Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[C:7]([CH3:16])([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>O1CCCC1>[Br:1][CH2:2][C:3]([O:5][C:7]([CH3:16])([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)OC(=O)CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Bromoacetic acid (16.01 grams, 0.1 mole) is dissolved in tetra-hydrofuran (200 ml.) and 1,1-carbonyldiimidazole (16.22 grams, 0.1 mole) is added and the mixture stirred for an hour at 25° C. tert.-Butyl 2-hydroxy-2-methylpropanoate (10.41 grams, 0.1 mole) is added and the mixture stirred for 18 hours at 25° C. The solvent is removed by evaporation in vacuo to give tert. butyl 2-(2-bromoacetoxy)-2-methylpropanoate acid (0.1 mole). This compound is dissolved in ether, dried over anhydrous magnesium sulfate, filtered and the solvent removed by evaporation in vacuo. The product is dissolved in 1-propanol (100 ml.) and bis-(2-hydroxyethyl)amine (10.51 grams, 0.1 mole) and triethylamine (11.1 grams, 0.1 mole) are added and the mixture is stirred and heated at reflux for 3 hours. The volatile material is evaporated in vacuo, the residue dissolved in ether (250 ml.), washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo and dissolved in toluene (300 ml.). Methanesulfonic acid (2 grams) is added and the mixture refluxed for 2 hours. The mixture is cooled, extracted with water and the organic layer dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo. The yield of 2-[N,N-bis-(2-hydroxyethyl)aminoacetoxy]-2-methylpropanoic acid is 17.45 g. (70%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1S(O)(=O)=O.[Na]>>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(S(=O)(=O)O)ccc21
Agent: [Na]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
9,10-Anthraquinone-2-sulfonic acid, sodium salt
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[CH3:21][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 4-methylphenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14]2.Cl.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:22][O:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[C:11]1[C:12]=2[N:24]=[N:1][C:2]2[CH:7]=[C:6]3[O:8][CH2:9][O:10][C:5]3=[CH:4][C:3]1=2
Reactant: COc1ccc2cc(-c3cc4c(cc3N)OCO4)ccc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(ccc3c4cc5c(cc4nnc23)OCO5)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.3 %

Procedure:
6-(2-Amino-4,5-methylenedioxyphenyl)-2-methoxynaphthalene 46 (170 mg, 0.58 mmol) was dissolved in acetic acid (4.5 mL) and concentrated hydrochloric acid (0.9 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.36 g in 3.6 mL water). The resulting diazonium solution was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution containing some precipitate was added 50 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 50:50 hexanes:ethyl acetate to give the pure 43 (20 mg) in 11% yield; mp 258-260° C.; IR (KBr) 2922, 1611, 1497, 1465, 1414, 1370, 1272, 1201 cm−1; UV (MeOH) 286, 228 nm (log ε=4.72, 4.41); 1H NMR (CDCl3) δ4.01 (3H, s), 6.23 (2H, s), 7.30 (1H, J=2.6), 7.48 (1H, dd, J1=9.1, J2=2.6), 7.75 (1H, s), 7.95 (1H, s), 8.00 (1H, d, J=9.2), 8.19 (1H, d, J=9.1), 9.62 (1H, d, J=9.2); 13C NMR δ56.01, 97.95, 102.88, 107.48, 108.31, 119.09, 119.61, 119.71, 120.57, 125.89, 126.56, 132.26, 134.59, 142.52, 145.88, 150.21, 152.14, 160.16; HRMS (EI) calcd for C18H12N2O3 m/z: 304.0848; found: 304.0843.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[NH:10][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>O.CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[NH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a stirred DMF solution (40 mL) containing methyl 4-bromo-1H-pyrrole-2-carboxylate (1.0 g, 4.9 mmol), commercially available from Bionet, and Pd(Ph3)4 (195 mg, 0.17 mmol) was added Na2CO3 (1.3 g, 12.52 mmol) (dissolved in minimum amount water) and 4-chlorophenyl boronic acid (0.85 g, 5.43 mmol) under Ar. The mixture was degassed with Ar prior to stirring overnight at 110° C. After cooling the reaction to RT, it was diluted with 10 mL of water and 200 mL of EtOAc. The aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to yield a brown oil. The oil was purified by column chromatography (silica gel, 0%-15% gradient elution with EtOAc/hexanes) to yield 288 mg (25%) of product as white solid. MS (ESI) 236 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:26]2[C:21](=[C:22]([CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[CH:27]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[CH2:31][CH3:32])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(N2CCCCCC2)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 420 (M+H)+; MS (ESI−) m/z 418 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.90 (t, J 7.5, 3H), δ 1.55 (m, 4H), 1.76 (m, 6H), 2.20 (m, 1H), 3.34 (m, 5H), 4.18 (m, 2H), 6.81 (m, 1H), 7.62 (m, 1H), 8.00 (m, 2H), 8.27 (d, J 7.1, 1H), 8.45 (d, 1H), 8.77 (d, 1H), 8.82 (m, 1H), 9.90 (s, 1H), 10.18 (br s, 1H); Anal. Calcd for C26H30FN3O+0.45H2O: C, 73.02; H, 7.28. Found: C, 73.05; H, 7.20.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26])=[CH:21][CH:20]=1>C(O)C>[ClH:15].[NH2:30][C:28]1[NH:27][C:25]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:32][CH:31]=2)=[N:26][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:29]=1
Reactant: CCCCCCCCCCCCC=O
Reactant: COc1ccc(CNC(=N)NC(=N)N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCc2ccc(OC)cc2)=N1

