Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)[CH2:19][CH3:20]
Reactant: CCCN
Reactant: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Product: CCCNC(=O)c1ccc(C=Cc2ccccc2)cc1

Procedure:
Using preparation method 1, 73B (67 mg, 0.3 mmol) was reacted with n-propylamine (27 μL, 19.5 mg, 0.33 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/EtOAc 80:20. White crystals were obtained (48 mg, 61%). NMR 1H (ppm, CDCl3): 7.74 (d, J3=8.4 Hz, 2H), 7.53 (d, J3 8.1 Hz, 2H), 7.51 (d, J3=6.4 Hz, 2H), 7.35 (t, J3=7.1 Hz, 2H), 7.27 (tt, J3=7.2 Hz, J4=2.4 Hz, 1H), 7.17 (d, J3=16 Hz, 1H), 7.09 (d, J3=16 Hz, 1H), 6.21 (br. s, 1H), 3.45-3.38 (m, 2H), 1.64 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C(C)C)=[O:15])=O)(=O)=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)(C)C=O.C(Cl)Cl.CCOCC>[NH:36]1[CH:37]=[C:33]([CH2:32][CH2:13][C:14]([NH2:16])=[O:15])[N:34]=[CH:35]1
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)CCc1c[nH]cn1
Reaction time: 24 h

Procedure:
130 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 130 mg of p-toluenesulphonic acid in 1 ml of trimethylacetaldehyde and 10 ml of methylene chloride are left to stand at room temperature for 24 hours. Thereafter, the reaction mixture is taken up in ether and the organic phase is washed in succession with 2N sodium bicarbonate solution and water, dried and evaporated. Chromatography of the residue on 30 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia yields (S)-N-[(S)-1-[(2R or S,4R,5S)-2-t-butyl-5-isopropyl-1,3-dioxolan-4-yl]-2-cyclohexylethyl]-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 701 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C(#N)C>O1CCOCC1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1)=[O:35]
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: COc1ccccc1C(=O)c1cccc(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 62 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (4.5 g) is added, at a temperature between 62° and 69° C., to a solution of 3'-amino-2-methoxybenzophenone (3.4 g) and triethylamine (3.05 g) in dioxane (90 cc) which is heated to a temperature in the vicinity of 62° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed with distilled water (100 cc), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 45° C. A crude product (6.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (60 cc). Decolourizing charocal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and 3 times with diethyl ether (60 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-methoxybenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (4.1 g) in the form of white crystals, m.p. 184° C., is thereby obtained.
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:45]=[N+:46]=[N-:47])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:39])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:47][N:46]=[N:45][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), trimethylsilylazide (0.54 mL), dibutyltinoxide (0.086 g) and toluene (3 mL) was stirred at 100° C. for 5 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.075 g, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.BrBr.[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[N:18]1([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCOC(=O)CCCc1c[nH]c2ccccc12
Reactant: c1c[nH]cn1
Agent: BrBr
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)CCCc1c(-n2ccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl-4-(3-indolyl)butyrate (3.00 g) and imidazole (4.43 g) in dioxane (75 ml) stirring at 10° is added dropwise while stirring a solution of bromine (0.65 ml) in dioxane (25 ml) over a period of 2.5 hours. Immediately upon the addition of bromine the reaction mixture becomes a thick suspension. Additional dioxane (30 ml) is added to keep the reacton mixture more mobile. Upon complete addition to cooling bath is removed and the reaction mixture allowed to stir at room temperature overnight. The suspended solid is removed by vacuum filtration and the filtrate concentrated in vacuo to give an orange oil. This oil is suspended in either (100 ml) and extracted with 1N hydrochloric acid (1×50 ml). The aqueous layer is washed with ether (1×100 ml), made basic with 3 N sodium hydroxide (12 ml), and extracted with ether (2×100 ml). This ether extract is washed with brine, dried (MgSO4 ), filtered, and concentrated in vacuo to give an orange oil which becomes partially crystalline. This material (1.38 g) is dissolved in 20 ml ether and to the solution is added 0.65 ml of 7.1M ethanolic hydrogen chloride. The salt separates as an oil which crystallizes on addition of a few milliliters of ethanol to yield 2-(1-imidazolyl)-3-(-3-ethoxycarbonylpropyl)indole hydrochloride, m.p. 152°-155°.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:28])[CH2:25][C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:28][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:25][C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2cc(F)c(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (1.50 g, 5.75 mmol), 2-amino-5,6-difluoro-indan-2-carboxylic acid ethyl ester (1.39 g, 5.75 mmol), HATU (2.63 g, 6.90 mmol) in anhydrous DMF (6 mL) is added DIPEA (1.14 mL, 6.90 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (200 mL) and washed with water (1×20 mL) and brine (2×20 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (400 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give a pure product (156) as white solid (2.32 g, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:10](=[O:22])[CH2:9]1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([O-:29])=[O:24].[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH2+:8][CH2:9][C:10]2=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: O=C1C[NH2+]CCN1Cc1ccc(F)cc1

