Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([C:9](=O)[CH2:10][C:11]#[N:12])[CH2:8][CH2:7]1.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>O.C1CCCCC1.C1(C)C=CC=CC=1>[CH:6]1([C:9]2[C:10]([C:11]#[N:12])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:8][CH2:7]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCCCC1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
Into a glass flask having an internal volume of 200 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 80 mL of toluene and 20 mL of cyclohexane were put in an atmosphere of nitrogen, and 2.94 g (30.6 mmol) of methanesulfonic acid, 3.50 g (32.1 mmol) of 3-cyclopropyl-3-oxopropanenitrile and 6.59 g (30.6 mmol) of 2-amino-4′-fluorobenzophenone were added thereto with stirring. Then, the temperature was raised, and reaction was carried out at a temperature of from 90 to 95° C. for 4 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, and 100 mL of water and 5.5 mL (44.0 mmol) of 8 mol/L sodium hydroxide aqueous solution were added to make the reaction liquid basic. The obtained reaction liquid was extracted with 200 mL of ethyl acetate twice, then the organic layer was separated, and 2 g of anhydrous magnesium sulfate, 2 g of silica gel and 2 g of activated carbon were added, followed by stirring at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain 8.45 g of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile as a pale yellow solid with a purity of 99% (area percentage by high performance liquid chromatography) (yield: 95%).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2)[CH3:9])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.O>CO>[Cl:30][C:11]1[C:10]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH3:9])=[CH:28][CH:27]=[C:26]([Cl:29])[C:12]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2
Reactant: CC(=O)OCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)c2n1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 8-[3-(N-acetoxyacetyl-n-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (640 mg) in methanol (6.4 ml) was added potassium carbonate (395 mg), and the mixture was stireed for 2 hours at ambient temperature. To the mixture was added chloroform and water, the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (chloroform:ethyl acetate=3.1, V/V) to give 8-[2,6-dichloro-3-(N-hydroxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (580 mg) as colorless amorphous.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[OH2:11].[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Nc1ncccc1CO
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncccc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 9.6 g (63 mmole) of 2-mercaptobenzimidazole and 7.7 g (62 mmole) of 3-hydroxymethyl-2-pyridinamine was dissolved in 60 ml of 48% aqueous hydrobromic acid and 60 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and make alkaline with potassium carbonate. The oil that separated solidified upon addition of diethyl ether to the aqueous mixture. The solid was collected by filtration, washed with portions of diethyl ether and water, and air dried to yield 12.4 g of analytically pure 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C13H12N4S.1/2H2O: C, 58.84; H, 4.93; N, 21.11; S, 12.08. Found: C, 59.06; H, 4.48; N, 20.82; S, 12.16.]A mixture of 4.0 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, 1.9 ml (ca. 18 mmole) of 50% aqueous chloroacetaldehyde, and 1.5 g (18 mmole) of sodium bicarbonate in 25 ml of ethanol was stirred at room temperature. After three days the mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue from the filtrate with a mixture of water and dichloromethane induced crystallization. The solid was collected, washed sequentially with water and dichloromethane, and air dried to yield 3.0 g of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:15][CH:16]=O>O>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:15]=[CH:16][N:1]=2)[C:6]=1[C:8]([OH:10])=[O:9]
Reactant: O=CCCl
Reactant: Cc1ccc(N)nc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2nccn2c1C(=O)O
