Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]1[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]1)=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCC(O)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4-hydroxypiperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]>CO.C(O)(=O)C>[Cl:3][CH2:4][CH:5]([OH:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C(O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (621 mg, 16.42 mmol) was added to a mixture of (R)-tert-butyl (4-chloro-3-oxobutan-2-yl)carbamate (910 mg, 4.10 mmol) in methanol (9 mL) at 0° C., and the mixture was stirred for one hour at 0° C. A few drops of acetic acid were added then the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl ((2R)-4-chloro-3-hydroxybutan-2-yl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 6.65 (d, J=8.1 Hz, 1H), 5.24 (d, J=5.6 Hz, 1H), 3.58-3.53 (m, 1H), 3.50-3.44 (m, 2H), 3.44-3.34 (m, 1H), 1.36 (s, 9H), 0.99 (d, J=6.3, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:13][C:14]([OH:16])=[O:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:42])=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2CC)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-ethyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Br)[C:10]([O:18][CH2:19][C@@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH2:1]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH3:30])[C:10]([O:18][CH2:19][C@@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)c(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1
Temperature: 155 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Under an argon atmosphere, a mixture of methyl 1-benzyl-4-bromo-3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate (1.03 g), trimethylboroxin (552 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (181 mg), potassium carbonate (912 mg) and DMF (20 ml) was stirred at 155° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (330 mg).
Reaction SMILES: [NH2:1][C:2](=[C:6]([OH:10])[CH2:7][O:8][CH3:9])[C:3]([OH:5])=[O:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][CH:2]([CH:6]([OH:10])[CH2:7][O:8][CH3:9])[C:3]([OH:5])=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COCC(O)=C(N)C(=O)O
Solvent: O
Product: COCC(O)C(NC(C)=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of amino acid 7 (34 g, 0.23 mol) in 300 ml of water cooled to 0° was added dropwise with stirring, 10 ml of acetic anhydride. After 1 hr, an additional 10 ml of acetic anhydride was added. The process was continued until a total of 35 ml of acetic anhydride had been added. The reaction mixture was allowed to stand at 0° for 3 hrs. The solvent was then removed in vacuo at 50°. Water was added to the residue and after a homogeneous solution was obtained, the water was removed in vacuo at 50°. The addition and removal of water was repeated 3 more times. The resultant residue was subjected two more times to the entire sequence beginning with the addition of 35 ml of acetic anhydride in portions. The residue resulting from this treatment was dried in vacuo (0.1 mm) for 48 hr yielding 2-Acetamido-3-hydroxy-4-methoxybutanoic acid as a glass. This material was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[C:29]([CH3:30])=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][C@@H:16]2[CH3:31])=[N:10][S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[C:29]([CH3:30])=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][C@@H:16]2[CH3:31])=[N:10][S:11](=[O:14])(=[O:13])[N:12]=[CH:34][N:35]([CH3:37])[CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1c[nH]c2ncnc(N3CCN(C(=NS(N)(=O)=O)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NS(=O)(=O)N=CN(C)C)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
Crude (S)—N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N′-sulfamoylpiperazine-1-carboximidamide from Example 20, step C, (˜25 mg, 0.068 mmol) was dissolved in MeOH (0.5 ml) and N,N-dimethylformamide dimethyl acetal (7 μl) added. The mixture was stirred at room temperature for 20 minutes and then concentrated. The mixture was purified by preparative HPLC to afford the desired compound (5 mg, 0.0088 mmol, 13%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4cc(F)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (106 mg, 0.314 mmol) was suspended in acetonitrile (3.1 mL). Isocyanatoethane (30.8 μl, 0.393 mmol) and 1 drop of pyridine were added and the mixture was heated at 75° C. for 2 hours. The mixture was cooled to give a solid which was collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (3H, t, J=7.07 Hz) 2.38 (3H, s) 3.34-3.45 (2H, m) 7.25-7.42 (3H, m) 7.76 (1H, ddd, J=9.47, 6.06, 3.16 Hz) 7.93 (1H, s) 8.41 (1H, d, J=5.30 Hz) 8.54 (1H, s) 8.60 (1H, s) 9.09 (1H, t, J=5.81 Hz) 11.05 (1H, s). MS [M+H] found 409.4.
