Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][C:35]([NH2:37])=[O:36].CO>C(Cl)Cl>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: NC(=O)CBr
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC(=O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 172 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.42 (s, 1H); 8.28 (s, 1H); 7.81 (td, J=8.75, 5.92 Hz, 1H); 7.63 (ddd, J=10.33, 9.01, 2.79 Hz, 1H); 7.39-7.27 (m, 2H); 7.11 (s, 1H); 7.03 (s, 1H); 6.96-6.89 (m, 2H); 4.23 (t, J=5.01 Hz, 2H); 3.66 (t, J=7.02 Hz, 2H); 3.62-3.52 (m, 1H); 3.16 (t, J=6.65 Hz, 2H); 3.10-2.98 (m, 4H). LCMS: RT=7.00 min, M+H+=478
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:26]2[C:27](=O)[NH:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[N:16]1([C:26]2[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[N:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (315.6 mg, 1.12 mmol) was added to a solution of methyl 3-(3, 4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200.0 mg, crude) and pyridine (176.8 mg, 2.24 mmol) in dichloromethane (50 ml). After stirring overnight at room temperature, the reaction was quenched with water (50 ml) and extracted with dichloromethane (3×80 ml). Then the organic layers were combined dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude), which was used directly in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20]Cl)[N:19]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[N:19]=[C:15]([CH3:14])[S:16][CH:17]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(CN(C(=O)CCl)c2c(C)cccc2C)cs1
Yield: 18 %

Procedure:
A mixture of 5.33 g N-chloroacetyl-2,6-dimethylaniline and 4 g 2-methyl-4-chloromethylthiazole (prepared in Example 4A above) in dry dimethylformamide was treated with 1.56 g sodium hydride as in Example 3 above. After workup, the solid product was purified by high-pressure liquid chromatography to yield 1.5 g pure product, m.p. 62°-64° C. This product is shown as Compound 3 in Table I. C15H17ClN2OS: calc., %C 58.35, %H 5.51, %N 9.08; found, %C 59.23, %H 5.79, %N 9.28.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH:2]=[CH:3]1
Reactant: BrCCCCBr
Reactant: O=C1NC=COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC=CN1CCCCBr
Reaction time: 0.5 h

Procedure:
1.0 g of 4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 50 ml of dimethylformamide, then 298 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 4.7 g (3 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1.[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)c(OC2CCCCO2)c1

Procedure:
To solution of 4-bromo-3-hydroxybenzoic acid (G.1) (available from Combi-Blocks Inc.) (2.50 g, 115 mmol) in DCM (100 mL) at 23° C., was added 3,4-dihydro-2H-pyran (2.10 mL, 23.0 mmol) followed by PPTS (0.289 g, 1.15 mmol). The reaction gave a mixture of bis THP protected compound and G.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: CI
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5H-pyrimido[4.5-b][1,4]diazepin-6(7H)-one (474.7 mg, 1.78 mmol) and methyl iodide (0.122 ml, 1.96 mmol) in DMA (4.5 ml) stirred at −10° C. and treated with sodium hydride 60% oil dispersion (75 mg, 1.87 mmol). The mixture was warmed to 0° C. for 20 min and then to 20° C. for 40 min. A further 0.12 ml methyl iodide and 8 mg sodium hydride were added and the mixture stirred at ambient overnight. Ice was added and the mixture concentrated under reduced pressure. The residual oil was treated dropwise with water (6 ml), filtered and the buff solid dried under high vacuum at 60° C. (486 mg, 98%). NMR DMSO D6 1.45-1.72 (6H, m), 1.76-1.91 (2H, m), 2.61 (2H, d), 3.18 (3H, s), 3.64 (2H, d), 4.65-4.74 (1H, m), 8.15 (1H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C(N)CCC>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: CCO
Product: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Reaction time: 21 h
Yield: 44.5 %

