Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([S:25](Cl)(=[O:27])=[O:26])=[C:16]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:17][C:11]=2[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]1=[O:33]>>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([S:25]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)(=[O:27])=[O:26])=[C:16]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:17][C:11]=2[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:9]1=[O:33]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)Cl)c(Cc3cccnc3)sc21
Reactant: O[C@@H]1CCNC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)N3CC[C@@H](O)C3)c(Cc3cccnc3)sc21
Reaction time: 1 h

Procedure:
(R)-3-Hydroxypyrrolidine (50 mg) was added to the solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(3-pyrdinyl)methyl-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonyl chloride (20 ml). After 1 hour, the solution was dried over anhydrous magnesium sulfate and filtered through a small silica pad, washing with ethyl acetate/methanol (19:1). The filtrate was evaporated and the residue was purified by preparative HPLC with dichloromethane:ethanol gradient elution followed by crystallisation from ethyl acetate/isohexane to give the title compound (11 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([O:19]S(C)(=O)=O)[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)[N:29]=[N:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([O:19][C:34]3[CH:35]=[CH:36][C:31]([N:30]4[C:26]([CH3:25])=[N:27][N:28]=[N:29]4)=[CH:32][CH:33]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnnn1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nnnn1-c1ccc(OC2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Temperature: 70 °C
Yield: 49.4 %

Procedure:
To a solution of (R)-tert-butyl-4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.03 g, 2.84 mmol) and 4-(5-methyl-1H-tetrazol-1-yl)phenol (500 mg, 2.84 mmol) in DMSO (10 mL) was added K2CO3 (1.18 g, 8.51 mmol). The reaction was heated to 70° C. for 12 hours and then diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×15 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to EtOAc to yield tert-butyl-4-(3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (621 mg, 52%) as an off white solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:15])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CCCCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (5.35 g, 7.0 mmol), 2-nonanone (14.2 g, 1.0 mol) and orthophosphoric acid (20 ml). νmax 2925, 2850, 1700, 1450, 1410, 1350, 1220, 1120, 870, 770, 720 cm−1. 1H n.m.r. δ (CDCl3) 0.87, t J 7.2 Hz, 3H, CH3; 1.29, m, 8H, CH2; 2.39, s, 3H, CH3; 2.77, t J 6.8 Hz, 2H, CH2; 6.50, s, CH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[O:17][CH3:18].CON(C)[C:22](=[O:25])[CH2:23][Cl:24]>C1COCC1>[Cl:24][CH2:23][C:22]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[O:17][CH3:18])=[O:25]
Reactant: CCCCCC[C@H](OC)c1cccc(Br)c1OC
Reactant: CON(C)C(=O)CCl
Solvent: C1CCOC1
Product: CCCCCC[C@H](OC)c1cccc(C(=O)CCl)c1OC
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a THF solution of (S)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9, 12.5 g) obtained in the second step was added dropwise a 2M isopropyl magnesium chloride THF solution (44 mL) under ice-cooling. After the reaction solution was stirred at 45° C. for 3 hours, N-methyloxy-N-methyl-2-chloroacetamide (10, 3.5 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and purified by silica gel chromatography to obtain (S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)([O-:18])=[O:17]>C(O)C>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:3][CH2:2][NH:4][CH2:5][C:6]([OH:8])=[O:7])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCNCC(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 55.9 g. (4.0 × 10 -1 moles) of ethyl glycine hydrochloride in 300 ml. of absolute ethyl alcohol was slowly added (~5 minutes) under a nitrogen atmosphere a solution of 70 ml. (5.0 × 10-1 moles) of triethylamine in 200 ml. of absolute ethyl alcohol. The mixture was heated to reflux and a solution of 17.2 g. (1.0 × 10-1 moles) o-nitrobenzylchloride in 200 ml. of absolute ethyl alcohol was added over a 1.5 hour period. Upon complete addition, the mixture was allowed to reflux for 18 hours, cooled to room temperature and the solvent removed in vacuo. To the solid residue was added 500 ml. of water and enough 10% hydrochloric acid to make the solution acidic (pH~3). The acidic solution was washed with methylene chloride (2 × 150 ml.), made neutral (pH~7) by the addition of saturated sodium bicarbonate and the insoluble oil extracted with methylene chloride (2 × 250 ml). The methylene chloride extracts were combined, washed with water (250 ml.), dried (K2CO3) and the solvent removed in vacuo resulting in a yellow oil. Owing to the instability of the oil toward distillation, the compound was used as such in subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][OH:31]>C(Cl)(Cl)Cl>[OH:31][CH2:30][CH2:29][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: NCCO
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCO)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
The crude product (130 mg, 0.39 mmol) from the preparation of 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride was suspended in chloroform. Triethylamine (0.1 mL) and 2-aminoethanol (26 mg, 0.43 mmol) were then added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the product was purified using preparative TLC eluting with EtOAc:hexanes:MeOH=6/4/0.3 to yield 22 mg (16%) of the product as a cream coloured powder. MS (m/z, ES+): 354 (M+1, 100%); 1H NMR (400 MHz, ppm, DMSO-d6): δ 12.25-11.75 (br s, 1H, exchangeable), 8.47 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.59 (br s, 1H, SO2NH, exchangeable), 7-5.5 (br s, 2H), exchangeable), 4.66 (t, J=5.6 Hz, 1H, OH, exchangeable), 3.34 (m, J=6.2 Hz, 2H), 2.80 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:24]=[C:16]2[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20](Cl)[N:15]2[N:14]=1)(=[O:12])=[O:11].C[O-].[Na+].CS(C)=O.[C:32](O)(=[O:34])C>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:24]=[C:16]2[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([O:34][CH3:32])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)O
Reactant: COc1ccc(Cl)n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(OC)n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Temperature: 70 °C

