Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3].[CH3:12][O:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:4]([CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3]
Reactant: COCCO
Reactant: C=CCN(CCl)C(=O)C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCN(COCCOC)C(=O)C(Cl)Cl

Procedure:
A solution of N-allyl-N-chloromethyldichloroacetamide (21.7 g., 0.1 mole) and 2-methoxyethanol (8.4 g., 8.7 ml., 0.11 mole) in dry chloroform (50 ml.) is placed in a round-bottomed, four-necked flask of 250 ml, equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1g., 13.9 ml., 0.1 mole) is added under stirring and external cooling in such a rate that the temperature does not exceed 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×70 ml) for removing the triethylamine hydrochloride formed, the chloroform solution is dried over anydrous sodium sulfate and, after distillation of the chloroform, the product is dried under reduced pressure to give 23.6 g. (92%) of a pale yellow oil which is the named compound of 95% purity according to an analysis by gas chromatography; nD25 =1.4801. This product is directly useful for practical purposes.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6].[CH3:10][S-:11].[Na+]>CO>[F:1][C:2]([F:9])([F:8])[CH:3]([S:11][CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: C[S-]
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CSC(CC(=O)O)C(F)(F)F
Yield: 99.5 %

Procedure:
To a 100 mL round bottom flask was added (E)-4,4,4-trifluorobut-2-enoic acid (8 g, 57.1 mmol) and Methanol (24 mL), the solution was stirred in a water bath, then sodium methanethiolate (10.01 g, 143 mmol) was added in three portions. Vigorous bubbling was observed, the mixture was stirred at 25° C. overnight, NMR showed no more starting material. To the reaction mixture was added 2 N HCl until acidic. The mixture was extracted with chloroform (5×50 mL), combined organic layer was dried over Na2SO4, concentrated in vacuo and further dried under high vacuum until there was no weight loss to give 4,4,4-trifluoro-3-(methylthio)butanoic acid (10.68 g, 56.8 mmol, 99% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 3.53 (dqd, J=10.5, 8.3, 4.0 Hz, 1H), 2.96 (dd, J=16.9, 4.0 Hz, 1H), 2.65 (dd, J=16.9, 10.4 Hz, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.78 (s), 126.61 (q, JC-F=278.8 Hz), 44.99 (q, JC-F=30.3 Hz), 34.12 (d, JC-F=1.7 Hz), 15.95 (s); EIMS m/z 162.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:11](#[N:14])[CH:12]=[CH2:13]>CO>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:12][C:11]#[N:14])=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: C=CC#N
Reactant: Oc1ccc2c(c1)CCO2
Solvent: CO
Product: N#CCCOc1ccc2c(c1)CCO2

Procedure:
40.8 g of 2,3-dihydro-5-hydroxybenzofuran (the synthesis of which is described in Synthesis 1988, 950-952), 3 ml of a 40% solution of Triton B in methanol and 200 ml of freshly distilled acrylonitrile are mixed at room temperature. The mixture is heated at reflux for 46 hours, then the acrylonitrile is evaporated off as far as possible. The residue is taken up in ethyl acetate, washed with 2N sodium hydroxide solution, N hydrochloric acid and water. The organic phase, dried over magnesium sulphate, is concentrated in vacuo, and then the residue is recrystallised from 300 ml of isopropanol to yield 38 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:37][C:38]([CH3:40])=[CH2:39]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([CH2:39][C:38]([CH3:40])=[CH2:37])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (60 mg, 0.179 mmol) in tetrahydrofuran (THF) (2 mL) was treated with LiHMDS (0.447 mL, 0.447 mmol, 1.0M in THF) and 3-bromo-2-methylpropene (0.271 mL, 2.68 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was used crude in the next step (65 mg, 94%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43-8.56 (m, 1 H) 7.40-7.57 (m, 2 H) 7.09-7.20 (m, 1 H) 6.95-7.08 (m, 2 H) 6.78-6.86 (m, 1 H) 4.68-4.75 (m, 1 H) 4.44-4.54 (m, 1 H) 3.91-4.03 (m, 1 H) 3.68 (s, 3 H) 3.53 (s, 3 H) 2.40 (br. s., 3 H) 2.04 (s, 3 H) 1.59-1.68 (m, 2 H) 1.49 (br. s., 3 H). LC/MS (m/z) ES+=390 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=5[CH:22]=4)[CH:18]=[CH:17][C:16]=3[F:35])=[O:13])[N:8]([CH3:36])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH2:38]>>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:38][CH3:37])[N:27]=[CH:28][C:23]=5[CH:22]=4)[CH:18]=[CH:17][C:16]=3[F:35])=[O:13])[N:8]([CH3:36])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C5CCCC5)nn4C)c3)c(=O)n(C)c2n1
Reactant: CN
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C5CCCC5)nn4C)c3)c(=O)n(C)c2n1
Yield: 20 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.068 g, 0.134 mmol) and MeNH2 (2.0 M in THF, 1.4 mL) were combined to afford 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.013 g, 20%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.38-7.34 (m, 2H), 6.11 (s, 1H), 3.70-3.68 (m, 6H), 2.99-2.94 (m, 4H), 1.99-1.94 (m, 2H), 1.73-1.68 (m, 2H), 1.67-1.60 (m, 4H); MS (ESI) m/z: 491.2 (M+H+).
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2S[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=2[C:26]([OH:28])=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.N1(C(OC(C)(C)C)=[O:36])CCNCC1>>[C:20]1([C:18]2[O:36][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH2:9][CH2:10]3)=[C:16]([C:26]([OH:28])=[O:27])[N:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2sc(-c3ccccc3)nc2C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: O=C(O)c1nc(-c2ccccc2)oc1CN1CCCC1
Yield: 38 %

