Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].O[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:10])[CH3:9].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:20][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)c1cccc(C(C)(C)O)c1
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: CC(C)(C)OOC(C)(C)c1cccc(C(C)(C)OOC(C)(C)C)c1

Procedure:
1,3-Bis(2-t-butylperoxy-2-propyl)benzene (meta I) was prepared by reacting 29.7 grams (0.231 mole) of aqueous 70% t-butyl hydroperoxide with 20.4 grams (0.105 mole) of 1,3-bis(2-hydroxy-2-propyl)benzene in the presence of 26.8 grams (0.21 mole) of 77% sulfuric acid according to the procedure of Example I. The stripped product weighed 32.6 grams. It crystallized upon cooling and had a melting point of 45°-52° C. This example is for comparative purposes and does not fall under the specifications of this invention. The peroxide assay was 97% of theoretical.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si:30]([O:37][CH2:38][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:40][OH:41])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CC(C)([O-])C.[K+]>C1COCC1>[Si:30]([O:37][CH2:38][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:40][O:41][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCO1)CO[Si](C)(C)C(C)(C)C
Yield: 69.8 %

Procedure:
A mixture of Example 32B (87 mg, 0.2 mmol), (R)-tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethylcarbamate (62 mg, 0.2 mmol) and 1N potassium tert-butoxide in THF (0.2 mL, 0.2 mmol) in THF (10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure to afford 100 mg of the title compound. MS (DCI/NH3) m/z 716 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][C:18]([C:26](OCC)([O:31]CC)[CH2:27][CH2:28][CH2:29]Cl)=[CH:19][CH:20]=3)[CH2:15][C:14]=2[CH:13]=1)(OCC)[O:6]CC.[I-].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>O1CCCC1>[O:42]1[CH2:43][CH2:44][N:39]([CH2:2][CH2:3][CH2:4][C:5]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:6])[CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: CCOC(CCCCl)(OCC)c1ccc2c(c1)Cc1cc(C(CCCCl)(OCC)OCC)ccc1O2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCOCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCOCC3)ccc1O2
Temperature: 110 °C

Procedure:
A mixture of 43.2 g (0.08 mole) 2,7-bis(4-chloro-1,1-diethoxybutyl)xanthene, 2 g. of potassium iodide, 100 ml. of morpholine and 100 ml. tetrahydrofuran was heated for 24 hours with stirring in a Paar bomb at 110°C. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was cooled, dissolved in 300 ml. of 10% HCl and refluxed for 1 hour. The solution was cooled, filtered, the filtrate made alkaline, and extracted with chloroform. The chloroform extract was evaporated to dryness and the residue was recrystallized twice from a 1:4 mixture of benzene in heptane. Upon drying under vacuum, the desired product was obtained. M.P. 110°-111.5°C.
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[OH:19][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH:8]=[O:9]
Reactant: OC[C@@H]1CCCN1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.9 g, 10.0 mol) in dichloromethane (40 ml) was added dropwise to a stirred solution of (S)-pyrrolidin-2-yl-methanol (1.0 g, 10.0 mmol) and triethylamine (2.8 ml, 20.0 mmol) in dichloromethane 60 ml. The reaction mixture was stirred for 10 minutes at ambient temperature and then allowed to stand for 3 h at ambient temperature. The reaction mixture was washed with 1M NaOH (30 ml) and 2M HCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.76 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1). 1.28 g (49% of theory) of (3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-((S)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone was obtained in form of an oil.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][NH:9][CH:10]=[CH:11][CH:12]=1.[C:13](=O)([O-])[O-:14].[K+].[K+]>O.C(OC)=O>[CH:13]([N:9]1[CH:10]=[CH:11][CH:12]=[C:6]([O:5][CH2:4][CH2:3][Br:2])[CH:7]=[CH:8]1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: BrCCOC1=CC=CNC=C1
Agent: Br
Agent: [K+]
Solvent: COC=O
Solvent: O
Product: O=CN1C=CC=C(OCCBr)C=C1
Reaction time: 24 h

