O)COC3)cc(F)c1O2
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(F)COC3)cc(F)c1O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a RBF was added (S)-3-(2-amino-5′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)oxetan-3-ol (0.28 g, 0.75 mmol, prepared as described in Method CCl4) and DCM (5 mL). The resulting mixture was then cooled to 0° C. and (diethylamino)sulfur trifluoride (0.20 mL, 1.50 mmol, Alfa Aesar) was added drop wise. The mixture was then stirred at 0° C. for 15 min and at room temperature for 15 min. Then, the mixture was quenched with saturated sodium bicarbonate (5 mL). The mixture was stirred at 0° C. for 5 min and at RT for 5 min. Then, the organic layer was collected and the aqueous layer was extracted with DCM (1×10 mL). The combined organic extracts were dried over MgSO4 and silica gel was added. The solvent was removed and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 20-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 375 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)[O:3]1.[ClH:23]>ClCCl.C(O)(C)C>[Cl-:23].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[CH2:14][CH2:13][NH2+:12][CH2:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OB(C2=CC[NH2+]CC2)OC1(C)C
Product: [Cl-]

Procedure:
Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].CCCCCCCCCCCCCCCCCC(O)=O>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCC(=O)O

Procedure:
C16:0 56.9; C18:0 6.9;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([O:20]C(=O)C)[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([OH:20])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(=O)C(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1O

Procedure:
A solution of 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine (1 g, 2.9 mmol) and p-toluenesulfonic acid (0.28 g, 1.5 mmol) in-methanol (10 mL) is heated at reflux for 5 h. The solvent is removed in vacuo to give 4-nitro-2-(3-fluoro-5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which is further purified by column chromatography.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH2:11]([C:13]1[NH:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:11]([C:13]1[NH:17][C:16]([CH:9]=[O:10])=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1cc(C#N)c[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCc1cc(C#N)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
POCl3 (3.3 ml, 35.67 mmol) was added to 1,2-dichloroethane (4 ml), then anhydrous DMF (2.75 ml, 35.67 mmol) was added very slowly. The mixture was stirred at room temperature for ˜10 minutes. 5-Ethyl-1H-pyrrole-3-carbonitrile (Intermediate 30, 856 mg, 7.13 mmol) in 1,2-dichloroethane (2 ml) was added dropwise and the mixture was heated at 80° C. for ˜30 minutes. The mixture was cooled to room temperature and sodium acetate (2.5 g/5 ml) was added and the mixture was stirred for 1 h. The brown/black emulsion was extracted with DCM (4×50 ml). The combined organic phase was washed with water (2×50 ml) dried over Na2SO4 and concentrated in vacuo to give the title compound. (819 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16](=[O:19])([O-])[O-].[K+].[K+]>C(O)CCC>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]([CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:16][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=C([O-])[O-]
Reactant: Nc1ccccc1
Agent: [K+]
Solvent: CCCCO
Product: OCCCCCCN(CCCCCCO)c1ccccc1
Yield: 60 %

Procedure:
A mixture of 9.3 g (100 mmol) freshly distilled aniline, 30.0 g (220 mmol) 6-chloro-1-hexanol and 30.4 g (220 mmol) potassium carbonate were heated in 50 ml of n-butanol under reflux for 4 days. After cooling the solids were filtered of and the solvent is removed in vacuum. Purification by liquid chromatography (ethyl acetate/hexane 2:1) afforded 17.6 g (60%) of a colorless oil.1 H-NMR (400 MHz, CDCl3): δ=7.18 (m, 2H), 6.61 (m, 3H), 3.91 (t, J=6.4 Hz, 4H), 3.67 (t, J=6.4 Hz, 4H), 1.90–1.77 (m, 4H), 1.70–1.53 (m, 4H), 1.50–1.31 (m, 8H). 13C-NMR (100 MHz, CDCl3); 148.19, 129.31, 115.33, 111.86, 62.793, 51.06, 32.78, 27.30, 27.05, 25.76. EI-MS: 293 (M+), 206 (M+-C5H10OH), 120 (M+-2 C5H10OH). Calcd for C18H31NO2: C, 79.67; H, 10.65; N, 4.77; O, 10.90
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[NH:24][N:23]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[NH:24][N:23]=[C:22]([CH2:25][C:26](=[O:27])[NH2:28])[N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: NC(=O)Cc1n[nH]c(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: NC(=O)Cc1n[nH]c(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Yield: 58.4 %