Procedure:
The title compound was prepared by the procedure described for 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylic acid substituting pyrrolidine for t-butyl piperazine-1-carboxylate in 38% yield.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[F:6][CH:7]([F:31])[C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH:22]=[O:23])[O:21][C:17]=3[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:10][CH:9]=1>CC#N.C(OCC)(=O)C.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](F)([O-])(=O)=O>[F:31][CH:7]([F:6])[C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([C:22]([OH:2])=[O:23])[O:21][C:17]=3[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C=O)oc2c1
Agent: O=[Cr](=O)([O-])F
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To acetonitrile (10 mL) was added periodic acid (209 mg, 0.916 mmol) and stirred vigorously at room temperature for 15 min. Ethyl 4-[4-(difluoromethyl)phenoxy]-2-formyl-1-benzofuran-6-carboxylate (300 mg, 0.833 mmol) was then added (in ice-bath) followed by addition of pyridium fluorochromate (3.32.mg, 0.02 mmol) in CH3CN (5 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine/water (1:1), dried over MgSO4 and concentrated to give the title compound (300 mg, 96%) as an orange solid, which was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (t, J=7.16 Hz, 3 H) 4.33 (q, J=7.16 Hz, 2 H) 6.61 (t, J=56.52 Hz, 1 H) 7.06 (d, J=8.48 Hz, 2 H) 7.37 (s, 1 H) 7.43-7.54 (m, 3 H) 8.02 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].Cl>CN(C)C=O.O>[C:19]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][C:14]3[N:13]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C(=O)O)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in 100 cm3 of dimethylformamide is added dropwise to a suspension of 1.45 g of sodium hydride (at 60% in oil) in 25 cm3 of dimethylformamide cooled to a temperature in the region of 0° C. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is cooled to a temperature in the region of 0° C. and 4.18 cm3 of (2-chloromethoxyethyl)trimethylsilane are added dropwise. The mixture is stirred for about 20 hours at a temperature in the region of 20° C. After cooling this mixture to a temperature in the region of 0° C., 100 cm3 of water and 16 cm3 of aqueous 1N hydrochloric acid solution are added. The mixture is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed with three times 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 1.8 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C[C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])C>>[C:17]1([CH2:25][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]5[CH:35]=[CH:34][CH:40]=[CH:39][CH:38]=5)[N:7]=4)=[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][N:11]4[N:10]=3)[CH:18]=2)=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)Cc1cccc(N)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Yield: 78 %

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 3-(dimethylaminomethyl)aniline using displacement conditions described in Example 1, Step D to generate the product in 78% yield. ES-LC/MS m/z=532 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)CCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 3-phenyl propionyl chloride.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(OCC1C=CC=CC=1)=O>CO.C(Cl)Cl.C([O-])(O)=O.[Na+].[Pd]>[Si:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C#CCCNC(=O)OCc2ccccc2)c2ccccc12
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCCCNC(=O)OCc2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A solution of carbamate 18 (2.0 g, 4.3 mmole) and 10% Pd/C (300 mg) in MeOH (60 mL) was subjected to hydrogenation conditions (50 psi) for 8 h at room temperature. The reaction mixture was filtered through a plug of diatomaceous earth and the plug was washed with MeOH (2×20 mL). The filtrate was then concentrated in vacuo to afford crude amine (1.4 g) which was dissolved in 1:1 CH2Cl2/NaHCO3 (saturated solution) (30 mL). Benzyl chloroformate (0.62 mL) was added dropwise at room temperature and the reaction mixture was stirred for 1 h. The mixture was concentrated, the residue was dissolved in EtOAc (500 mL), and the solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 4:1 hexanes/EtOAc) to afford butylcarbamate 19 (1.5 g, 77%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 8.24 (m, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.51-7.42 (m, 2H), 7.34-7.28 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.08 (br s, 2H), 4.75 (br s, 1H), 3.22 (q, J=6.4 Hz, 2H), 2.99 (q, J=7.4 Hz, 2H), 1.76-1.71 (m, 2H), 1.67-1.56 (m, 2H), 1.09 (s, 9H), 0.27 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][F:12])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:16][CH2:17][F:18]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:12][CH2:11][CH2:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:1][CH2:16][CH2:17][F:18])=[CH:8][CH:7]=1
Reactant: FCCBr
Reactant: OCc1ccc(OCCF)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FCCOCc1ccc(OCCF)cc1
Yield: 30.3 %

