Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>C1COCC1>[CH2:1]([NH:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNCC(F)(F)F
Yield: 38 %

Procedure:
A solution of 8 ml. BH3 in THF (8 mM) is added dropwise to a solution of 1.12 g. (4 mM) dodecyl-trifluoroacetamide in 6 ml. THF at 0° C. under N2. The mixture is refluxed 16 hours, cooled in ice, and 6 ml. concentrated HCl added slowly. The THF is distilled off at atmosphere pressure, the mixture cooled in ice, and solid NaOH added slowly with cooling until alkaline to pH paper. The aqueous solution is then extracted three times with hexane. The combined organic layers are washed with water, dried over K2CO3, filtered, stripped to give 2.0 g. crude product. It is then chromatographed in cyclohexane/EtOAc (10:1) on silica gel (Rf =0.4) to give 870 mg. oil which is distilled at 0.3 mM., b.p. 135° C., to give 405 mg. pure product, 38% yield. NMR (CDCl3, δ): 3.22 q, J=10 (2H); 2.79 m (2H); 1.40 s (20H); 0.93 m (3H). IR shows no carbonyl bands.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH2:23])=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(F)cc1C(F)(F)F
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid (1.22 g, 5.2 mmol) in THF (10 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (0.99 g, 7.80 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.53 g (40%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Cl)[CH2:14][OH:15].[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1Cl
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)c(NCCO)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
18.7 g (0.1 mole) of 1,4-diamino-2-nitro-5-chlorobenzene were dissolved in 20 ml methylglycol and 12 g ethylenechlorohydrin (1.5 mole) and the solution then heated on a bath having a temperature of 120°C. 6.6 g of sodium hydroxide dissolved in 60 ml water were then slowly added dropwise over a period of 3 hours. Heating was then continued for 1 hour whereupon a chromatographic check wss made to ascertain whether most or all of the starting compound had been reacted. After cooling the mass was diluted with water and the precipitated hydroxyethylated compound was removed by suction. Recrystallation was effected from water and thereafter from a 20% acetic acid. Yield: 4.5 g; m.p.: 130°-131°C. Analysis: C8H10ClO3N3
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][C:2]1[C:3]([CH3:15])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(C(=O)OC)c(O)c1C
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc(C(=O)OC)c(OC)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl 4-hydroxy-3-methyl-2,5-thiophene dicarboxylate (4.26 g) in acetone (100 ml) containing anhydrous potassium carbonate (2.34 g) was stirred for 1 hour at room temperature. Dimethyl sulphate (1.62 ml) was added and the solution refluxed for 2 hours. The solvent was then removed under vacuum and, after treating the residue with water-ethyl acetate, was extracted several times with ethyl acetate; the organic extracts were collected, washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent evaporated to give a solid, m.p. 61°-64° ex methanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:24][C:25]([CH2:27][CH:28]1[C:33](=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:28]([CH2:27][C:25]([OH:26])=[O:24])[CH2:33][CH2:32][CH2:31][C:30]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-trifluoromethylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared. m.p. 167°-168° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:16]I>C1OCCOCCOCCOCCOC1.CN(C)C=O>[CH3:1][O:2][C:3]([CH3:16])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CI
Reactant: CCOC(=O)C(OC)C(=O)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OC)C(=O)OCC
Yield: 50 %

Procedure:
Diethyl methoxymalonate (31.0 grams, 0.2 mole), prepared in Example LIII Part A, sodium hydride (3.91 grams of 60% reagent, 0.2 mole), methyl iodide (46.27 grams, 0.3 mole) and 15-crown-5 (2 drops) were reacted in 300 millilaters of N,N-dimethylformamide in a manner similar to that described in Example LII Part A to give 23.77 grams (0.1 mole) of diethyl methoxy(methyl)malonate. NMR analysis of the product indicated the following:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 100 °C