Procedure:
The intermediate 1-[4-(methylthio)phenyl]-2-nitro-1-propene was prepared as follows: [U.S. Pat. No. 3,117,160, Example V]; a mixture containing 15.2 g of 4-(methylthio)benzaldehyde, 7.5 g of nitroethane, 0.73 g of n-butylamine and 40 ml of absolute ethanol was refluxed with stirring for 21 hours and the solvent then removed by distilling in vacuo. The residue was recrystallized from absolute ethanol (total volume of 60 ml) washed with a small quantity of cold ethanol and dried in vacuo at room temperature to produce 9.3 g of 1-[4-(methylthio)phenyl]-2-nitro-1-propene, m.p. 74°-76° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH:34]([S:35]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:37])=[O:36])=[CH2:33]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (260 mg, 0.8 mmol) in CH2Cl2 at 0° C., triethylamine (0.44 mL, 3.2 mmol) and 2-chloroethylsulfonyl chloride (0.168 mL, 1.6 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic phase washed with brine (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (245 mg, 75%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@H:8]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:6])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@@H]1CCNC[C@H]1C(=O)OCC
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A solution of 259B (680 mg, 1.9 mmol) in CH2Cl2 (10 mL) was treated with TFA (1 mL) at room temperature. The reaction mixture was stirred for 16 hours, then concentrated. The residues was dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 170 mg of Compound 259C.
Reaction SMILES: O.[CH:2]1([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC)=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>CO>[CH:2]1([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)CC3CCCCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)O

Procedure:
Water (20 mL) and MeOH (80 mL) were added to ethyl 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (F) (4.9 g, 14 mmol) and NaOH (5.6 g, 0.14 mol), and the resultant mixture was stirred at RT under a blanket of nitrogen as inert gas until completion of the reaction. Following removal of MeOH, 2N hydrochloric acid solution in water (250 mL) and DCM (250 mL) was added. The phases were separated, and the aqueous phase was extracted a number of times with DCM. Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (G) in a yield of 3.9 g (corresponding to 87% of theory).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)OC1CCCCC1
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. Yield: 40% of theory, C32H35N7O5 (597.7) Rf value: 0.26 (silica gel; dichloromethane/ethanol=19:1) ##EQU85##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]21[O:21][CH2:20][CH2:19][O:15]2
Reactant: CC(Br)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1

Procedure:
Forty-five (45) grams of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethylbromide were dissolved in 200 ml of benzene and then incorporated with 12.7 g of ethylene glycol and 0.12 g of p-toluenesulfonic acid, after which the whole was refluxed under agitation for 4 hours. After the end of the reaction, the reaction mixture was washed with water, an aqueous solution of sodium hydrogen carbonate and water in this order. Then, the organic layer obtained was dried and thereafter freed of the solvent at a reduced pressure thereby to obtain 51 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethylbromide.
Reaction SMILES: [C:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>C(O)(=O)C.[Pt](=O)=O>[NH2:2][CH2:1][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.1 %

Procedure:
Platinum(IV) oxide (0.724 g, 3.19 mmol) and 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (Intermediate 7) (9 g, 31.9 mmol) in acetic acid (100 ml) were stirred under an atmosphere of hydrogen at 5 bar and 25° C. for 1 day. The crude product was filtered through celite and the filtrate purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (7.59 g, 83%) as a colourless oil.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)([Cl:23])=O>ClC1C=CC=CC=1>[C:1]([Cl:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: Clc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reaction time: 0.5 h

Procedure:
200 g (0.7 mol) of oleic acid and 725 g of monochlorobenzene are introduced into the reactor and 574 g (5.8 mol) of phosgene are then added. The set pressure is adjusted to 11.2 bar relative and the reaction medium is heated. The reaction is complete after 1 hour 30 min. The level of residual acid is 0.5 mol % and the level of oleoyl chloride obtained is 99.5 mol %.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=[O:26])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][O:12][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=[O:26])=[CH:17][CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(C(C)(C)C)nc1CCOc1ccc(C=O)c2ccccc12
Reaction time: 4 h

