Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4]1.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:8][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1([N:2]([CH3:9])[CH3:1])[CH2:6][CH2:5][CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: CN(C)C1(C#N)CCC1
Product: CN(C)C1(C(N)c2ccccc2)CCC1

Procedure:
The title compound, yellow liquid, MS: m/e=205.2 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-dimethylamino-cyclobutanecarbonitrile (intermediate Q) and phenyllithium.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[O:21]=[C:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23]1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=4)[NH:23][C:22]3=[O:21])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(NC=O)cc43)c(C)c2C1=O
Yield: 80.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (55 mg, 80.6%) as an orange solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:21])=[CH:7][C:8]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].Cl>CO.C1COCC1>[CH3:3][O:4][C:5]1[C:6]([CH3:21])=[CH:7][C:8]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(OC)c(C)cc1-c1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(-c2ncccn2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1M aq. NaOH (4 mL) was added to a rt suspension of methyl 5-methoxy-4-methyl-2-(pyrimidin-2-yl)benzoate (503 mg, 1.95 mmol) in MeOH (5 mL) and THF (5 mL) and stirred at rt for 2 days. The residue was acidified with 25% aq. HCl, washed with DCM and concentrated in vacuo to yield the title compound A-1-16 as a off-white solid as its HCl-salt. LC-MS A: tR=0.63 min, [M+H]+=245.06.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]([F:15])=[C:10]2[CH:14]=[CH:13][NH:12][C:11]=12)=[O:5])C.[OH-].[K+].[C:18]([C:22]1[CH:42]=[CH:41][C:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:18]([C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:39])([F:40])[F:38])[CH:31]=2)[C:4]([C:6]2[N:7]=[CH:8][C:9]([F:15])=[C:10]3[CH:14]=[CH:13][NH:12][C:11]=23)=[O:5])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1ncc(F)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(C(F)(F)F)c2)C(=O)c2ncc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A solution of 4-fluoro-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid ethyl ester (50 mg, 0.24 mmol) in THF (0.7 mL) was treated with 2 M aq. potassium hydroxide solution (0.24 mL, 0.48 mmol) and stirred for 90 min at RT. The reaction mixture was then evaporated, the residue dissolved in DMF (3.2 mL) and treated with (4-tert-butyl-benzyl)-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-amine (98 mg, 0.26 mmol), N-methylmorpholine (73 mg, 0.72 mmol), and HBTU (137 mg, 0.36 mmol). After 16 h, the reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane/ethyl acetate 97:3) afforded the title compound (95 mg, 74%). White foam, MS (ISP) 532.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[CH2:9]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: BrCCCCCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: c1cn(CCCCCCCCn2ccnc2)cn1
Temperature: 40 °C

