Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH:7]([CH3:10])[CH2:6][S:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O.S(Cl)(Cl)(=O)=O.C(Cl)Cl.Cl>C(Cl)Cl.O>[C:1]([C:4]1[S:5][CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)C1SCC(C)C1=O
Agent: Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1scc(C)c1O
Reaction time: 0.5 h

Procedure:
36.0 g (0.227 mol) of 2-acetyl-3-keto-4-methyl-4,5-dihydrothiophene are initially introduced into 260 ml of methylene chloride 21.9 ml of sulphuryl chloride in 260 ml of methylene chloride are then added dropwise at 0° C. While the sulphuryl chloride/methylene chloride mixture is added dropwise, a stream of nitrogen is passed into the solution to expel the HCl gas which is formed. When the addition is complete, stirring is continued for 30 minutes at 10°-15° C. The mixture is then introduced into 600 ml of water, and the organic phase is extracted with a 5% strength NaHCO3 solution, dried and concentrated in vacuo.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](N)=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[ClH:28].N([O-])=O.[Na+].[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]([CH3:36])=[CH2:35]>O.CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:35][C:34]([Cl:28])([CH3:36])[C:33]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)OCC
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1

Procedure:
Following the same procedure as described in Preparation 18, 2 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman (prepared as described in Preparation 50), 25 ml of acetone, 3 ml of 35% w/v aqueous hydrochloric acid, 0.7 g of sodium nitrite, 1 ml of water, 8 g of ethyl methacrylate and 0.2 g of cuprous oxide were reacted, to give the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 90 °C
Yield: 98 %

Procedure:
Pyrrolidine (4.26 g, 60 mmol) was added to a solution of cyclohexene oxide (1.96 g, 20 mmol) in H2O (6 mL), and the resulting mixture was heated at 90° C. for 16 hours. After cooling, the solvent was removed under reduced pressure and the resulting residue was extracted with DCM (10 mL×3). The organic phases were combined and dried with anhydrous Na2SO4. After removing the Na2SO4 by filtration, the solvent was evaporated and the material dried under vacuum to afford the desired compound (+/−)-1 (3.3 g, 19.5 mmol, yield 98%). 1H NMR (CDCl3) δ 4.06 (s, 1H), 3.45-3.30 (m, 1H), 2.75-2.63 (m, 2H), 2.62-2.50 (m, 2H), 2.51-2.42 (m, 1H), 1.90-1.58 (m, 8H), 1.45-1.15 (m, 4H).
Reaction SMILES: O=P(Cl)(Cl)Cl.O=[C:7]1[CH:13]([NH:14][CH:15]=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2>C1(C)C=CC=CC=1>[O:16]1[C:7]2[C:8]3[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=3[S:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]=2[N:14]=[CH:15]1
Reactant: O=CNC1C(=O)c2ccccc2Sc2ccccc21
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)Sc1ccccc1-c1ocnc1-2