Procedure:
To a solution of (D) (10 g) in water (5 ml), methyl formate (50 ml) and potassium carbonate (10 g) were added. The mixture was stirred for 24 hours, and the organic phase was decanted. The residue was extracted twice with methyl formate. The combined organic solutions were concentrated in vacuo, and the residue was dissolved in ether, dried and chromatographed on silica gel (50 g) with ether as eluent to give (E) as a colourless oil. The IR spectrum (chloroform) showed a strong band at 1650 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Yield: 76.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 4-chloro-3-nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane (500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol) and 4-amino-1-butanol (46.87 g, 525.87 mmol) to give a homogeneous, dark yellow solution. The reaction was judged to be complete after heating at reflux for 30 minutes. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined and then concentrated under reduced pressure to afford of 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (104.67 g, 400.60 mmol) as a dark yellow solid. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH3:13].CC1C=CC=C(C)[C:25]=1[NH2:26].BrCCC(Br)C.Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cccc(C)c1NCCC(C)Nc1c(C)cccc1C
Reactant: Cc1cccc(C)c1N
Agent: CC(Br)CCBr
Agent: Cl
Product: Cc1cccc(C)c1N1CCC(C)N(c2c(C)cccc2C)C1=N
Yield: 45.6 %

Procedure:
1,3-Bis(2',6'-dimethylphenyl-amino)-butane, applied as starting substance, can be prepared e.g. by the method of Shapiro et al. (loc. cit.), utilizing 2,6-dimethylaniline and 1,3-dibromobutane as starting materials. The free base boils at 159°-160° C./0.1 mm Hg, and the hydrochloride melts at 178°-180° C. Yield: 45.6%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[CH3:22][O:23][CH:24]([O:28][CH3:29])[C:25](=[O:27])[CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:25]([OH:27])([CH3:26])[CH:24]([O:28][CH3:29])[O:23][CH3:22])=[CH:9][N:10]=1
Reactant: COC(OC)C(C)=O
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)C(C)(O)c1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (1.00 g) in tetrahydrofuran (20 mL) was slowly added a 1.6M n-butyllithium hexane solution (4.5 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and 1,1-dimethoxypropan-2-one (1.50 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.58 g, yield 90%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 276 (MH+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Ca+2].[Cl-]>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Ca+2]
Agent: [Cl-]
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 33 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and calcium chloride (1 g, 9 mmol) were added to (S)-epichlorohydrin (185 g, 2 mol). The mixture was stirred at room temperature (33° C.) for 8 hours. Filtered, and the solvent was evaporated to provide 57 g of colorless oil in 97% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Yield: 19.3 %

Procedure:
To a solution of (2R,6S)-2,6-dimethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (0.29 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.5 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH3:42])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-hydrochloride and methyl chloroformate. Yield: 62% of theory, C28H29N7O5 (543.6) Rf value: 0.19 (silica gel; dichloromethane/ethanol=19:1) ##EQU86##
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29]>>[CH3:12][C:8]1([CH3:11])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:30][C@H:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[CH3:29])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc2ccccc2c1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc2ccccc2c1
Yield: 78 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-naphthalen-2-yl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 78% of theory; LC (method 6): tR=1.27 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:34])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2([CH:23]=[C:22]([F:34])[CH2:21][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:4]=3)[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 0 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.5 g), tetrahydrofuran (2 ml) and magnesium (38.6 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-chlorophenyl)cyclopropane (Example 17) (0.34 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: Nitrile; solvent: methanol; flow rate: 2 ml/min) to afford 1-(4-chlorophenyl)-1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)cyclopropane (0.11 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][O:11][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: C/C(CO)=C(\C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(C)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 95.3 %

Procedure:
The title compound (0.91 g, 95% yield) was prepared from (Z)-3-(4-bromophenyl)-2-methyl -but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH2:26]([N:22]1[CH2:23][C:24](=[O:25])[N:9]2[C@H:10]([CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][CH:4]=2)[C:21]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NS(C)(=O)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O