Reaction SMILES: [Na].C[O-].[Na+].C[CH2:6][O:7][C:8](/[CH:10]=[C:11](/[CH2:13]P(OCC)(OCC)=O)\[CH3:12])=[O:9].[CH3:22][CH:23]([N:25]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:39])=[CH:36]/[CH:37]=O)=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[CH3:24].[Cl-].[NH4+]>CO>[CH3:24][CH:23]([N:25]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:39])=[CH:36]/[CH:37]=[CH:13]/[C:11](/[CH3:12])=[CH:10]/[C:8]([O:7][CH3:6])=[O:9])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[CH3:22]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: C/C(=C\C=O)c1ccc2c(c1)CCCN2C(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
56 mg (2.46 mmol) of metallic sodium was added to methanol to prepare a methanolic solution of sodium methoxide. This solution was concentrated in a vacuum and suspended in N,N-dimethylformamide, followed by the addition of 560 mg (2.14 mmol) of triethyl 3-methyl-4-phosphonocrotonate under cooling with ice. After 30 minutes, 400 mg (1.64 mmol) of (E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal was added to the mixture obtained above. The mixture thus obtained was stirred for one hour, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (15% ethyl acetate/n-hexane) to give 330 mg of the title compound as a reddish-brown oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24]
Reactant: Cc1c(O)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(O)c([N+](=O)[O-])cc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 67 %

Procedure:
Nitric acid (65%, 0.370 ml) was added dropwise with vigorous stirring to 1,1-dimethylethyl 7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (600 mg) and silica gel (1.67 g) in DCM (5.7 ml) at −15° C. After 30 min a mixture of DCM/MeOH/conc.NH4OH: 10/3/1.5 was added and silica gel was filtered off. The solvent was evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 15/85) obtaining the desired compound (470 mg, 67% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.F[C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:21][C:16]1[N:15]=[C:14]2[O:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=3)=[N:20][C:19]2=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN(C)c1ccc(-c2nc3ccc(F)nc3o2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 4-dimethylamino-benzoic acid (635 mg, 3.84 mmol) in CH2Cl2 (38 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (0.51 mL, 3.84 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (7.8 mL) before 2,6-difluoro-pyridin-3-ylamine (500 mg, 3.84) was added in one portion. After an additional 1 h, the reaction mixture was concentrated to dryness affording a residue to which was added DMF (5 mL) and K2CO3 (531 mg, 3.84 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered, concentrated and purified by silica gel flash chromatography (0 to 100% EtOAc in hexanes) to afford [4-(5-fluoro-oxazolo[5,4-b]pyridin-2-yl)-phenyl]-dimethyl-amine (430 mg, 1.67 mmol, 44%). ES MS (M+H+)=258; 1H NMR δ (ppm)(DMSO-d6): 8.28 (1H, dd, J=8.36, 7.14 Hz), 8.01-7.94 (2H, m), 7.24-7.18 (1H, m), 6.87 (2H, d, J=8.89 Hz), 3.05 (6H, s); HRMS m/z 258.1039 (C14H12FN3O+H+ requires 258.1037).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:27]([NH2:28])[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13].F[C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>CN(C=O)C>[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:27]([NH:28][C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Fc1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
A suspension of anhydrous toluene-p-sulphonic acid (0.74 g.) and 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (1.17 g.) in dry DMF (17.5 ml.) was stirred for 15 minutes at room temperature to effect partial solution. One portion of 2-fluoroimidazole (0.74 g.) was then added and the mixture stirred at 90° for 2 hours. The solvent was evaporated at ambient temperature, 2% v/v aqueous HOAc (20 ml.) was added to the residue and the mixture was extracted with EtOAc (20 ml.). The aqueous layer was concentrated to 15 ml., filtered and the filtrate purified by preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 80:20:1 v/v/v as solvent. The product was further purified by trituration with acetone and washing with acetone and ether to give 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (0.42 g.) as a hydrated mixed acetate/toluene-p-sulphonate salt having m.p. >160° (decomp.) and the following n.m.r. in D2O: 2.28 (s, 3H); 3.58 (d, 1H); 3.89 (d, 1H); 4.92 (d, 1H); 5.13 (d, 1H); 5.42 (d, 1H); 5.70 (d, 1H); 7.08 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-3-nitrobenzenesulfonyl chloride (235 mg, 0.918 mmol) was treated with a 2 M solution of dimethylamine in methanol (0.55 mL, 1.10 mmol), and triethylamine (0.13 mL, 0.918 mmol) in methanol (1 mL), and the suspension was stirred at room temperature for 2.5 h. The volatiles were removed in vacuo, and the residue was purified by column chromatography using heptane/ethyl acetate, 70:30-50:50 as an eluent, affording 2-chloro-N,N-dimethyl-3-nitrobenzenesulfonamide, 202 mg (83%) as a white solid. MS (ESI) m/z 265 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 2.95 (s, 6 H); 7.56 (t, J=8.0 Hz, 1H), 7.88 (dd, J=8.1, 1.5 Hz, 1H), 8.31 (dd, J=8.1, 1.5 Hz, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[F:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[CH:34]=[CH:33][C:32]=1O.FC1C=CC=C(F)C=1F.C([Li])CCC.O=O.C(O)(=O)C(O)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:16]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[C:36]([F:37])[C:35]=2[F:38])=[O:26])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Fc1cccc(F)c1F