Procedure:
7-ACA and 5-mercapto-1,2,4-triazol-3-ylacetamide were reacted as in example 23a to give the title compound, 58.4% yield; δ(CF3CO2H) 3.87 (2H, bs, C2 methylene), 4.38 (2H,s, --CH2CONH2), 4.55 (2H,bs, --CH2S--), 5.40 (2H,s, β-lactam protons), 7.1-7.8 (2H,m, --CONH2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7]O)[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7][Cl:17])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(CO)cc1OCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CCl)cc1OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-diethoxybenzyl alcohol (736 mg) dissolved in toluene (10 ml) were added pyridine (one drop) and thionyl chloride (0.41 ml), and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with water, an aqueous saturated solution of sodium hydrogen carbonate and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3,4-diethoxybenzyl chloride (802 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(O)C.C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(Cl)ccc1NC(=O)C(C)(C)C
Temperature: 0 °C
Yield: 96.8 %

Procedure:
A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na2CO3 until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 then brine. The solution was dried (MgSO4) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH2Cl2 and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5 N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1 N HCl, dilute K2CO3, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give 4.68 g (97%) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66-69° C. 1H NMR (300 MHz, CDCl3) δ 6 8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(d, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C12H17NO2Cl(M+H)+ : 242.0948, found: 242.0943. Analysis calculated for C12H16NO2Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[NH:18][N:17]=2)=[CH:11][CH:10]=1)(OC(C)(C)C)=O.Cl.C(OCC)C>CO>[ClH:32].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[NH:18][N:17]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.25 g (0.553 mmol) of 3-[4-(N-BOC-amino)-phenylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Example 65) and 10 ml of a 3N solution of hydrochloric acid in methanol is stirred at RT for 20 hours. Then 10 ml of diethyl ether are added, the reaction mixture is filtered and the filter residue is digested in hot methanol. After cooling, filtering and washing the filter residue with diethyl ether, the crystals are dried for 15 hours under a high vacuum at 100° C. and then left to stand under ambient conditions for 24 hours, yielding the title compound containing 10.97% hydrogen chloride and 4.34% water; m.p. 211-213° C.; EI-MS: (M)+ =351.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([CH3:12])[CH:10]=[N:9][N:8]=1>>[ClH:3].[Cl:3][CH2:6][C:7]1[N:11]([CH3:12])[CH:10]=[N:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cnnc1CO
Product: Cl
Product: Cn1cnnc1CCl

Procedure:
To thionyl chloride (2.0 ml) was added at 0° C. 3-hydroxymethyl-4-methyl-4H-1,2,4-triazole (0.15 g), and the mixture was refluxed for 1.5 hour. The reaction mixture was concentrated under reduced pressure, to which was added diethyl ether. Resulting crystals were collected by filtration and dissolved in ethanol, to which was added diethyl ether for recrystallization to afford 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.22 g) as colorless prisms, m.p. 96°-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-:24])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1

Procedure:
A solution of 3-(benzyloxy)-5-bromopyridine (from step 1) (1.0 eq.) and meta-chloroperbenzoic acid (mCPBA) (4.0 eq.) in dichloromethane (0.1 M) was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The crude residue was purified by a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give 3-(benzyloxy)-5-bromopyridine 1-oxide.
Reaction SMILES: [Br:1]Br.[CH3:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[F:17])=[O:6]>ClCCl>[Br:1][CH:4]([CH3:3])[C:5]([C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=1[F:17])=[O:6]
Reactant: BrBr
Reactant: CCC(=O)c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Product: CC(Br)C(=O)c1cc(C(F)(F)F)ccc1F
Yield: 99.5 %