Procedure:
To a stirred solution of 5.0 grams (0.029 mole) of 2-fluoroethyl 4-hydroxymethylphenyl ether in 50 ml of tetrahydrofuran was added 15 ml of a 50% aqueous, sodium hydroxide solution, 7.6 grams (0.060 mole) of 1-bromo-2-fluoroethane, and 0.78 gram (0.0023 mole) of tetrabutylammonium hydrogen sulfate. The resultant mixture was stirred and heated at reflux for approximately 18 hours. The mixture was cooled and was extracted with diethyl ether. The extract was washed in succession with a dilute, aqueous, sodium hydroxide solution, an aqueous 10% lithium chloride solution, and a saturated, aqueous, sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil. Analysis of this oil by nmr indicated a large amount of starting material remained. The oil was again heated at reflux with the same quantities of the above reactants for 30 minutes. The reaction mixture was cooled and extracted with diethyl ether. The extract was washed several times with water followed by an aqueous, 15% lithium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an oil. Analysis of this oil by nmr indicated starting material was still present. This oil was heated at reflux with the same quantities of the above reagents for approximately 24 hours. The mixture was cooled and extracted with diethyl ether. The extract was washed with water and was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.9 grams of 4-(2-fluoroethoxymethyl)phenyl 2-fluoroethyl ether as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COc1cc(CN)ccc1O
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: COc1cc(CNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 4 was coupled with 4-Aminomethyl-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 3H) 7.6 (m, 2H) 7.3 (m, 2H) 6.8 (m, 2H) 4.4 (s, 2H) 3.8 (s, 2H) 3.7 (m, 2H) 3.4 (s, 3H) 2.9 (s, 3H) 2.8 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:28][OH:29])[CH2:27][CH2:26]2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(#N)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:28][OH:29])[CH2:26][CH2:27]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1cnn(C2(CO)CC2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3cnn(C4(CO)CC4)c3)n2)C1=O
Temperature: 90 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclopropyl)methanol (120 mg) obtained in Step C of Example 128, cesium carbonate (500 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg) in tetrahydrofuran (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (70 mg), and the mixture was stirred at 90° C. for 10 hr under argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 5 mM AcONH4), to the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (71 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([O:21][CH3:22])=[CH:9][C:8]=1[CH:23]=O)[CH3:2].N12CCCN=C1CCCCC2.C(O)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([O:21][CH3:22])=[CH:9][C:8]=2[CH:23]=1)=[O:25])[CH3:2]
Reactant: CCOC(=O)COc1cc(OCc2ccccc2)c(OC)cc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(OC)c(OCc3ccccc3)cc2o1
Temperature: 25 °C

Procedure:
(5-Benzyloxy-2-formyl-4-methoxyphenoxy)acetic acid ethyl ester (1.5 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 g) and acetic acid (0.026 g) in N,N-dimethylformamide (8 ml) were stirred at 100° C. under nitrogen for 5 hours. After cooling to room temperature the mixture was poured in ice water and the precipitate was filtered.
Reaction SMILES: C([NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.C(O)(=O)C.[ClH:25]>O>[ClH:25].[CH3:20][C:4]([NH2:3])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(N)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A mixture of 0.50 gram of N-formyl-α,α-dimethyl- 4-(phenylethynyl)-benzylamine, 10.7 ml. of glacial acetic acid 6.7 ml. of water, and 1.07 ml. of concentrated hydrochloric acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness and α,α-dimethyl-4 -(phenylethynyl)-benzylamine hydrochloride is obtained as a light tan solid. The product is recrystallized from an isopropyl alcohol-methanol-ether mixture to give pure α,α-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 275°-278° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[CH:10]([NH2:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].O.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[CH:10]([NH:19][C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(NC(=O)C(N)CCc1ccccc1)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a mixture of the crude compound obtained in step b above (1400 mg) in dioxane (18 mL) and water (2 mL) was added phenyl chloroformate (0.9 mL, 7.16 mmol) and DIEA (1.6 mL, 8.95 mmol). The mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (1165 mg, 79% yield, three steps).
Reaction SMILES: N1CCC[C@H:2]1[C:3](O)=[O:4].[OH:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11]1>>[OH:4][CH2:3][CH2:2][N:13]1[CH2:14][C@H:10]([OH:9])[CH2:11][C@H:12]1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1CCO

Procedure:
The procedure was as in Example 5 but in place of (2S)-proline there were employed 39.3 grams of (2S, 4R)-4-hydroxy-proline (0.3 mole). There were obtained 35.4 grams (67.4% of theory) of colorless crystals of (2S, 4R)-N-(2-hydroxyethyl)-4-hydroxy-proline.