Procedure:
N-(2,6-Difluorophenyl)-5-chloro-8-methoxy[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (1.0 g, 2.7 mmol), sodium methoxide (25 percent in methanol, 2.5 mL, 0.58 g, 11 mmol) and dimethyl sulfoxide (20 mL) were mixed with stirring and slowly heated to 70° C. over a 40-min period. After a short reaction period, the reaction mixture was acidified with acetic acid and diluted With dichloromethane and water. The solid that separated was recovered by filtration. The organic layer was separated, was washed several times with water, and was concentrated by evaporation under reduced pressure. The residue obtained was washed with water and combined with the previously obtained solid. The combined solids were washed with ether and hexane and dried to obtain 0.7 g of the title compound as an off-white powder melting at 319°-320° C.(d).
Reaction SMILES: C[N+]1([O-])CCOCC1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:31])[CH:17]([C:19]2[CH:30]=[CH:29][C:22]3[N:23]([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:21]=3[CH:20]=2)[OH:18])=[C:12]([Cl:32])[CH:11]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:31])[C:17]([C:19]2[CH:30]=[CH:29][C:22]3[N:23]([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:21]=3[CH:20]=2)=[O:18])=[C:12]([Cl:32])[CH:11]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)c1ccc2c(c1)n(C)c(=O)n2C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Methyl-morpholine-4-oxide (280 mg) and tetrapropylammonium perruthenate (36 mg) were added to a solution of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (424 mg) in DCM (5 ml) with 3A molecular sieves. The mixture was stirred for 3 h at room temperature, filtered over SiO2 (10 g) and concentrated to give the title compound (410 mg) as a white foam. MS (m/e)=409.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[OH-].[K+].Br[CH2:18][CH2:19][CH3:20]>C(O)CCC>[CH2:18]([O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCOc1ccccc1C(=O)CCC(=O)O

