Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].[C:26]([O-])(=O)C>C1C=CC=CC=1>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:26][C:14]1[CH:13]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[C:17]([O:24][CH3:25])=[O:23]
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: CC(=O)[O-]
Reactant: COC(=O)CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of benzyloxybenzaldehyde (10.6 g, 50.0 mmol) and dimethyl malonate (6.6 g, 50.0 mmol) in benzene (100 mL) containing a catalytic quantity of pipiridinium acetate was refluxed in a Dean-Stark trap for 16 h. After cooling to room temperature, the solution was concentrated. The residue was crystallised from ethyl acetate/heptane to give 14.5 g (90%) of 2-(4-benzyloxy-benzylidene)-malonic acid dimethyl ester: mp 134-135° C. 1H NMR (300 MHz, CDCl3): δ3.82 (s, 3H), 3.86 (s, 3H), 5.08 (s, 2H), 6.95 (d, 2H), 7.30-7.45 (m, 7H), 7.70 (s, 1H)
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].CCN(C(C)C)C(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:8](=[O:9])[N:10]2[C@H:14]([C:15]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1000 ml round bottom flask under N2 was added (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol) in dichloromethane (DCM) (700 mL) at 0° C., followed by 2-pyridinamine (14.79 g, 157 mmol), DIPEA (68.6 mL, 393 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (21.40 g, 157 mmol) and EDC (30.1 g, 157 mmol). The mixture was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the desired product was ˜56%. After another 24 h, LCMS indicated no starting material left. The organic solution was washed with water (300 mL), 10% citric acid (2×300 mL) and brine, dried (Na2SO4), filtered, and concentrated to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{(5S)-5-[(2-pyridinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (29.1 g, 58.4 mmol, 74% yield) as a brown gummy solid. LCMS: [M+H]+: 429.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2cc(Br)ccc2c1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 6-bromo-2-naphthylmethyl alcohol (6.71 g, 28.3 mmol) in CH2Cl2 (350 mL) was added pyridinium chlorochromate (6.71 g, 31.13 mmol) all at once. The mixture visually went from orange-red to black over 30 minutes and 150 mL of ether was added. The black mixture was passed through a silica gel column and eluted with ether. The solvents were evaporated and the solid was further purified on silica gel (hexane:CH2Cl2 1:1) to give 6.25 g of 6-bromo-2-naphthaldehyde (94%) as a white solid. %). 1H NMR (300 MHz; CDCl3): δ 7.65 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H); 7.84 (t, J=8.0 Hz, 2H); 7.97 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 8.06 (d, J=2.0 Hz, 1H); 8.29 (s, 1H); 10.14 (s, 1H); 13C NMR (300 MHz; CDCl3): ppm 123.5, 123.9, 128.0, 130.1, 130.5, 130.8, 130.9, 133.9, 134.2, 137.1, 191.6.
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]2[C:22](=[O:36])[CH:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:22]2([OH:36])[C:21]3[CH:37]=[CH:38][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=3[O:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Under nitrogen atmosphere, 3-bromomagnesium phenyl trimethylsilyl ether prepared from 3-bromophenyl trimethylsilyl ether (2.35 g, 9.57 mmol) and magnesium turning (0.23 g, 9.57 mmol) in dry tetrahydrofuran (3 ml) was cooled to -78° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran-4-one (1 g, 2.9 mmol) dissolved in dry tetrahydrofuran (2 ml) was slowly added dropwise thereto, and the mixture was stirred for one hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was then subjected to column chromatography (n-hexane:ethyl acteate=4:1) to obtain 903 mg (yield: 74%) of the title compound as a foam.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=[O:10])C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38](N(OC)C)=[O:39])=[CH:36][N:35]=[C:34]2[S:44]([CH2:47][C:48]2[C:53]([F:54])=[CH:52][CH:51]=[C:50]([F:55])[C:49]=2[F:56])(=[O:46])=[O:45])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:10])=[O:39])=[CH:36][N:35]=[C:34]2[S:44]([CH2:47][C:48]2[C:53]([F:54])=[CH:52][CH:51]=[C:50]([F:55])[C:49]=2[F:56])(=[O:45])=[O:46])=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1cnc(S(=O)(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(S(=O)(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfonyl)-1H-imidazole-5-carboxylic acid (22) was prepared in a similar manner as that described for the synthesis of compound 7 using 1-(4-fluorophenyl)-N-methoxy-N-methyl-2-((2,3,6-trifluorobenzyl)sulfonyl)-1H-imidazole-5-carboxamide (21) (50 mg, 0.11 mmol), lithium hydroxide (10 mg, 0.44 mmol), THF (0.1 mL), methanol (0.2 mL), and water (0.4 mL).