Procedure:
Slowly add a solution of bromine (3.34 g, 0.95 equiv) in dichloromethane (80.00 mL) to a solution of 2-fluoro-5-(trifluoromethyl)propiophenone (5 g, 22.03 mmol) in dichloromethane (80 mL) is with stirring so that the brown color of bromine just disappears. Wash the reaction mixture with saturated NaHCO3, dry over Na2SO4 and concentrate to provide 6.22 g of crude material.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][C:4]([CH3:11])=[N:3]1.CCCCCCC.[C:19](OCC)(=[O:21])C>ClC(OC(Cl)(Cl)Cl)=O>[CH3:1][N:2]1[C:6]([C:7]2[O:8][C:19](=[O:21])[NH:10][N:9]=2)=[CH:5][C:4]([CH3:11])=[N:3]1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)NN)n(C)n1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: Cc1cc(-c2n[nH]c(=O)o2)n(C)n1

Procedure:
After suspending 2,5-dimethyl-2H-pyrazole-3-carboxylic acid hydrazide (CAS 89187-40-6) (1.15 g) in ethyl acetate (10 ml), trichloromethyl chloroformate (0.90 ml) was added dropwise while stirring on ice. Upon completion of the dropwise addition, the mixture was heated to reflux overnight. It was then allowed to cool, n-heptane (10 ml) was added to the reaction mixture, and the precipitate was collected by filtration to obtain the title compound (1.58 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[NH:9][C:10]([C@@H:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)[CH2:14][C@H:13]2[C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>CN(C=O)C>[F:45][C:44]([F:47])([F:46])[C:42]([O-:48])=[O:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][C:10]([C@@H:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:22])[CH2:20][NH+:39]([CH2:40][CH3:41])[CH2:37][CH3:38])[CH2:14][C@H:13]2[C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:11])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Reactant: O=C(O)C(F)(F)F
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CC[NH+](CC)CC(=O)N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Product: O=C([O-])C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The product of Example 55 (9.2 mg, 0.016 mmol) was dissolved in DMF (0.5 mL), and diethylamine (8 mg, 0.112 mmol) was added. The reaction was heated at 60° C. for 3 h and then aged at rt overnight. TFA (20 μL) was added, and the reaction was purified by RP HPLC on a C18 column by eluting with 10-100% MeCN/water (0.05% TFA). Concentration of the desired fractions afforded the title compound. HPLC/MS: 612.2/614.2 (M+1); Rt=3.04 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH:20]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2/[CH:20]=[CH:23]/[C:24]([OH:26])=[O:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)/C=C/c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a solution of 0.41 g of 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carbaldehyde in 3 mL of pyridine, 0.35 g of malonic acid and 0.02 mL of piperidine were added, and the resulting mixture was stirred at 80° C. for 3 hours. After the solution was allowed to cool, 50 mL of water and concentrated hydrochloric acid were added to adjust the pH to pH3, and the precipitated solid was collected by filtration and washed with ethanol to obtain 0.29 g of (2E)-3-{1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl} acrylic acid as a pale yellow solid.
Reaction SMILES: C(OC([N:8]([S:64]([C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][CH:68]=1)(=[O:66])=[O:65])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:54]([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=[O:56])=[O:55])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=O)(C)(C)C>Cl>[CH3:73][C:70]1[CH:71]=[CH:72][C:67]([S:64]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:54]([C:57]2[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=2)(=[O:56])=[O:55])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)(=[O:46])=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])(=[O:66])=[O:65])=[CH:68][CH:69]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCCCCCN(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)NCCCCN(CCCCCCCN(CCCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Dissolve 1,19-bis(t-butyloxycarbonyl)-1,6,14,19-tetra[(4-methylphenyl)sulfonyl]-1,6,14,19-tetraazanonadecane (11.7 g, 10 mmol) in saturated methanolic hydrochloric acid (100 mL). Stir for several hours and evaporate the solvent in vacuo. Dissolve the residue in water and neutralize with saturated sodium hydrogen carbonate and extract with ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:7]([CH3:9])[CH3:8])(Cl)[Cl:5])[CH3:3].O.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)([O-:20])(=[O:19])=[O:18].[CH3:1][N:2]([C+:4]([N:7]([CH3:9])[CH3:8])[Cl:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C(Cl)(Cl)N(C)C
Solvent: O
Product: CN(C)[C+](Cl)N(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
3.0 g (17.5 mmol) of bis(dimethylamino)dichloromethane and 3.33 g (17.5 mmol) of p-toluenesulfonic acid monohydrate are mixed. The mixture is heated to 100° C. over the course of 30 min, and a vacuum of 7 Pa is subsequently applied over one hour. Cooling to room temperature gives 5.25 g of bis(dimethylamino)chlorocarbenium tosylate, corresponding to a yield of 97.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CO>CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (125 mg, 0.3 mmol) and PtO2 in EtOAc (15 mL) was stirred at rt under 1 atm of H2 gas for 2 h. Toluene (4 mL) and MeOH (5 mL) were added to the reaction mixture, stirred for 20 minutes, filtered the catalyst, and the filtrate solution was concentrated in vacuo to obtain the product (117 mg, 100%) as a white solid. 1H NMR (DMF-d7) δ 8.52 (d, 1H, J=5.0 Hz), 7.68-6.67 (m, 12H), 6.48 (d, 1H, J=5.0 Hz), 5.38 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.C(O)C.[CH2:31](Br)[CH:32]=[CH2:33]>CCOCC>[CH2:33]([N:16]1[CH2:17][CH2:18][C@@:7]23[C:8]4[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=4[CH2:14][C@@H:15]1[C@:2]2([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:32]=[CH2:31]
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Reactant: C=CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCN1CC[C@]23CCCC[C@@]2(O)[C@H]1Cc1ccc(OC)cc13