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), acetic anhydride (0.4 g) and dry pyridine (4 mL) was heated at 100° C. for 3 hours. The reaction mixture was cooled and water (about 35 mL) and sodium bicarbonate (0.6 g) were added. The mixture was chilled in ice and stirred. The resulting white solid was removed by filtration, washed with water and dried to give 6-(4-acetoxypiperidino)-2(1H)-quinolinone. 1/4 hydrate (0.3 g); m.p. 245°-250° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: OB(O)c1cncnc1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2ncc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-pyrido[3,2-d]pyrimidine (120 mg, 0.0003647 mol), pyrimidine-5-boronic acid (40.4 mg, 0.0003282 mol), sodium carbonate (57.9 mg, 0.0005471 mol), DMF (5 mL) and water (3 mL) were added and the reaction vessel degassed with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (15 mg, 0.0003 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 0-1.5% MeOH in chloroform) to yield the desired product [55 mg, 43%]. 1H NMR (300 MHz, CDCl3): δ 9.35 (s, 1H), 9.08 (s, 2H), 8.91 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 3.89-3.92 (m, 8H); LC-MS (ESI): Calculated mass: 328.1; Observed mass: 329.1 [M+H]+ (RT: 0.56 min).
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[C-:13]#[N:14].[Na+].O.[OH-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[C:13]([C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2])#[N:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 150 °C
Yield: 64 %

Procedure:
3,4-Methylenedioxynitrobenzene (1.67 g, 10.0 mmol) was dissolved in 20 mL of HMPA and sodium cyanide (0.49 g, 10.0 mmol) was added. The reaction was heated to 150° C. under nitrogen and three portions of sodium cyanide (0.245 g, 5.00 mmol, total) were added over 15 min. The reaction was maintained at 150° C. for 45 min, cooled, and poured into 50 mL of H2O followed by the addition of 50 mL of 5% NaOH. The aqueous layer was extracted with ether (2×25 mL) and the organic layer was discarded. The basic aqueous layer was carefully acidified to pH 4 by addition of 10% HCl and extracted with ether (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave 1.05 g (64%) of compound 477A as a yellow-brown solid. HPLC: 91.6% at 1.03 min (retention time) (Phenomenex column, 30×4.6 mm, 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220 nm. MS (ES): m/z 165.23 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:8][C:9](=O)[CH:10]([NH:13][C:14]([C:16]1[C:17]2[CH:24]=[N:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:18]=2[CH:19]=[N:20][CH:21]=1)=[O:15])[CH2:11][CH3:12])[C@H:5]([OH:7])[CH3:6].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[C@H:5]([CH3:6])[O:7][C:9]([CH:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])=[N:8]1)=[O:33]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C(=O)N[C@H](C(=O)OC)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)[C@H](C)O1

Procedure:
To a solution of (2S,3R)-2-(2-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-butyrylamino)-3-hydroxy-butyric acid methyl ester (0.900 g, 1.96 mmol) in THF (20.0 mL) was added Burgess reagent (0.586 g, 2.46 mmol). The mixture was warmed at reflux for 23 hours. The mixture was then concentrated in vacuo, dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in ethyl acetate to afford (4S,5S)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester as white foam.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:38][CH2:37][N:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)[CH2:41][CH2:40]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: Fc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
100 mg (0.25 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 45.7 mg (0.25 mmol) of 1-(3-fluorophenyl)piperazine (Example 15A) and a spatula tip of silica gel are stirred in 15 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:29])=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:29])=[C:25]([CH2:27][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C=O
Reactant: C1COCCN1
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1CN1CCOCC1

Procedure:
Method as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-5-methyl-1,3-oxazol-2-yl)hexanamide (preparation 160) (300 mg, 0.73 mmol) and morpholine (64 μl, 0.73 mmol) as starting materials.
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2([O:53]C(C)=O)CO[C@@H:10]2C[C@@H]1O)=O.C[OH:64]>>[CH3:10][C:11]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:19][C:2]([OH:64])=[CH:3][CH:15]=1)=[O:53]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: CO
Product: CC(=O)CCc1ccc(O)cc1

Procedure:
Taxus wallichiana known as the Himalayan yew is available in India. The applicants have investigating the different parts of this plant from different Himalayan regions of India for isolation of naturally occurring analogues of taxol, its important precursors and other biologically active compounds. During the course of investigation the applicants have isolated 2 compounds of 4-aryl-2-butanol namely betuligenol having formula C10H14O2, mp 69-70° C., [α]n+20 (C1, MeOH) and betuliloside having formula C16H24O7 mp 187-188°, [α]n+22° (C1, MeOH) from the leaves of T. wallichiana.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[Na].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16].C1(C)C=CC=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH2:16][C:15]#[CH:14])[CH:3]=1
Reactant: C#CCBr
Reactant: O=Cc1ccc(Br)cc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: C#CCOc1cc(Br)ccc1C=O