Procedure:
100 ml of ethanol, 9.2 ml (38.7 mmol) of 1-tridecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (19.4 mmol) of N1-(4-methoxybenzyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 70% aqueous acetonitrile to obtain 3.0 g of colorless crystals (1) having a melting point of 162 to 164° C., and the second main eluate was recrystallized from 70% aqueous acetonitrile to obtain 1.3 g of colorless crystals (2) having a melting point of 182 to 184° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:15])([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11].N1([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:25][C:26](=[O:28])[O-:27])C=CC=N1>CC#N>[C:32]([O:31][C:30](=[O:36])[N:29]=[C:24]([NH:25][C:26]([O:27][C:3]([CH3:4])([CH3:18])[CH3:2])=[O:28])[NH:1][CH2:2][C:3]1[CH:18]=[CH:17][CH:16]=[C:5]([CH2:6][CH2:7][C:8]([OH:15])([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH:4]=1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Reactant: CCCC(O)(CCC)CCc1cccc(CN)c1
Solvent: CC#N
Product: CCCC(O)(CCC)CCc1cccc(CNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(aminomethyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate in CH3CN gives tert-butyl(tert-butoxycarbonylamino)(3-(3-hydroxy-3-propylhexyl)benzylamino)methylenecarbamate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCBr)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
162.1 g (0.6 mol) of 4-hydroxyphenyl 4-allyloxybenzoate, known from U.S. Pat. No. 5,211,877, were dissolved in 3 l of methyl ethyl ketone, and 1.32 kg (6 mol) of commercial 1,4-dibromobutane, and 414 g (3 mol) of potassium carbonate were added. The mixture was heated to 80° C. with stirring and held at this temperature for 4 h. It was subsequently cooled, the remaining potassium carbonate was filtered off and the filtrate was concentrated. After the excess dibromobutane had been stripped off, the crude product was recrystallized twice from isopropanol. 4-(4-Bromobutoxy)phenyl 4-allyloxybenzoate was obtained in a yield of 90%. The ester shows the following phase behavior: C 64, N 81-85, isotropic.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:61])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:61])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 106a (150 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (107 μL, 0.61 mmol) followed by methanesulfonyl chloride (29 μL, 0.37 mmol). The reaction mixture was stirred for 2 h. After warming to RT, additional amount of DIPEA (65 μL) and methanesulfonyl chloride (30 μL) were added and stirring was continued for 2 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.59 min, m/z 653 [MH+].
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[CH3:13][N:14]1[C:18]([CH2:19][Li])=[N:17][N:16]=[N:15]1>C(OCC)(=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[O:11])[CH2:19][C:18]1[N:14]([CH3:13])[N:15]=[N:16][N:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: [Li]Cc1nnnn1C
Solvent: CCOC(C)=O
Product: Cn1nnnc1CC(=O)c1ccccc1N