Temperature: 150 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To the title compound of Step A (340 mg, 2.2 mmol) in H2O (7 mL) was added 1M aq. NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210 μL, 3.4 mmol) and the reaction mixture heated in a microwave reactor at 150° C. for 2 h. Additional 1M aq. NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210 μL, 3.4 mmol) were added and heating continued at 150° C. for 2 h. The reaction was purified via prep HPLC to give the title compound (282 mg, 72%). MS (ESI) mass calcd. for C9H8N2O2, 176.1; m/z found 177.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH2:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[N:11][C:3]=2[C:2]([F:1])([F:13])[F:12])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1C(F)(F)F

Procedure:
A solution of 204 mg (1 mmol) of 2-trifluormethyl nicotinic acid, 200 mg (0.9 mmol) of 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine and 620 mg (1.3 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 230 mg (1.8 mmol) N,N-Diisopropylethylamine in 8 ml methylene chloride is stirred for 20 h at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.N1C=CC=CC=1.[CH2:37]=[C:38]1[O:41][C:40](=[O:42])[CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:40](=[O:42])[CH2:39][C:38](=[O:41])[CH3:37])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (28 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, in DCM (1 mL) was added pyridine (0.01 mL, 0.12 mmol). The reaction was cooled to 0° C., followed by the addition of 4-methyleneoxetan-2-one (0.01 mL, 0.13 mmol). The reaction mixture was stirred at rt for 2 h and concentrated. The residue was purified by preparative HPLC (Axia luna column, 30×75 mm, 40-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251) as colorless oil (23 mg, 58% yield). LCMS: RT=3.71 min [M+H] 510.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (1H, s), 7.04-7.20 (5H, m), 6.96-7.02 (2H, m), 6.87-6.92 (3H, m), 6.61 (2H, d, J=7.07 Hz), 5.87 (1H, t, J=2.78 Hz), 3.94 (1H, d, J=12.88 Hz), 3.71 (1H, d, J=12.88 Hz), 3.43 (2H, s), 2.24 (3H, s).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24]2[CH:25]=[C:26]([C:41](O)=[O:42])[CH:27]=[C:28]3[C:33]=2[O:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:29]3=[O:40])[CH3:23])[CH:17]=[C:18]([F:20])[CH:19]=1.[Si:44]([O:61][CH2:62][CH2:63][NH:64][CH3:65])([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Si:44]([O:61][CH2:62][CH2:63][N:64]([CH3:65])[C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([NH:21][C:16]3[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([F:13])[CH:15]=3)[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:42])([C:57]([CH3:59])([CH3:60])[CH3:58])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 1; [α]D20°: +115°), 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (221 mg, 0.71 mmol) and 2-hydroxy-pyridine N-oxide (78 mg, 0.71 mmol) dissolved in DCM (2 mL) under argon. The resulting solution was stirred at RT overnight. The solution was evaporated to dryness, water was added and product was extracted with DCM. The organic phase was washed with brine and dried over magnesium sulfate, the solvent was evaporated to afford N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (94%) as a white solid. Mass Spectrum: M+H+ 726.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[CH3:23].C([OH:26])C>>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:12]([O-:26])[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[CH3:23])([O-:3])=[O:2]
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: CCO
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Product: Cc1[nH]c2ccc([NH+]([O-])c3cnccc3[N+](=O)[O-])cc2c1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-nitro-3-fluoropyridine N-oxide (4.2 g) and 5-amino-2,3-dimethylindole (4.2 g) in 100 mL of thoroughly degassed absolute ethanol was stirred at 50° C. for 30 minutes and then cooled slowly to 0° C. The precipitate was collected and air dried to give 7.3 g of N-(4-nitro-3-pyridinyl)-2,3-dimethyl-1H-indol-5-amine N5 -oxide as a powder. This powder was taken up in 225 mL of isopropanol and hydrogenated at 50° C. over 3% platinum on carbon at 50 psi in the presence of lithium hydroxide (0.21 g). Filtration and concentration left 4.7 g of a solid which was recrystallized twice from methanol giving 2.4 g of crystals. This material was then azeotroped repeatedly with absolute ethanol and dried at 85° to give 1.4 g of crystals, mp=112°-115° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2/[C:7](=[C:10]3\[C:11](=[O:24])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]([S:19](=[O:23])(=[O:22])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[CH2:8][CH2:9][C:4]=2[C:3]=1[C:25]([OH:27])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[OH:51][CH:44]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:43][NH:42][C:25]([C:3]1[C:4]2[CH2:9][CH2:8]/[C:7](=[C:10]3/[C:11](=[O:24])[NH:12][C:13]4[C:18]/3=[CH:17][C:16]([S:19](=[O:22])(=[O:23])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[C:5]=2[NH:6][C:2]=1[CH3:1])=[O:27]