Procedure:
0.800 g of the above prepared 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (4.37 mmol) was dissolved in 25 ml of toluene and treated successively at 0° C. with 0.752 g of 4-hydroxy-naphthalene-1-carbaldehyde (4.37 mmol), 1.145 g of triphenylphosphine (4.37 mmol), and 0.883 g (4.37 mmol) of DIAD. The cooling bath was then removed and stirring continued for 4 h. Pouring onto crashed ice, twofold extraction with EtOEt, washing with dil. NaOH and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) and crystallization from EtOEt, delivered finally 0.791 g of the title compound as off-white crystals of mp. 155–57° (dec.).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[N:25][N:24]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:28]([C:26]1[S:27][C:23]([C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[Cl:13])=[N:24][N:25]=1)(=[O:30])=[O:29])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=[N+]([O-])c1ccc(-c2nnc(S(=O)(=O)Cl)s2)c(Cl)c1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2-chloro-4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.60 (d, 1H), 8.54 (d, 1H), 8.40 (dd, 1H) 4.05 (q, 2H), 3.27 (s, 2H), 3.19 (t, 2H), 2.67 (t, 2H), 1.16 (t, 3H).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1([NH2:12])[CH2:10][CH:9]([CH3:11])[CH2:8]1)=[O:6])C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:7]2([C:5]([OH:4])=[O:6])[CH2:8][CH:9]([CH3:11])[CH2:10]2)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: CCOC(=O)C1(N)CC(C)C1
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)CC(C)C2)cc1OCCc1cccc(C)c1

Procedure:
The compound of step 1 (65 mg, 0.413 mmol) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture of the cis isomer and the trans isomer.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)[CH3:2].O>C(O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[N:10][C:9]([Cl:12])=[N:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc(Cl)nc1Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cnc(Cl)nc1
Temperature: 99.5 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Zinc powder (3.55 g, 54.3 mmol) was added to a solution of (2,4-dichloro-pyrimidin-5-yl)acetic acid ethyl ester (Example 43-(1); 1.57 g, 6.70 mmol) in ethanol (10 mL)-water (8.5 mL), and the mixture was heated while stirring at an external temperature of 96 to 103° C. for 10 minutes. The reaction mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (820 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[CH2:14]([NH:18][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 24b from 4-chloro-3-nitro-benzoylchloride, isobutylamine and triethylamine in tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1.C(=O)(O)[O-].[Na+]>[C:43]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1)(=[O:45])[CH3:44]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)n1)OCC2c1ccc(C(C)C)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of N-(7-(6-aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (94.3 mg, 0.2 mmol) and triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL) was added acetyl chloride (0.015 mL, 0.22 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 51 mg (yield: 50%) of the title compound. Melting point: 205-208° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1O)([O-:3])=[O:2].C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1.CCN(C1C=CC=CC=1)CC.[N+](C1C=CC=CC=1)([O-])=O>Cl>[Cl:26][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:14](=[O:16])[CH3:15])=[CH:7][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 95 °C
Yield: 87.5 %

Procedure:
A mixture of 22.6 grams (0.1 mole) of 3',5'-dinitro-4'-hydroxyacetophenone, 19.0 grams of p-toluenesulfonyl chloride (0.1 mole), 16.0 grams (0.107 mole) of diethylaniline, and 18.0 grams of nitrobenzene was heated at about 95° C. for 8 hours. The reaction mixture was poured into 200 milliliters of 10 percent aqueous hydrochloric acid and the nitrobenzene steam distilled from the mixture. The residue was cooled to room temperature, the aqueous layer decanted, and the dark oil which slowly solidified (yield 87.5 percent) recrystallized from ethanol (charcoal) to give a pale yellow crystalline compound, melting point 86°-86.5° C.