Procedure:
To a stirred mixture of 900 mg. (3.3. mmole) of the aminoalcohol XXI and 1.7 g. (16.5 mmole) of triethylamine in 12 ml. of absolute ethanol was added, at room temperature and under nitrogen, a solution of 0.605 g. (5 mmole) of allyl bromide. After the addition had been completed, the reaction mixture was refluxed for eighteen hours and then evaporated to dryness. The residue was mixed with a 20% aqueous sodium carbonate solution and the resulting mixture extracted with several portions of ether. The combined ether extracts were dried over Na2SO4 and evaporated to yield 940 mg. of an oil which was dissolved in ether. The resulting solution was filtered through a celite-charcoal mixture and the filtrate concentrated at reduced pressure. The remaining oil was converted, in ether, into the hydrochloride salt. Recrystallization from a methanol-ether mixture yielded 600 mg. of a white solid melting at 244°-46° C. (dec.). Yield, 51.9%. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: Br[CH2:2][C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][OH:5].[S-:10][C:11]#[N:12].[K+].CN(C)C=O.C(OCC)C>O>[OH:5][CH2:4][C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:2][S:10][C:11]#[N:12]
Reactant: N#C[S-]
Reactant: CCC(CC)(CO)CBr
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(CO)CSC#N
Temperature: 130 °C
Reaction time: 7 h
Yield: 98.6 %

Procedure:
A mixture of 3-bromo-2,2-diethyl-1-propanol (23.3 g), potassium thiocyanate (17.5 g) and dimethylformamide (80 ml) was stirred for 7 hours at 130° C. The reaction solution was cooled to room temperature, to which a mixture of diethyl ether (50 ml) and water (100 ml) were added. The ethernal layer was collected. The aqueous layer was extracted with 80 ml of diethyl ether. The combined ethernal layers were washed with a saturated saline, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was distilled under reduced pressure to obtain 3-hydroxy-2,2-diethyl-1-propylthiocyanate (20.4 g) as oil.