Procedure:
To a solution of POCl3 (0.137 g, 0.892 mmole) in dry toluene (5 ml), N-(11-oxo-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-formamide (III; X=S, Y=Z=H. A=NH, R1=H) (0.06 g, 0.223 mmole) dissolved in toluene (10 ml) was added. The reaction mixture was heated under reflux for 2 hours. Then toluene was evaporated to dryness and water was added and it was extracted with ethyl acetate. The organic extract was washed with a saturated NaHCO3 solution and water and dried over anhydrous Na2SO4. The solvent was evaporated and, after purifying by chromatography on a column, an oily product was isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.[CH3:21][C:22]([O:25][C:26]([NH:28][C@H:29]([CH2:33][CH3:34])[C:30](O)=[O:31])=[O:27])([CH3:24])[CH3:23].CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:14]=[CH:15][C:16]([NH:19][C:30]([C@H:29]([NH:28][C:26](=[O:27])[O:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH2:33][CH3:34])=[O:31])=[CH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC2(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 33, 220 mg, 0.81 mmol) was dissolved in ethyl acetate (10 mL) and of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (181.1 mg, 0.89 mmol) was added followed by the addition of Et3N (0.35 mL, 2.02 mmol). The resulting solution was cooled down to 5° C. and a solution of T3P 50% w/w in ethyl acetate (0.53 mL, 0.89 mmol) was added drop wise in 15 min. The reaction mixture was stirred for 30 min at 5° C. The reaction was quenched with water (50 mL) and ethyl acetate (50 mL), two phases were separated and the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 60:40 as eluent affording the title compound (213 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:31]2[CH2:30][CH:29]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:34])[F:35])=[CH:23][CH:24]=3)[CH2:33][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 5-Methanesulfonyl-2-morpholin-4-yl-benzoic acid and 4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 495.4 (MH+, 100%)
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]>CO.C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20]([S:2][CH3:1])[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N(Cc1ccccc1)c1cc(SC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Sodium methanethiolate (180 mg) was added portion-wise to a stirred suspension of (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (300 mg) in methanol:THF (3:1, 4 ml). The mixture was sealed in a ReactiVial then left to stir at room temperature for 2 hours. The reaction mixture was diluted with methanol then pre-absorbed directly onto silica gel. The crude was columned on Isco Companion on a silica column (12 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 30:70 to 50:50 over 6 column volumes. The desired fractions were combined and evaporated to provide the title compound (297 mg) as a yellow gum.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:44][C:45]1[CH:49]=[C:48]([Sn](C)(C)C)[S:47][N:46]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:48]2[S:47][N:46]=[C:45]([CH3:44])[CH:49]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Cc1cc([Sn](C)(C)C)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)sn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g, 0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) were combined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel was added 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and, after purging with argon, the reaction was stirred at 100° C. for 2 h and then concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting first with 100% EtOAc followed by 20% EtOAc in hexanes -isocratic) to yield 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) as a yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine was converted to the title compound using a procedure similar to 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[Cl:14].[I-:20].[Na+]>CC(C)=O>[Cl:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[O:6][CH:5]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:3][CH2:2][I:20]
Reactant: ClCCCC(Oc1cc(Cl)ccc1Cl)c1cccs1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(Cl)c(OC(CCCI)c2cccs2)c1
Yield: 95 %

Procedure:
2-[4-Chloro-1-(2,5-dichlorophenoxy)butyl]thiophene (2.4 g, 7.1 mmol) was dissolved in a saturated solution of sodium iodide in acetone (200 ml) and the reaction refluxed for 20 hours. The reaction mixture was cooled and the solid filtered off. The filtrate was evaporated in vacuo and the residue taken up in water (50 ml). The mixture was extracted with diethyl ether (3×70 ml) and the combined organic portions were washed with water (3×30 ml), dried (magnesium sulphate), filtered and evaporated in vacuo to give the title compound as a pale straw coloured oil (2.91 g, 95%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][O:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](C)(C)C)[N:18]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][O:13][CH:12]1[C:17]1[N:18]=[C:19]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: C[Sn](C)(C)c1cccc(C2OCCCO2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1cc(-c2n[nH]c3ccccc23)nc(C2OCCCO2)c1
Reaction time: 0.25 h