Procedure:
Sodium hydride (11.0 g of 60 wt % dispersion in mineral oil, 276 mmol) was added to a 500-mL, 3-neck round bottom flask equipped with stir bar and reflux condenser under argon purge. Anhydrous tetrahydrofuran (300 mL) was vacuum-transferred into the reaction vessel. Imidazole (15.0 g, 221 mmol) was added to the stirred slurry. The reaction was heated to 40° C. and held there until H2 gas evolution had visibly ceased. After this time, 1,8-dibromooctane (20.4 mL, 111 mmol) was injected into the reaction mixture and the reaction heated at reflux (65° C.) under argon overnight. The reaction was allowed to cool to room temperature and the solids were filtered and washed with tetrahydrofuran. The product solution was concentrated by rotary evaporation and then dissolved in methanol (100 mL). Addition of methanol caused residual mineral oil to separate from the product. The methanol solution was washed with hexanes (3×100 mL), and concentrated by rotary evaporation. The product was dried under vacuum overnight to yield an off-white waxy solid. Yield: 21.5 g (85%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:33][CH3:34])([CH2:35][CH3:36])[CH2:37][CH3:38])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)(CC)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(CC)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 106b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([S@@:4]([NH:6][C@:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:8][C:9]([O:11]C)=[O:10])=[O:5])[CH3:3].[Li+].[OH-]>CO.O.CO.O>[CH3:3][C:2]([CH3:20])([S@@:4]([NH:6][C@:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:13])[CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:1]
Reactant: COC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[S@](=O)N[C@](C)(CC(=O)O)c1ccccc1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of (R)-methyl 3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoate (280 mg, 0.94 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added LiOH (138 mg, 3.29 mmol). The solution was stirred for 4 h and then concentrated to give the residue. The residue was dissolved in 15% MeOH/H2O and filtered to give (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoic acid (266 mg, 100%). 1H NMR (CDCl3): 1.10 (s, 9H), 1.51 (s, 3H), 2.43-2.52 (d, 1H), 2.73-2.86 (d, 1H), 7.15-7.18 (m, 1H), 7.06-7.12 (m, 3H), 7.30-7.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:23]([O:30][C:31](=[O:41])[N:32]([CH2:34][C:35](N(OC)C)=[O:36])[CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([O:30][C:31](=[O:41])[N:32]([CH2:34][C:35]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[CH3:9])=[CH:11][CH:12]=1)=[O:36])[CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CON(C)C(=O)CN(C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
200 mg of the compound [1-1] was dissolved in 4 mL of tetrahydrofuran, and the mixture was cooled to −78° C. and then 626 μL of n-butyllithium (2.66 M hexane solution) was added thereto. After a 1 hour stirring at the same temperature, 0.6 mL of tetrahydrofuran solution containing 177 mg of the compound [2-1] was added thereto, and the mixture was further stirred for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/4), to obtain 36.2 mg of benzyl[2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-oxoethyl]methylcarbamate [2-2] (hereinafter, referred to as the compound [2-2]) as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>N1C=CC=CC=1>[NH2:25][C:23]([NH:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1)=[O:24]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Solvent: c1ccncc1
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(NC(N)=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1.00 g (3.7 mmol) of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 50 mL of pyridine and 1 mL (8.0 mmol) of trichloroacetylisocyanate were added. The mixture was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residue was treated with 50 mL of methanol. After 2 hours under stirring the solvent was removed, the residue redissolved with dichloromethane and washed with a diluted solution of ammonium hydrate. After drying over anhydrous Na2SO4 the organic layer was evaporated to dryness and the residue purified by chromatography on a silica gel column (eluant: dichloromethane/acetone 4/1) leading 0.40 g (34% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[S:33])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Product: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIb) was prepared by reacting 0.0019 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=342.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[C:19]([O:24][CH3:25])[CH:18]=1)S(C1C=CC(C)=CC=1)(=O)=O.ClCCl.CC(C)([O-])C.[K+]>O1CCOCC1.Cl.CN(C=O)C.C(O)(C)(C)C>[I:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:24][CH3:25])[CH:16]=[N:5][CH:4]=[CH:3]2
Reactant: COc1cc(CN(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)ccc1I
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1cc2cnccc2cc1I
Temperature: 40 °C
Reaction time: 3 h

Procedure:
20.5 g (39.6 mmol) of N-(2,2-dimethoxyethyl)-N-(4-iodo-3-methoxybenzyl)-4-methylbenzenesulfonamide was dissolved in a mixture of 240 ml of dioxane and 70 ml of 6 N hydrochloric acid, and the obtained solution was heated under reflux for 2 hours. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was dissolved in a mixture of 100 ml of DMF and 100 ml of t-butyl alcohol. 2.54 g (22.6 mmol) of potassium t-butoxide was added to the obtained solution and they were stirred at 40° C. for 3 hours. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]([C:13]#[N:14])[C:9]([S:15][CH3:16])=[N:8]1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]([C:13]#[N:14])[C:9]([S:15]([CH3:16])=[O:30])=[N:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Reaction time: 15 h
Yield: 77.5 %