Reaction SMILES: [O:1]=[C:2]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][CH2:32][CH2:33]2)[CH:3]1[O:8][CH2:7][CH2:6][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1.FC(F)(F)C(O)=O.N1CCOCC1.C(=O)([O-])O.[Na+]>O>[O:1]=[C:2]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][CH2:32][CH2:33]2)[CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: O=C(Oc1cccc2c1CCC2)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCN1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1cccc2c1CCC2)C1CNCCO1
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To 1 g. of 2-(1-oxo-4-indanyloxymethyl)-4-triphenylmethyl morpholine was added 10 ml. of trifluoroacetic acid under ice-cooling to dissolve the morpholine and 10 ml. of water was immediately added to the solution followed by stirring for 15 minutes at 5°-10° C. Then, after neutralizing the reaction mixture with sodium hydrogencarbonate, the product was extracted with chloroform. Then, the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The sticky residue formed was subjected to a silica gel column chromatography (column diameter 3 cm., height 7 cm,) and from the fraction recovered therefrom using a 98 : 2 mixture of chloroform and methanol as an eluting solution, 0.45 g. (yield 89.1%) of sticky 2-(1-oxo-4-indanyloxymethyl)morpholine was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl.Br[C:9]1[CH:14]=[CH:13][NH+:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(O)C>O>[N:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: Brc1cc[nH+]cc1
Reactant: OC1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: OC1CCN(c2ccncc2)C1
Temperature: 150 °C

Procedure:
A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol), 4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine (47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tube reaction vess 1, was purged with nitrogen and sealed. The mixture was heated to 150° C. for 96 hours and cooled. The solvent was evaporated and ethyl acetate (50 mL) was added. After trituration, the organic solvent was decanted off and saved. Methylene chloride (80 mL) and 2 N sodium hydroxide (60 mL) were added to the solid. The mixture was shaken vigorously and was filtered with water and methylene chloride wash to give the title compound as an off-white solid. The organic supernatant and the methylene chloride and water washes were combined. This mixture was extracted with methylene chloride. The organic layer was sodium sulfate dried and concentrated. The residue was triturated with methylene chloride and the solid was filtered. This solid was combined with the solid from above and vacuum dried (100° C. at 133 Pa for 14 hours) to give the title compound as an off-white solid (8.52 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]=[CH2:30])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:31]1CCOCC1>O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A solution of Example 173B (150 mg, 0.35 mmol) in dioxane (6 mL) and water (2 mL) was added OSO4 (2.5% wt in t-butanol, 0.5 mL) was stirred for 8 minutes at ambient temperature, treated with NaIO4 (128 mg, 0.6 mmol), stirred for 30 minutes, treated with brine, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in anhydrous THF (6 mL), cooled to 0° C., treated dropwise with methyl magnesium bromide (3.0M in diethyl ether, 0.37 mL), treated with water (20 mL) and 1N HCl (1.0 mL), and extracted with ethyl acetate (2×20 mL). The ethyl acetate solution was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 40% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C(N(CC)CC)C>[C:15]1([CH:4]2[CH:3]([CH2:2][O:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[S:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2C(=O)Nc3ccccc3SC2c2ccccc2)cc1
Yield: 91.3 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 was dissolved in 20 ml of triethylamine. 3.8 g of p-toluenesulfonyl chloride was added to the solution while stirring and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from a mixture of dichloromethane-n-hexane to obtain 8 g of 2,3-dihydro-2-phenyl-3-[(p-toluenesulfonyloxy)methyl]-1,5-benzothiazepin-4(5H)-one as colorless prisms having a melting point of 215° C.
Reaction SMILES: [N:1](CCC[Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[NH2:17]CCC[Si](OCC)(OCC)[O:22][CH2:23][CH3:24]>>[NH2:1][C:2]([NH2:17])=[O:3].[CH3:24][CH2:23][O:22][Si:7]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Product: CCO[Si](OCC)(OCC)OCC
Product: NC(N)=O

Procedure:
3-Isocyanatopropyltriethoxysilane (12.4 g, 50 mmol) is added dropwise over a period of 25 minutes to vigorously stirred 3-aminopropyltriethoxy-silane (11.6 g, 50 mmol). After sixty minutes, the exothermic reaction is complete yielding a white waxy solid with the following structure: ##STR7##
Reaction SMILES: N[CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4].[CH2:22]=O.[C:24]([BH3-])#[N:25].[Na+]>CO>[C:11]([NH:10][C@H:8]1[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:25]([CH3:24])[CH3:22])[C@H:6]([C:19]([OH:21])=[O:20])[CH2:7]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of (2S,4R) 1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (Compound 2, 0.05 g, 0.17 mmol) in methanol (3 mL) at room temperature was added 37% aqueous formaldehyde (Aldrich) (0.1 mL). The resulting mixture was stirred at this temperature for 3 hours, then cooled to 0° C., and sodium cyanoborohydride (Aldrich) (0.043 g, 0.69 mmol, 4 equivalents) was added portion-wise over 5 minutes. After stirring for 1 hour at room temperature, the solvent was removed in vacuo and the solid residue was purified by preparative HPLC (column: XTerra MS C18, 5 u, 19×150 mm) using 5% to 95% methanol/water gradient (0.1% formic acid in methanol and 0.1% formic acid in water) to afford 0.017 g (31% yield) of the desired product.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].C[N:37]1CC[O:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([NH:35][C:39](=[O:40])[CH2:38][NH:37][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: CCN