Procedure:
To a solution of Example 98 (0.2 g) in THF (5 mL) was added triethylamine (228 μL) and methanesulfonyl chloride (126 μL) and the solution was heated at reflux for 6 hours. After evaporation of THF, the residue was taken up in CH2Cl2, washed with water and dried over Na2SO4. After evaporation of CH2Cl2, the residue was purified by radial chromatography eluting with CH2Cl2 /MeOH (95/5) to give the title compound as a brown powder (30 mg) m.p.:188° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].CN1C(NCCCO)=C(C)C(=O)N(C)C1=O.S(Cl)(Cl)=O.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1(C)C(C)=CC=CC=1.C(N(CCC)CCC)CC>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:47]2[CH2:46][CH2:45][N:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[OH:37])[CH2:49][CH2:48]2)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1c(NCCCCl)n(C)c(=O)n(C)c1=O
Agent: CCCN(CCC)CCC
Agent: Cc1c(NCCCO)n(C)c(=O)n(C)c1=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(NCCCN2CCN(c3ccccc3O)CC2)n(C)c(=O)n(C)c1=O

Procedure:
The 1,3,5-trimethyl-6-(3-chloropropylamino)-2,4(1H,3H)-pyrimidinedione prepared from 6.8 g (30 mmol) of 1,3,5-trimethyl-6-(3-hydroxypropylamino)-2,4(1H,3H)pyrimidinedione with thionyl chloride is refluxed for 15 h with 4.5 g (25 mmol) of 1-(2-hydroxyphenyl)piperazine in 140 ml of xylene and 20 ml of tripropylamine. The dark oil obtained after customary work-up is purified by column chromatography on silica gel using dichloromethane/methanol (1-10%). From the product fractions, the fumarate is precipitated from ethyl acetate/ethanol using fumaric acid, yield 5.9 g (47%), m.p. 203-205° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:12][S:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)n1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (2.90 g, 20.0 mmol) in methylene chloride (40 mL) was added with methanesulfonyl chloride (1.86 mL, 24.0 mmol) and diisopropylethylamine (3.10 g, 24.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the objective 1-(methanesulfonyl)-1H-indole-3-carboxaldehyde (4.06 g, 91%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: CC1CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 81.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 170 mg of 3-methylindoline and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 310 μl of pyridine and 6.0 ml of N,N-dimethylformamide. 367 mg of 2-[2-(3-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white crystalline powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CCCCOC(=O)c1nc(-c2cnccn2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 4-bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and 2-(tributylstannyl)pyrazine: MS (m/z) 345.2 (M+1)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C(Cl)Cl>[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:14])[CH:5]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Nc1cnnc(Cl)c1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(Nc1cnnc(Cl)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(6-chloropyridazin-4-yl)amino]-2-methylpropanoic acid dihydrochloride I-21b (1.23 g, 4.26 mmol), HOBT (0.979 g, 6.39 mmol), EDC (1.226 g, 6.39 mmol), and trifluoroethyl amine hydrochloride (0.866 g, 6.39 mmol) were added to DCM (20.0 ml) followed by the addition of TEA (29.7 ml, 213 mmol). The reaction was allowed to stir at room temperature for 17 hrs. The reaction was then diluted with DCM, washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and concentrated in vacuo to an oil. Purification on Biotage Normal Phase system (DCM:MeOH, 0-8% B) to afford the product I-21 as a solid. The solid was dried under vacuum (295 mg, 22.3%). LRMS (ESI) m/z 297.0 [(M+H)+; calcd for C10H12ClF3N4O: 297.0].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:20]=1[NH2:21])([CH3:18])[CH3:17]>>[CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[C:20]=1[N:21]1[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[C:7]2[C:12]1=[O:13])([CH3:28])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc(C(C)(C)C)cc2C1=O

Procedure:
0.605 g of 4-tert-butylphthalic anhydride and 0.630 g of 2,6-diisopropylaniline were mixed, and the mixture was reacted at a temperature of 200° C. for 1 hour.