Procedure:
2.7 g of 1-(3-trifluoromethylbenzyl)-3-methylmercapto-4-cyano-5-amino-pyrazole are dissolved in 30 ml of chloroform. A mixture of 1.8 g of 3-chloroperbenzoic acid and 20 ml of chloroform are added dropwise to this solution at 20° C. and stirred for 15 hours. The mixture is subsequently washed with saturated sodium bicarbonate solution, 2% strength sodium thiosulphate solution, and again with saturated aqueous sodium bicarbonate solution. The organic phase is dried using anhydrous sodium sulphate, concentrated, and triturated in petroleum ether. 2.2 g (75% of theory) of 1-(3-trifluoromethylbenzyl)-3-methylsulphinyl-4-cyano-5-amino-pyrazole of melting point 143° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[CH3:34][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:34])=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (71.2 mg, 0.15 mmol) was initially charged in absolute THF (6 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (180 μl; 1.2 eq.) was added at −78° C. After 20 min of stirring, iodomethane (47 μl; 5 eq.) was added, and the mixture was stirred with gradual warming from −78° C. to RT for 60 h. The reaction mixture was then purified directly by preparative HPLC (column: Gromsil, C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (60 mg, 82% of theory).
Reaction SMILES: [C:1]([N:8]([CH3:13])[C@H:9]([CH2:11][OH:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].[K+].[Br-].Cl[O-].[Na+]>ClCCl.O>[C:4]([O:3][C:1](=[O:2])[N:8]([CH3:13])[C@@H:9]([CH3:10])[CH:11]=[O:12])([CH3:6])([CH3:7])[CH3:5]
Reactant: C[C@@H](CO)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a solution of 18.0 g Boc-N-methyl-alaninol (95 mmol) in 95 ml dichloromethane was added a solution of 3.2 g NaHCO3 (38 mmol) and 1.14 g KBr (9.5 mmol) in 95 ml deionized water. The reaction mixture was cooled to 0° C. and after the addition of 152 mg 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO, 0.95 mmol), 72 g 10.3% aqueous sodium hypochlorite (105 mmol Cl2) were added under stirring over 2.5 h at 0-5°. After additional stirring for 30 min the excess of NaOCl was destroyed by the addition 38% aqueous sodium bisulfite (1 ml) and the reaction mixture was warmed up to 20°. The aqueous layer was extracted with 100 ml dichloromethane and the organic layers were washed with 100 ml 10% brine and dried (Na2SO4). Removal of the solvent by rotary evaporation afforded 14.4 g (80%) crude product as a light orange oil, [α]D=−82 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17](=[O:20])[NH:18][NH2:19])([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([NH:18][N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of phthalic anhydride (29.63 g, 200 mmol) and tert-butylcarbazate (26.40 g, 200 mmole) in toluene was refluxed for two hours using a Dean-Stark trap. The mixture was allowed to cool and crystallize overnight. The crystals were filtered of and washed with cold toluene. The crystals were dried in vacuum.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C@@H:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]([O:24]CC)=[O:23])=[O:19])=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Li+]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C@@H:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]([OH:24])=[O:23])=[O:19])=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 5 c), (S)-ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-4-methylpentanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e=385.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[NH:4].[IH:9]>O>[I-:9].[CH3:1][N:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[NH:4]
Reactant: I
Agent: CN(C)C(=N)N(C)C
Solvent: O
Product: [I-]

Procedure:
1,1,3,3-tetramethylguanidine (1.21 g, 10.5 mmol) was dissolved in water (32.8 g). MoO3 (0.225 g, 1.58 mmol) and hydroiodic acid (1.65 g, 7.35 mmol, 57 wt % solution in water) were slowly added to this solution. This yielded a solution of 1,1,3,3-tetramethylguanidine iodide and 1,1,3,3-tetramethylguanidine molybdate with concentrations of 0.22M and 0.094M, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH2:17].CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:17][C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1
Reactant: COc1cc(OC2CCN(C)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Yield: 7.2 %

Procedure:
Following a procedure analogous to 251c, 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine (0.17 g, 0.72 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (130 mg, 0.36 mmol) were converted to the title compound (14 mgs, 7%). (CDCl3) δ 8.73 (s, 1H), 8.02 (d, J=10.7 Hz, 1H), 7.97-7.94 (m, 1H), 7.30 (s, 1H), 7.02-7.00 (m, 1H), 6.87-6.83 (m, 1H), 6.52 (s, 1H), 6.33 (d, J=10.6 Hz, 1H), 4.25 (Broad s, 1H), 3.89 (s, 3H), 3.15 (s, 3H), 2.75-2.68 (m, 2H), 2.66 (s, 3H), 2.32 (s, 3H), 2.31-2.26 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.81 (m, 2H); LC/MS (ESI+): 537 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][C:30]#[N:31])(=[O:28])=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:29](/[S:26]([NH:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:28])=[O:27])\[C:30]#[N:31])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C(C)C)c1O

Procedure:
M44 was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under similar conditions as described for M40.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][S:11]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:23]([CH3:24])[C:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:27][CH:26]=3)=[C:20]([CH3:21])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: Nc1cc(O)ccc1Cl
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (1.0 g), 3-(4-methanesulfonylbenzyl)pentane-2,4-dione (0.53 g), methanesulfonic acid (3 drops) and toluene (20 mL) was heated at reflux for 3 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 99:1 by volume) gave title compound as a pale yellow solid, 0.32 g.