Reactant: NCC(O)CN1CCCC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)O)C(=O)N2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)NCC(O)CN1CCCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-methyl-6-[5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidene]-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example 5, 78 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) and EDC (77 mg, 0.4 mmol) in dry DMF (2 mL) was stirred at room temperature for 30 min. Then 1-amino-3-pyrrolidine-1-yl-propan-2-ol (0.4 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was crystallized and purified on a silica gel column to give 54 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C.O>[CH3:25][O:26][CH2:27][CH2:28][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COCCBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COCCOc1cccc(C)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The required 1-(2-methoxy-ethoxy)-3-methyl-2-nitrobenzene was prepared from 3-methyl-2-nitrophenol. To a stirred solution of the phenol (2.0 g, 13.1 mmol) in DMF (65 mL) was added potassium carbonate (2.16 g, 15.7 mmol) and bromoethyl methyl ether (1.47 mL, 15.7 mmol) at room temperature. After the mixture was stirred at 50° C. for 48 h, water was added. The mixture was extracted with EtOAc (3×), washed with brine, dried over anhydrous MgSO4 filtered and evaporated. After chromatographic purification on silica gel, 1-(2-methoxy-ethoxy)-3-methyl-2-nitrobenzene was obtained in 85% yield (2.34 g). 1H NMR (500 MHz, CDCl3) δ 7.28 (1H, t, J=8.0 Hz), 6.89 (1H, d, J=9.0 Hz), 6.85 (1H, d, J=8.0 Hz), 4.19 (2H, t, J=4.5 Hz), 3.72 (2H, t, J=5.0 Hz), 3.41 (3H, s), 2.30 (3H, s).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=NS[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OCC2OC2)=[CH:13][CH:12]=1)=O)C.[CH2:22](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC(C2SN=NC=2C(OCC)=O)=CC=1>[NH2:7][CH:6]1[CH2:4][CH2:22][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]1
Reactant: CCO
Reactant: CCOC(=O)c1nnsc1-c1ccc(OCC2CO2)cc1
Agent: CCOC(=O)c1nnsc1-c1ccc(OCC(O)CNC2CCc3ccccc3C2)cc1
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)-1-(2,3-epoxypropoxy)benzene (2.94 g) and 2-aminotetralin (1.49 g) in absolute ethanol (20 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[4-(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)phenoxy]propanamine hydrochloride is obtained ((i): R=H, Ar=radical 63, wherein Z is a 4-COOC2H5 group, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[NH2:22]>>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]([Cl:21])=[C:13]2[C:12]=1[NH:11][C:2](=[O:4])[C:1](=[O:8])[NH:22]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1c(N)c(Cl)c(Cl)c(Cl)c1Cl
Product: O=c1[nH]c2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrachloro-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.97 g, 20.0 mmol) and 1,2-diamino-3,4,5,6-tetrachlorobenzene (500 mg, 2.03 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the orange solid collected by vacuum filtration and rinsed with cold EtOH (10 mL) and air dried. This solid was recrystallized from abs. ethanol to give 97.0 mg (16%) of an orange solid mp 326°-328° C. (dec). (Lit., >360°). FT-IR: 3198, 3135 cm-1 (N--H), 1750, 1623 cm-1 (C=O). 1H NMR δ (d6 -DMSO) δ11.7 (br s, 2H, N--H) EIMS m/z 306 (M+8, 1.7), 304 (M+6, 11.5), 302 (M+4, 47.4), 300 (M+2, 93.9), 288 (M+, 76.7), 274 (50.0), 272 (bp), 270 (79.0), 209 (61.0), 207 (64.0). EIHRMS calc. for C8H2Cl4N2O2 297.8870, found 297.8864.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][C:22]1[N:23]=[C:24]([NH:29][CH2:30][CH2:31][NH2:32])[S:25][C:26]=1[C:27]#[N:28]>CS(C)=O>[NH2:21][C:22]1[N:23]=[C:24]([NH:29][CH2:30][CH2:31][NH:32][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)[S:25][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1sc(NCCN)nc1N
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1sc(NCCNc2nc(Br)cn3ccnc23)nc1N
Temperature: 140 °C

Procedure:
300 mg (1.08 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine were dissolved in 10 ml of DMSO, and 0.6 ml (4.3 mmol) of triethylamine and 360 mg (1.3 mmol) of 4-amino-2-[(2-aminoethyl)amino]-1,3-thiazole-5-carbonitrile dihydrochloride (Example 8A) were added. The mixture was heated at 140° C. in a microwave for 1 h. Purification by preparative HPLC gave 376 mg (83% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN(C)C=O>CO>[CH3:17][N:18]([CH:20]=[CH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Into a reaction flask were introduced 89.7 g of methyl 4-methyl-3-nitrobenzoate, 82.1 g of dimethylformamide dimethyl acetal and 200 ml of dimethylformamide (DMF), and the content of the flask was stirred at 120° C. for 6 hours. DMF was distilled off to obtain a red-violet colored solid product. Then, 300 ml of methanol was poured into the flask to wash the crystalline matter, and filtered. Thus, 104.8 g (yield 91%) of methyl 4-dimethylaminovinyl-3-nitrobenzoate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH:9]=[CH:8]1)[CH3:2].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)(CC)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH:9]=[CH:8]1)[CH3:2].[C:4]([OH:17])([C:19]([F:18])([F:28])[F:29])=[O:3]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CCn1ccc2c(Cl)ncnc21
Solvent: CCC(C)O
Product: CCOC(=O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Product: O=C(O)C(F)(F)F
Temperature: 120 °C
Reaction time: 2 h
Yield: 540.4 %

Procedure:
To a solution of 3-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-propionic acid ethyl ester (100 mg, 0.37 mmol) in sec-BuOH (3 mL) was added 4-trifluoromethoxyaniline (73 mg, 0.41 mmol). The mixture was heated at 120° C. and stirred for 2 h. The reaction mixture was concentrated and purified by prep-HPLC to afford the title compound as brown solid as TFA salt (114 mg, 60%). MS m/z 408.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4](C)=[CH:3]1.O=O.[O:13]=[O+][O-].[OH2:16]>ClCCl>[CH3:7][C:6]([CH3:8])([CH2:9][C:2](=[O:1])[CH3:3])[CH2:5][C:4]([OH:13])=[O:16]
Reactant: O=[O+][O-]
Reactant: O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=O
Solvent: ClCCl
Product: CC(=O)CC(C)(C)CC(=O)O
Reaction time: 3 h

Procedure:
A solution of 16 g of isophorone in 100 g of dichloromethane was cooled down to 0° C. A stream of oxygen, which contained about 4 percent of ozone, was conducted through this solution until the solution was saturated with ozone. Then the ozonolyzed solution was added drop by drop into 150 ml of boiling water, the dichloromethane was distilled off and the aqueous solution was boiled for another 3 hours. The 3,3-dimethyl-5-oxo-hexanoic acid formed was isolated by reducing under vacuum.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH:15](I)([CH3:17])[CH3:16].Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NS(=O)(=O)c1cccc(CO)c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% oil dispersion, 0.177 g) was added to 3-hydroxymethylbenzenesulfonamide (0.77 g) with stirring in DMF (15 ml) under nitrogen at 21°. After 10 min, isopropyl iodide (0.45 ml) was added followed by a further 0.3 ml after 1 h. After an additional 2 h more isopropyl iodide (0.2 ml) was added. After 3 days more sodium hydride oil dispersion (0.08 g) was added. After another day, the solution was poured into water acidified with 2M hydrochloric acid and the product was extracted with ethyl acetate twice. The combined extracts were washed with brine and evaporated to an oil. This oil was loaded onto a column of silica gel (60 g) and the column was eluted successively with 30%, 50% and 70% ethyl acetate in 40-60 petroleum ether to give the title compound (0.527 g) LCMS RT=2.22 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=O.[CH3:20][CH2:21][Mg+].[Br-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([OH:12])[CH2:21][CH2:20]1
Reactant: CC[Mg+]
Reactant: O=C(CCOC1CCCCO1)OCc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(CCOC2CCCCO2)CC1
Temperature: 18 °C
Reaction time: 0.5 h
Yield: 345.8 %

Procedure:
To a mixture of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (4.2 g, 15.9 mmol) in 60 mL of THF was added Ti(Oi-Pr)4 (2.4 mL, 07.95 mmol, d=0.955 g/L, Aldrich) via a syringe under nitrogen at rt. After stirring at 18° C. for 30 min, EtMgBr (13.25 mL, 3.975 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 3 hrs. The reaction was quenched with 50 mL of water. The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to afford the title compound as colorless oil (2.56 g, 86.5%).