Procedure:
A solution of 34 (1.4 g, 4.5 mmol) in 6 mL of a 1:1 solution of CH2Cl2:TFA was stirred at ambient temperature for 2 hours when all of the starting materials were consumed as judged by TLC. The reaction mixtures were dried in vacuo to yield 1.5 g of 35 as a thick oil which was used in the next reaction without purification.
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=1[OH:10])([CH3:7])([CH3:6])[CH3:5].[CH3:16][C:17](O)([C:20]#[N:21])[CH:18]=[CH2:19].P(=O)(O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:10][C:9]1[CH:11]=[C:12]2[C:13](=[CH:14][C:8]=1[C:4]([CH3:7])([CH3:5])[CH3:6])[O:15][C:17]([CH3:16])([C:20]#[N:21])[CH2:18][CH2:19]2
Reactant: C=CC(C)(O)C#N
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C#N)CCc2cc(O)c(C(C)(C)C)cc2O1
Yield: 30 %

Procedure:
Using the method described in the last paragraph of Example 1, but with methylene chloride instead of toluene, 56.0 g (0.338 mole) of tert.-butyl hydroquinone were reacted with 33.6 g (0.338 mole) of methyl vinyl ketone cyanohydrin, which was stabilized with 1 g of phosphoric acid. After chromatography of the crude product over silica gel, using toluene/ethyl acetate, 6-hydroxy-7-tert.-butyl-2-methyl-2-cyanochromane was obtained in 30% yield, as colorless crystals of melting point 153°-155° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[C:5]2[CH:4]=[N:3]1.O.O.Cl[Sn]Cl.N>CCO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[C:5]2[CH:4]=[N:3]1
Reactant: CN1CCN(Cc2cc(-c3ccc([N+](=O)[O-])cc3)c3cnn(C)c3n2)CC1
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2cc(-c3ccc(N)cc3)c3cnn(C)c3n2)CC1
Yield: 68.2 %