Procedure:
60 mg of Pd(PPh3)4 are added to 0.82 g (3.35 mmol) of 3-iodoindazole in 10 ml of DMF at room temperature under argon, and the mixture is stirred for 15 minutes. 1.1 g (3.35 mmol) of 2-(1,3-dioxan-2-yl)-6-trimethylstannylpyridine are added and the mixture is stirred at 100° C. for 4 hours. It is then evaporated in vacuo and the residue is chromatographed over silica gel. 300 mg (32% of theory) of an oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Clc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (19, 100 mg, 0.23 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (551 mg, 0.897 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (40 mL), and extracted with EtOAc (3×50 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 31.5 mg (30%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.95 (s, 1H), 7.65 (d, 1H), 7.50 (s, 1H), 7.35 (t, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 4.25 (m, 4H), 3.05 (t, 2H), 2.80 (t, 2H), 2.30 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(C(C)=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[O:27][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1SC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(Cl)c1SC(F)F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of 2-chloropyrimidine (150 mg), 2-chloro-5-[4-chloro-5-[(difluoromethyl)-thio]-1-methyl-1H-pyrazol-3-yl]-4-fluorophenol (0.3 g) and potassium carbonate (0.18 g) in N,N-dimethylformamide and methyl ethyl ketone (1:4, 20 ml) was heated at reflux overnight. The resulting mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo and the residue purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:3) to give 2-[2-chloro-5-[4-chloro-5-[(difluoromethyl)thio)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]pyrimidine, (0.29 g).
Reaction SMILES: FC1C=C(C2C3COCCC=3N([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])N=2)C=CC=1F.[F:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[C:39]1[C:40]2[CH2:47][CH2:46][O:45][CH2:44][C:41]=2[NH:42][N:43]=1.N[C@@H](C(C)(C)C)[C:50](NCCO)=[O:51]>>[OH:51][CH2:50][CH2:21][NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14]([N:42]1[C:41]2[CH2:44][O:45][CH2:46][CH2:47][C:40]=2[C:39]([C:32]2[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=2[F:30])=[N:43]1)=[O:15])[C:22]([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: Fc1cc(F)c(-c2n[nH]c3c2CCOC3)cc1F
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1COCC2)C(=O)NCCO

Procedure:
Compound 97 was prepared according to the procedure for the synthesis of compound 28 by replacing intermediate 16 with intermediate 16D, and replacing tert-leucine methylamide with intermediate 23. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.81 (d, J=9.1 Hz, 1H), 7.51-7.54 (m, 1H), 7.02-7.05 (m, 1H), 6.37 (br, 1H), 5.03 (d, J=8.9 Hz, 2H), 4.14 (d, J=9.2 Hz, 1H), 3.83-3.90 (m, 2H), 3.74 (br, 2H), 3.45 (br, 2H), 3.35 (br, 1H), 2.64 (br, 1H), 1.06 (s, 9H). Purity: 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5](S(C2C=CC(C)=CC=2)(=O)=O)[N:4]=1.[OH:21][CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:21][CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24])[N:6]=1
Reactant: COc1cc(OC)nc(S(=O)(=O)c2ccc(C)cc2)n1
Reactant: COC(=O)C(O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)C
Reaction time: 5 h

Procedure:
2.94 g (10.0 mmol) of 4,6-dimethoxy-2-(p-toluenesulfonyl)pyrimidine and 1.55 g (10.5 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide to 100° C. with stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 30 ml of water and 30 ml of dichloromethane. After the organic phase had been separated off, the aqueous phase was again extracted with 20 ml of dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 2.30 g (80.9 percent of theory) in the form of yellowish crystals (GC content 100 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[N:12](C)[N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)[CH:9]=1.COC1C=C(C=CC=1OC)OCC1NN=C([C@@H]2CCCN2C(OC(C)(C)C)=O)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[NH:12][N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)nn2C)cc1OC
Agent: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)n[nH]2)cc1OC
Product: COc1ccc(OCc2cc([C@@H]3CCCN3)n[nH]2)cc1OC

Procedure:
The procedure of Example 13-(3) was repeated, except that the compound obtained in Example 13-(2) was replaced by the compound (460 mg) obtained in Example 15-(1); this gave the titled compound (339 mg, pale brown oil.)
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([S:16]([CH3:15])(=[O:18])=[O:17])[S:16]([CH3:15])(=[O:18])=[O:17])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Product: CC1=NN(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)C(=O)C1