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C(=O)Oc2ccc(F)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 mmol of dicyclohexylcarbodiimide and 1.5 ml of toluene is added to a amixture of 10 mmol of p-pentylbenzoic acid, 10 mmol 2,3,4-trifluorophenol (prepared from 1,2,3-trifluorobenzene in accordance with the literature: A. M. Roe et al., Chem. Comm. 1965, 582, by metalation with n-butyllithium at -50° C. analogously to Example 2 and subsequent oxygenation with atmospheric oxygen), 1 mmol of 4-dimethylaminopyridine and 15.0 ml of toluene. After the mixture has been stirred at room temperature for 4 hours, 20 mg of oxalic acid are added and the mixture is stirred for a further 30 minutes. Customary working up gives 2,3,4-trifluorophenyl p-pentylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:26]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH2:29]2)=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cn1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.71 g of 3-(6-methyl-3-pyridyl)acrylic acid in 70 ml of dry tetrahydrofuran, a solution of 1.68 g of triethylamine in 5 ml of dry tetrahydrofuran is added at room temperature. The resulting solution is cooled to -5° C., and a solution of 2.0 g of pivaloyl chloride in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred at the same temperature for 0.5 hour and cooled to -10° C., and a solution of 6.43 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred for 0.5 hour at between -10° C. and -5° C. and then at room temperature overnight. To the reaction mixture is added 50 ml of 10% aqueous potassium carbonate, and the resulting mixture is extracted with three 100-ml portions of ethyl acetate. The combined extracts are washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is recrystallized from acetonitrile to give 5.63 g of the title compound, m.p. 129°-131° C.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].Cl.C([O-])(O)=O.[Na+].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(O)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxyisobutyric acid (15 gm) was dissolved in benzyl alcohol (80 mL) at 0° C. and the solution was saturated with HCl gas. This solution was stored at rt overnight and then was poured into sat. NaHCO3 solution. This was extracted twice with CHCl3 and the combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness. The residue so obtained was fractionally distilled and the title compound was obtained as a fraction that boiled at 85°-100° C. at 0.2 mm.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][SH:11])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.CO>CN(C)C=O>[CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: COC(=O)C(C)(C)CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCCSc1cc(-c2ccccc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To a solution of 4 g of methyl 2,2-dimethyl-6-mercaptohexanoate in 100 cc of dimethylformamide, is added 0.55 g of sodium hydride (50% w/w dispersion in mineral oil). The mixture is stirred for 2 hours until effervescence has stopped. A solution of 5 g of 2-chloro-4-phenylquinoline in 50 cc of dimethyl-formamide is then added. The obtained mixture is heated to 60 C. for 8 hours. After cooling, 10 cc of methanol is added and the mixture evaporated. The resultant residue is purified by flash chromatography on silica gel (30-60 mm; eluent: 8:2 hexane/ethyl acetate) to give methyl 2,2-dimethyl-6-[(4-phenyl-2-quinolyl)thio]-hexanoate is obtained as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:24]1([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:6][CH:7]=2)=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Fc1ccc(C(=C(c2ccccc2)c2ccc(OCCBr)cc2)C(F)(F)F)cc1
Reactant: C1COCCN1
Product: Fc1ccc(C(=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2)C(F)(F)F)cc1
Yield: 75.7 %

Procedure:
3.25 g (7 mmoles) of 1-[4-(2-bromoethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-fluorophenyl)-propene, prepared as described in Example 15, are reacted with morpholine as described in Example 1. The product is crystallized from hexane. 2.5 g (75.7%) of the aimed compound are obtained; m.p.: 67°-69° C.
Reaction SMILES: O=O.[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][CH2:11][C:4]1=2.C(O)(=[O:20])C(C)C>O>[O:20]=[C:11]1[C:4]2[S:3][CH:7]=[CH:6][C:5]=2[CH:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10]1
Reactant: CC(C)C(=O)O
Reactant: CC(=O)NC1CCCc2sccc21
Agent: O=O
Solvent: O
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 48 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Oxygen is passed into a mixture of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide (1.0 g; 5.13 m mole), cobaltous acetate (0.25 g; 1.4 m mole), cobaltous bromide tetrahydrate (0.32 g; 1.1 m mole), isobutyric acid (20 ml) and water (0.2 ml) in a sintered glass funnel fitted with a condenser and thermometer, via the stem of the funnel. The dark brown mixture is oxygenated for 100 minutes at room temperature, then heated briefly to 48° C. After 2 hours and 10 minutes, the mixture is reheated to 50° C. and the flow of oxygen is terminated 2 hours later. The mixture is then worked up as described in Example 1 to attain a 37% yield of the title compound.