Procedure:
In analogy to GP3, 1.06 g of 1-methyl-6-(4-methyl-piperazin-1-ylmethyl)-4-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 17.8; 2.89 mmol, 1 eq.) were dissolved in 15 mL EtOH, treated with 3.26 g SnCl2.2H2O (14.46 mmol, 5 eq.) and stirred at reflux for 2 h. The reaction was poured into conc. NH3, partitioned between CH2Cl2 and water, the aqueous layer was re-extracted, the combined organic layers were dried and concentrated in vacuo to yield 663 mg of the crude aniline (1.97 mmol, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:13][C:9]3([CH2:12][CH2:11][CH2:10]3)[CH2:8][CH:7](O)[C:6]=2[CH:15]=1.S(=O)(=O)(O)[OH:17].[C:21](#[N:23])[CH3:22]>>[C:21]([NH:23][CH:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8]1)(=[O:17])[CH3:22]
Reactant: CC#N
Reactant: OC1CC2(CCC2)Oc2ccc(Cl)cc21
Reactant: O=S(=O)(O)O
Product: CC(=O)NC1CC2(CCC2)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-Chloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1′-cyclobutane] (10 mmol) in acetonitrile (30-50 ml) was added to a solution of concentrated sulfuric acid (30 mmol) in acetonitrile (10 ml), at 0 to −10° C. The reaction mixture was stirred for about 2 hrs and was allowed to warm up, to room temperature. It was then added on ice. The corresponding acetamido derivative was separated out as a white solid which was filtered, washed with water and dried.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[S:33][C:11]2[NH:12][C:13]([C:15]([NH:17][CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29]SC)[C:19]3=[O:32])=[O:16])=[CH:14][C:10]=2[CH:9]=1.[CH3:34]O>O.CCOC(C)=O>[Cl:7][C:8]1[S:33][C:11]2[NH:12][C:13]([C:15]([NH:17][CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29][S:3]([CH3:34])(=[O:5])=[O:2])[C:19]3=[O:32])=[O:16])=[CH:14][C:10]=2[CH:9]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h

Procedure:
Oxone (701 mg, 1.14 mmol) in H2O (12 mL) was added to 2-chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 34; 462 mg, 1.10 mmol) in MeOH (12 mL) and stirred for 18 hours. The mixture was diluted with EtOAc (100 mL) washed with saturated NaHCO3 (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (3:2) then DCM:MeOH (4:1)) to give 2 yellow solids. Each solid was triturated separately with refluxing Et2O (25 mL) and filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compounds (Example 35, 104 mg, 22% and Example 36, 230 mg, 46%) as solids.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>>[CH3:1][N:2]1[C:6]([NH:7][C:13](=[O:14])[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][C:4]([C:8]([F:9])([F:10])[F:11])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Product: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Yield: 25.9 %

Procedure:
Using the procedure described in Example 161C, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.70 g, 10.3 mmol) and phenyl chloroformate (1.88 g, 12 mmol) were reacted to afford phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (0.760 g, 26%). LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([CH:12]1[N:16]([CH2:17][C:18]#[CH:19])[C:15](=[O:20])[CH2:14][CH2:13]1)=[O:11].C=O.N1CCC[C:24]1=O>CO.O1CCOCC1>[CH3:8][O:9][C:10]([CH:12]1[N:16]([CH2:17][C:18]#[C:19][CH2:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:24])[CH2:4][CH2:3]2)[C:15](=[O:20])[CH2:14][CH2:13]1)=[O:11]
Reactant: C#CCN1C(=O)CCC1C(=O)OC
Reactant: O=C1CCCN1
Reactant: CN1CCNCC1
Agent: C=O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C1CCC(=O)N1CC#CCN1CCN(C)CC1
Reaction time: 0.5 h

Procedure:
A stirred mixture of N-methylpiperazine (7.0 g), 5-methoxycarbonyl-1-(2-propynyl)-2-pyrrolidinone (12.86 g), paraformaldehyde (2.8 g), cuprous chloride (0.3 g) and anhydrous dioxane (50 ml) was held for 30 min at 58° C. Thin layer chromatographic analysis (silica gel, methanol) indicated the presence of the starting pyrrolidinone. The mixture was treated with a little N-methylpiperazine and heated to 80° for one hour. The mixture was decanted into water (300 ml), acidified with 5% hydrochloric acid solution and extracted with ether (3×200 ml). The aqueous phase was basified by portionwise addition of solid sodium carbonate and extracted with dichloromethane (4×150 ml). The combined and dried (Na2SO4) organic phase was filtered and concentrated to afford an oil. The oil was purified by preparative HPLC (silica gel, methanol as eluent) to give 9.84 g of the product as an oil.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Cl:26])=[CH:23][CH:22]=1>CCO>[ClH:26].[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-trifluoromethylbenzyl chloride (0.232 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 262 mg of the product 228. 1H NMR (DMSO-d6) δ 11.42 (s, 2 H), 7.95-7.90 (m, 4 H), 7.15-6.90 (m, 6 H), 6.90-6.65 (m, 4 H), 5.77 (s, 2 H), 4.92 (s, 2 H); MS: m/z 413 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cccc(CBr)c1
Product: CCOP(=O)(Cc1cccc(F)c1)OCC
Temperature: 160 °C