Procedure:
From the reaction of 5-methyl-2-(4-aminophenyl)-2,4-dihydro-pyrazol-3-one and methansulfonylchloride (reaction per Example 11, where methanesulfonylchloride is used in respective molecular amounts), N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-N-methylsulfonylmethanesulfonamide is obtained. Subsequent reaction with 2-ethyl aniline yields N-(4-(4-(2-Ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-N-methylsulfonylmethansulfonamide, Mp: 268° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][NH2:18])[CH3:13].[CH:21]([C:23]1[NH:27][C:26]([CH:28]([CH3:30])[CH3:29])=[C:25]([C:31](O)=[O:32])[C:24]=1[CH:34]([CH3:36])[CH3:35])=O>>[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][NH:18][C:31]([C:25]1[C:24]([CH:34]([CH3:35])[CH3:36])=[C:23]([CH:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:27][C:26]=1[CH:28]([CH3:30])[CH3:29])=[O:32])[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCN
Reactant: CC(C)c1[nH]c(C=O)c(C(C)C)c1C(=O)O
Product: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(C)C
Yield: 25.8 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (90 mg, 0.42 mmol) was conducted with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amine (140 mg) to give 54 mg (25%) of the title compound as red-brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([O:5][C:6](=[O:16])[C@H:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCC[C@@H](O)CC(=O)OC(C)(C)C
Reactant: CCCCCI
Product: CCCCCC[C@@H](O)[C@@H](CCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (2.49 g, 38%) was obtained in the same manner as in Production Example C-1, except that the (R)-3-hydroxynonanoic acid t-butyl ester (5.00 g, 21.7 mmol) obtained in Production Example B-3 and 1-iodopentane (5.59 g, 28.2 mmol) were used.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH3:16])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=2[N:10]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=1>>[ClH:18].[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH3:16])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[Cl:18])=[CH:27][CH:28]=3)=[O:33])=[CH:11][C:9]=2[N:10]=1.[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH3:16])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[Cl:18])=[CH:31][CH:30]=3)=[O:34])=[CH:11][C:9]=2[N:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CN(C)CCN(C)c1nc2cc(N)ccc2o1
Product: CN(C)CCN(C)c1nc2cc(NC(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3)ccc2o1
Product: Cl

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzooxazole-2,5-diamine (0.40 g, 1.71 mmol), and 2′,4′-dichloro-biphenyl-4-carboxylic acid (0.59 g, 2.22 mmol) to afford 2′,4′-dichloro-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzooxazol-5-yl}-amide (0.64 g, 77%). The prepared material (0.23 g, 0.473 mmol) is dissolved in EtOH and treated with 1.0 M HCl in EtOH (0.45 mL). The reaction is refluxed and the hydrochloride salt is isolated by centrifuge after precipitation with heptane as a white solid (0.18 g, 0.347 mmol, 73%). LC/MS (m/z): calcd for C25H24Cl2N4O2HCl (M+H)+: 483.4; found: 483.3.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH2:18][C:19]1[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=[C:21]([N:29]([CH2:33][CH:34]=[CH2:35])[CH2:30][CH:31]=[CH2:32])[N:20]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:33]([N:29]([CH2:30][CH:31]=[CH2:32])[C:21]1[N:20]=[C:19]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=1)[CH:34]=[CH2:35]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1

Procedure:
3.3 g. of benzoic acid are dissolved in 70 ml. of methylene chloride and 2.7 g. of triethylamine. The solution is stirred and treated at 0° C. with 3.5 g. of isobutyl chloroformate in 25 ml. of methylene chloride. The mixture is then stirred at 0° C. for 30 minutes and subsequently at room temperature for 1 hour. The solution is treated with a suspension of 5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one in 200 ml. of methylene chloride, 12.5 ml. of triethylamine and 0.6 g. of 4-dimethylaminopyridine. The mixture obtained is stirred at room temperature for 18 hours and then washed with 100 ml. of water. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by column chromatography, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.