Procedure:
3-(o-Hydroxybenzoyl)propionic acid (14.6 g.) was dissolved in n-butanol (300 ml.) containing 85% potassium hydroxide (10 g.) and the resultant solution was treated with 1-bromopropane (24.6 g.) and the mixture heated at reflux temperature for 4 hours. It was then cooled, filtered to remove potassium bromide and the filtrate washed with cold water. The butanol was evaporated at reduced pressure and the residual oil distilled at 0.3 mm when the fraction b.p. 160°-180°C was collected (16.4 g.). This was dissolved in methanol (50 ml.), treated with 20 % sodium hydroxide solution (20 ml.) and heated on the steambath for 30 minutes. The methanol was boiled off and the residue diluted with water (250 ml.) and acidified with hydrochloric acid. The precipitated acid was collected and crystallised from 50% methanol. It had m.p. 77°-79°C (Yield 13.3 g.).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([OH:13])(=[O:12])[CH2:8]C(O)=O.C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][CH:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:8][C:7]([OH:13])=[O:12]
Reactant: CC(C)CC=O
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(C)CC(N)CC(=O)O
Temperature: 0 °C
Yield: 55.1 %

Procedure:
To a solution of 43.06 gm (500 mMol) isovaleraldehyde in ethanol (150 ml) were added 52 gm (500 mMol) malonic acid followed by 57.75 gm (750 mMol) ammonium acetate. The suspension was stirred at reflux for 5 hours and the resulting solution was then cooled to 0° C. The resulting solid was filtered, washed with 1:1 ethyl acetate:ethanol (200 ml) and dried under vacuum for 18 hours to give 40 gm of crude 3-amino-5-methylhexanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Al+3].[Cl-:10].[Cl-:11].[Cl-:12].[Cl:13]Cl>ClCCCl>[F:1][C:2]1[C:7]([Cl:10])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([F:8])[C:3]=1[Cl:13]
Reactant: ClCl
Reactant: Fc1cccc(F)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCCl
Product: Fc1c(Cl)c(F)c(Cl)c(Cl)c1Cl

Procedure:
A solution of 100 g (0.88 mol) of 1,3-difluorobenzene in 1 l of 1,2-dichloroethane was admixed with 11.7 g (0.088 mol) of powdered AlCl3. 290 g of chlorine gas were subsequently passed into the solution at 0-5° C. After the end of the reaction, the HCl formed were driven out at about 20-25° C. by means of a stream of nitrogen, and the solution was filtered through silica gel. According to analysis by gas chromatography, the solution comprised 38.5% of dichlorodifluorobenzene, 33.6% of difluorotrichlorobenzenes, 14.5% of difluorotetrachlorobenzene as main components and also further components in the percentage range. A vacuum distillation gave, at 0.2 mbar in the temperature range 50-90° C., 60 g of a fraction comprising the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:27]N1C(=O)CCC1=O>ClCCl.CN(C)C=O>[Br:27][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[NH:1][CH:2]=1
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 339B (1 g) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was cooled in an ice bath. N-bromosuccinimide (0.582 g) was added and the mixture was stirred overnight while warming to ambient temperature. The reaction was concentrated and the crude product was chromatographed on silica gel with a methanol methylene chloride gradient.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[C:13]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([C:17]1[N:22]=[C:21]([NH:23][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=2[C:9]([O:11][CH3:12])=[O:10])[CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cccc(N)n1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Temperature: 130 °C
Yield: 34.8 %

Procedure:
A mixture of methyl 4,6-dichloropyridazine-3-carboxylate (0.69 g, 3.33 mmol) and 6-tert-butylpyridin-2-amine (1.00 g, 6.67 mmol) was dissolved in acetonitrile (3 mL) and heated at 130° C. for 14 h The dark brown mixture was cooled, concentrated onto silica, and purified by chromatography (silica, 80 g, 0-20% acetone in dichloromethane, 40 min) to give methyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (372 mg, 1.16 mmol, 35%) as a yellow solid. MS (EI/CI) m/z: 321.0 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[CH:44]1([C:42]([NH:41][C:39]2[N:40]=[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]4[CH:29]=[C:28]([NH:27][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([N:3]6[CH2:4][CH2:5][CH2:6][C:2]6=[O:1])[CH:8]=5)[CH:49]=[CH:48][CH:47]=4)=[N:37][N:36]3[CH:38]=2)=[O:43])[CH2:45][CH2:46]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(N2CCCC2=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(N2CCCC2=O)c1
Yield: 69.9 %