Procedure:
A mixture of 3-fluorobenzyl bromide (2 g) and triethyl phosphite (2.2 mL) was heated at 160° C. under nitrogen for 4 hours. After cooling, the were volatiles removed in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give diethyl (3-fluorobenzyl)phosphonate (2.46 g)
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:33])([CH2:23][N:24]([CH3:32])[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:34]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:33])([CH2:23][N:24]([CH3:32])[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[NH2:34]
Reactant: COC(=O)CC(=O)N(C)CC(C)(C(=O)N1CCCC1)c1ccc(N(C)Cc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: CNc1ccc(C(C)(CN(C)C(=O)CC(=O)OC)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1d from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and hydrogen/palladium on activated charcoal.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[F:9][C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[O:36][CH3:37])=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([CH2:23][S:24]([CH3:27])(=[NH:26])=[O:25])[CH:20]=[C:19]([F:28])[CH:18]=2)=[N:14][CH:15]=1>N1C=CC=CC=1>[CH3:6][O:5][CH2:4][CH2:3][O:2][C:1](=[O:7])[N:26]=[S:24]([CH2:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:12]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[O:36][CH3:37])[C:10]([F:9])=[CH:15][N:14]=2)[CH:18]=[C:19]([F:28])[CH:20]=1)([CH3:27])=[O:25]
Reactant: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CS(C)(=N)=O)c2)ncc1F
Reactant: COCCOC(=O)Cl
Solvent: c1ccncc1
Product: COCCOC(=O)N=S(C)(=O)Cc1cc(F)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methoxyethyl carbonochloridate (18 μL; 0.15 mmol; Sigma-Aldrich Corporation) was added dropwise to a stirred solution of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methyl-sulfonimidoyl)methyl]phenyl}pyrimidin-2-amine (Example 15; 50.0 mg; 0.12 mmol) in pyridine (1.1 mL) at 0° C. The mixture was stirred at RT for 24 hours before the batch was concentrated. Ethyl acetate and aqueous sodium chloride solution were added. The batch was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2].C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1Nc2ccccc2N(C)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CC1Nc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Methyl-3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene-acetic acid ethyl ester (1.1 g, 4.47 mmol) was suspended in 25 mL of MeOH/HOAc (2:1) at rt and sodium cyanoborohydride was added portionwise (281 mg, 4.47 mmol). The mixture became clear after five minutes and was continuously stirred at rt for 2 hours. The solvent was removed under reduced pressure. The crude residue was mixed with water (50 mL) and extracted with EtOAc (3×40 mL). The organic layers were combined, washed with water, brine and dried over MgSO4. After removal of the solvent, a pale brown oil was obtained as the desired pure product: 1H NMR (CDCl3) δ=6.97–6.94 (m, 3H), 6.74 (d, J=9.0 Hz, 1H), 4.28 (dd, J=3.0, 9.0 Hz, 1H), 4.23 (q, J=9.0 Hz, 2H), 3.37 (s, 3H), 3.11 (dd, J=3.0, 18.0 Hz, 1H), 2.68 (dd, J=9.0, 19.0 Hz, 1H), 1.28 (t, J=9.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si:6]1(C2C=CC=CC=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COCCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: COCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.5 g of 4-(4-(3-methoxypropyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.