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 15.6 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 24 mg, 0.049 mmol), ethanamine-HCl (6.01 mg, 0.074 mmol), 4-methylmorpholine (19.88 mg, 0.197 mmol), and HATU (24.29 mg, 0.064 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention=15.7 min) to provide (R/S)-N-(2-(ethylamino)-2-oxoethyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5 mg, 7.62 μmol, 15.52% yield): LCMS=516.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.59-7.84 (7 H, m), 5.20 (1 H, s), 3.79-3.99 (2 H, m), 3.15-3.27 (2 H, m), 1.11 (3 H, t, J=7.26 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].P(Cl)(Cl)(Cl)=O.O.CN(C)[CH:34]=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:34]=[O:35])[C:7]1=[O:21]
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CN1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was added to a solution of phosphorus oxychloride (0.55 ml.) in N,N-dimethylformamide (20 ml.) and the mixture was stirred at 60° C. for 90 minutes. The solution obtained was then poured into water (150 ml.). The solid which formed was collected by filtration, washed with water, air-dried and then recrystallised twice from ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-formyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.6 g.), m.p. 244°-46° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:3]=2)[CH2:9][CH:10]1[CH3:13]
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cccc(CO)c1
Product: CC1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 3-(hydroxylmethyl)benzonitrile.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[C:19]([CH3:37])=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][N:24]=[C:23]2[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].N>C1COCC1.CO.CC(O)=O>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:7]2[C:2]([NH:17][C:18]3[C:19]([CH3:37])=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][N:24]=[C:23]4[NH:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reactant: Fc1ncccc1-c1ncnc2[nH]ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 120 °C

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (78 mg, 363 μmol) and 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (100 mg, 363 μmol) in THF (4 mL) was sonicated until all solids became a fine powder. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran; 1.64 mL, 1.64 mmol) was then added dropwise with stirring (all solids dissolved and then some solid appeared again). The mixture was stirred at rt for 10 min and then heated in a microwave at 120° C. for 30 min. The mixture was poured into MeOH (10 mL) and AcOH (0.5 mL) and stirred for 10 min, then 2 M NH3 in MeOH (20 mL) was added. Solvent was removed under vacuum and the residue was purified by flash chromatography eluting with MeOH(NH3)/DCM to give 4-(8-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 470.2 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C.CCOCC>[Cl-:1].[C:26]1([P+:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Solvent: CC#N
Solvent: CCOCC
Product: [Cl-]
Product: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 2-chloromethyl-quinoline (2.9 g, 20 mmol) in acetonitrile (32 mL) is added triphenylphosphine (4.49 g, 17 mmol). The resulting mixture is warmed to 60° C. and stirred at this temperature for 15 h. This mixture is cooled, diluted with ether, then filtered. The solid is washed with ether, then dried under high vacuum to give the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 8.06 (d, 1H), 7.95 (m, 6H), 7.42–7.8 (m, 13H), 6.10 (d, 2H).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH3:5][NH:6][N:7]=[CH:8][C:9](=[O:11])[CH3:10]>O>[OH:11][C:9]1[C:8]([C:1](=[O:2])[CH3:3])=[N:7][N:6]([CH3:5])[CH:10]=1
Reactant: CNN=CC(C)=O
Reactant: O=CC=O
Solvent: O
Product: CC(=O)c1nn(C)cc1O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a 40% aqueous solution of glyoxal (7.1 mL, 62 mmol) was added a solution of 2-oxopropanal methylhydrazone (6.17 g, 61.6 mmol) in water (300 mL). The mixture was heated at reflux for 1 hour before cooling to room temperature. The mixture was extracted with CH2Cl2 (4×). The combined organic extracts were dried over NaSO4, filtered, concentrated and purified by CombiFlash (120 g column, 30-40% EtOAc/hexanes gradient) to provide 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethanone (5.93 g, 69%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:14]=[CH:15][C:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C@@H:28]4[CH2:30][C@H:29]4[CH2:31][OH:32])[CH2:23][CH2:22]3)=[CH:19][S:18][C:17]=2[CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[F:34][C:12]([F:11])([F:35])[C:13]1[CH:14]=[CH:15][C:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C@@H:28]4[CH2:30][C@H:29]4[CH:31]=[O:32])[CH2:23][CH2:22]3)=[CH:19][S:18][C:17]=2[CH:33]=1
Reactant: OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reaction time: 0.58 h

Procedure:
A solution of oxalyl chloride (62 μl, 0.72 mmol) in anhydrous methylene chloride (10 ml) under N2 was cooled to −78° C. while stirring. Dimethy sulfoxide (104 μl, 1.44 mmol) was then added followed by a solution of {(1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropyl}-methanol (0.135 g, .36 mmol) in anhydrous methylene chloride (10 ml). Stirring was continued at −78° for 35 minutes and then triethyl amine (1.0 ml, .7.3 mmol) was added. This solution was stirred for 4 hours and then removed from the cold bath, filtered, concentrated and chromatagraphed on silica gel with methylene chloride/methanol (95:5). The resultant pure aldehyde, (1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarbaldehyde was verified by NMR and LC/MS, yielding 0.102 g, 76%.