Procedure:
In a similar way to that described in Example 8a, 1H-3,1-benzoxazine-2,4-dione was reacted with (1-methyl-1H-tetrazol-5-yl)methyl lithium to give the novel compound 1-(2-aminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 128°-132° (from ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]2[NH:13][CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A solution containing 34 (370 mg, 1.07 mmol), DIPEA (163 mg, 1.26 mmol), and 2-chloropyrimidine (135 mg, 1.17 mmol) in anhydrous DMF (6 mL) was warmed to 70° C. After 16 h, the reaction mixture was cooled to ambient temperature and diluted with water and subsequently extracted with diethyl ether. The organic extract was washed successively with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 210 mg (46%) of 70 as a white solid. Mass spectrum, m/z [424] (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH2:25]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH3:25])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: C=O
Agent: Cl
Product: CN1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with aqueous formaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-methyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 368.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:28])([F:27])[N:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[CH:21]=[CH:20][C:19]1=[O:26].[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:28])[N:18]1[CH:23]=[C:22]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:21]=[CH:20][C:19]1=[O:26]
Reactant: C=Cc1ccc(=O)n(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C(F)(F)F)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][S:2]([C:4](SC)=[CH:5][N+:6]([O-:8])=[O:7])=O.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:21])[CH2:19][NH2:20])[CH:13]=1>C(O)C>[OH:21][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=1)[CH2:19][NH:20][C:4]([S:2][CH3:1])=[CH:5][N+:6]([O-:8])=[O:7]
Reactant: Cc1cccc(C(O)CN)c1
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCC(O)c1cccc(C)c1
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
In 50 ml of anhydrous ethanol was suspended 9.3 g of 1-methylsulfinyl-1-methylthio-2-nitroethene, and the resulting suspension was stirred. A solution of 9.3 g of DL-[2-hydroxy-2-(3-methylphenyl)ethyl]amine in 5 ml of ethanol was added thereto dropwise at -10° C. to 0° C. over a period of 30 minutes in a nitrogen atmosphere. After the addition, the resulting mixture was stirred at the same temperature for 1.5 hours, and the crystals deposited were collected by filtration, washed with 10 ml of ethanol, and then dried to obtain 7.0 g (yield 50.8%) of 1-{[2-hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethene having a melting point of 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 94 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.25 (s, 4H), 3.76 (s, 4H), 4.15 (s, 3H), 6.86 (d, J=9.0 Hz, 2H), 7.22-7.45 (m, 4H), 7.72-7.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[CH2:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[Cl:19].[OH-:20].[Na+].OO>C1COCC1.O>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[C:5]([CH2:10][CH2:11][OH:20])[CH:4]=1
Reactant: [OH-]
Reactant: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CCO
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a stirring solution of 2,2′,5′-trichloro-4-methoxy-5-vinyl-1,1′-biphenyl (310 mg, 1 mmol) in THF (15 mL) under nitrogen at room temperature, BH3 (2 mL, 1N) was added. After stirring for 8 h, a mixture of NaOH (160 mg, 4 mmol) in water (3 mL) and H2O2 (30% in H2O, 0.3 g, 4 mmol) was added and the resulting mixture was stirred for 6 h. The reaction was quenched with NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desired product (180 mg, 54% yield) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.Br[CH2:20][CH2:21][CH2:22][Cl:23].O>COCCOC.CCOCC>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:7]2)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: O=S1(=O)c2ccccc2C2(CN1CCCCl)OCCO2
Temperature: 100 °C
Yield: 55.9 %

Procedure:
In 1,2-dimethoxyethane (450 mL) was suspended 60% sodium hydride (2.0 g, 502 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (12.06 g, 50 mmol.) was added to the suspension. The suspension was heated to 100° C. for 1 hour under stirring. The reaction liquid was cooled to 50° C., and to this was added a solution of 1-bromo-3-chloropropane (23.62 g, 150 mmol.) in 1,2-dimethoxyethane (50 mL). The mixture was heated to 100° C. for 21 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was evaporated to give a residue. The residue was treated with water and ether, and the organic layer was taken out. The organic solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to leave the desired compound (8.89 g, yield 56%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CN(C)C=O.[CH:12]([O:15][C:16]1[N:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH3:26])[NH:21]2)([CH3:14])[CH3:13]>O1CCOCC1>[CH2:1]([O:28][C:27]([C:19]1[CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:38])([F:39])[F:37])[C:17]2[C:22](=[CH:23][CH:24]=[N:25][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])[NH:21][C:20]=1[CH3:26])=[O:29])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Temperature: 3 °C
Reaction time: 0.67 h

Procedure:
31.4 mg oxalyl chloride are added to a solution of 0.5 mL anhydrous dimethylformamide in 3 mL anhydrous dioxan cooled to 3° C., followed by stirring for 40 minutes at 0° to 5° C. After adding 85 mg (+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid, dissolved in 1 mL anhydrous dioxan, the cooling is removed, followed by stirring for 2.5 hours. After adding 2 mL ethanol, the reaction mixture is first stirred for 2 hours at ambient temperature and thereafter for 30 minutes at 40° to 50° C. The reaction mixture is subsequently stirred with 30 mL 2N aqueous sodium carbonate solution and 10 mL dichloromethane. The organic phase is separated off and the aqueous phase subsequently extracted three times with 10 mL amounts of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and then evaporated to dryness. The residue is purified over silica gel with n-hexane/ethyl acetate (1:1 v/v) as elution agent and subsequently recrystallized from n-hexane. Yield: 32 mg (38.5% of theory); mp 130° C.; [α]D =+105° (c=0.5/dichloromethane).