Procedure:
Using 3-(2-oxopyrrolidin-1-yl)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 70%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:15]=[CH2:16])=[O:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:18].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([C:17](=[O:18])[CH2:16][CH2:15][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:14])=[CH:20][CH:21]=1)=[O:24]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C=CC(=O)c1ccc(OCCCCC)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Yield: 81.8 %

Procedure:
A suspension of 1-(4-n-pentyloxyphenyl)acrolein (2.38 g), methyl 4-formylbenzoate (1.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride and triethylamine (0.91 ml) in ethanol (10 ml) was refluxed for 18 hours. After cooling, the solvents were removed under reduced pressure. The solids were taken up in 1N HCl and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration and dried under reduced pressure to give 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (3.41 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.CN(C)C=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)C>[N:25]([CH2:12][C@H:13]1[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]1[OH:19])=[N+:26]=[N-:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](C)C[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](O)[C@@H](CN=[N+]=[N-])O1
Yield: 77.4 %

Procedure:
A mixture, under argon, of 0.560 g of product from Example 337, 2 ml of N,N-dimethylformamide and 0.250 g of sodium azide is stirred at 75° C. for 12 hours. The reaction mixture is diluted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 0.238 g of the desired product.
Reaction SMILES: [CH2:1]([C:5]1([CH2:36][CH3:37])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:35])[CH2:2][CH2:3][CH3:4].[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH:49]([C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)[CH:48]([CH2:58][CH2:59][CH:60]([OH:67])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:47]2=[O:68])=[CH:42][CH:41]=1>CN(C)C=O>[CH2:1]([C:5]1([CH2:36][CH3:37])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]4[C:47](=[O:68])[CH:48]([CH2:58][CH2:59][CH:60]([OH:67])[C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[CH:49]4[C:50]4[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=4)=[CH:42][CH:41]=3)[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCBr)c2)C1O
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(CN)cc2)cc1
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCNCc3ccc(N4C(=O)C(CCC(O)c5ccccc5)C4c4ccc(OC)cc4)cc3)c2)C1O
Temperature: 80 °C

Procedure:
100 mg of N-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]-5-bromopentanamide and 70 mg of 1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of dimethylformamide and, with stirring, heated at 80° C. for about 2 to 3 hours. After the reaction has ended (monitored by thin-layer chromatogram or HPLC-MS), the solvent is removed under reduced pressure and the residue is purified by chromatography. This gives product 1 of molecular weight 929.24 (C55H68N4O7S); MS (FAB): 929 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)NCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of ethyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-beta-alaninate obtained in Example 5 (470 mg), lithium hydroxide monohydrate (420 mg), water (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (298 mg, 69%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH3:18][O:19][C:20](=[O:41])[CH:21]=[C:10]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CC(C)(C)CCC2=O)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C)(C)CC1c1cccc(OC)c1
Yield: 33 %

Procedure:
Dissolve 2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohexanone (13.1 g, 56.4 mmol) in toluene (135 ml), add (triphenyl-λ5-phosphanylidene)-acetic acid methyl ester (28.3 g, 84.6 mmol. Heat reaction mixture at reflux stirring over night. Dilute with ether, filter and concentrate. Chromatograph on a biotage eluting with 10% ethyl acetate in hexanes to give the title compound (5.3 g 33%): 1H NMR (CDCl3) δ 7.27-7.23(m, 1H), 6.88-6.77 (m, 3H),5.01 (s, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.53-3.48 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.58 (m, 3H), 1.46-1.38 (m, 1H), 1.25-1.20 (m, 1H), 1.11 (s, 3H), 0.96 (s, 3H).