Procedure:
Conversion of 4-bromo-2-hydroxybenzaldehyde to its sodium salt was carried out as follows: A solution of 4-bromo-2-hydroxybenzaldehyde (3.0 g, 24.9 mmol) in MeOH (˜150 mL) was treated with 1N aq. NaOH (15.7 mL, 1.05 equiv). The resulting pale yellow solution was concentrated under reduced pressure. EtOH (30 mL) was added to the residue and the solution was concentrated under reduced pressure. This was repeated with EtOH (30 mL) and then with heptane (50 mL). The resulting yellow, powdery sodium salt was dissolved in DMF (60 mL) with stirring and to it was added propargyl bromide in toluene (80 wt %, 2.33 mL, 1.4 equiv). The reaction mixture was stirred at ambient temperature for 22 h, after which time the volatiles were concentrated under reduced pressure. The residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was separated and treated with charcoal (˜1 g) then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was crystallized from EtOAc and hexane (3:7). Crop I afforded 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (893 mg) as colorless needles. The mother liquor was concentrated under reduced pressure and crystallized again from EtOAc and hexane (7:93) to obtain a further Crop II of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (1.902 g). The mother liquor was concentrated again and subjected to one more crystallization as described before. Crop III yielded additional 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (344 mg). All the three crops were combined to give a total of 3.14 g (87% yield) of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde as colorless needles. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.24-7.28 (m, 1H), 4.85 (d, J=2.4 Hz, 2H), 2.64 (t, J=2.4 Hz, 1H); LCMS (Method A) (ESI) m/e 239.0, 241.0 Br pattern [(M+H)+, calcd for C10H7BrO2 239.0]; SiO2 TLC (EtOAc:Hexane=1:9) indicated Rf of 0.32 compared with an Rf of 0.43 for starting material aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5].[BH4-].[Na+].CI.[H-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COCC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced using sodium borohydride in methanol and the resultant alcohol was alkylated with methyl iodide using sodium hydride as base to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.53 (s, 6H), 3.25 (s, 3H), 3.38 (s, 2H), 7.53 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:18][OH:19])([CH2:8][O:9][CH2:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[CH2:6][OH:7].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:10][O:9][CH2:8][C:5]([CH2:18][OH:19])([CH2:6][OH:7])[CH2:4][OH:3])[CH2:14][OH:15]
Reactant: OCC(CO)(CO)COCC(CO)(CO)CO
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CCCCOCC(CO)(CO)COCC(CO)(CO)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
0.37 g (60%, 9.2 mmol) of sodium hydride was added to a solution of 2.35 g (9.24 mmol) of dipentaerythritol in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 1 hour at 50° C., the above (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added dropwise thereto, with additional stirring for 20 hours at 60° C. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain 494 mg of the title compound (19% yield in 2 steps) as a white solid. The results of NMR analysis of the thus obtained compound are as shown below.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[CH3:38][N:39]=[C:40]=[O:41]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:40]([NH:39][CH3:38])=[O:41])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and methyl isocyanate (5.8 uL, 0.1 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification to yield 3.4 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 506.2 (100).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][C:8]1[C:9]([CH3:11])=[CH:10][N:5]=[CH:6][C:7]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cncc(C)c1
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Cl
Yield: 75 %

Procedure:
Thionyl chloride was loaded into a reaction vessel equipped with a stirrer, a condenser, a dropping funnel, and a nitrogen bubbler. The temperature was lowered to 0-5ℑ C. and 3,5-lutidine was added dropwise, keeping the temperature between 0 and 10ℑ C. When the addition was complete the reaction mixture was refluxed for 18 hours. The mixture was cooled to 65ℑ C. and toluene (4 volumes) were added. 1.5 volumes of the mixture were distilled under vacuum. The heavy brown precipitate was collected by filtration. The crude product was recrystallized from methanol (3 volumes). Filtration afforded the product, 4-Chloro-3,5-Lutidine, as a beige solid, this was washed with methanol and dried under vacuum at 40ℑ C.; yield: 75%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si]([O:15][CH2:16][CH2:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH:20]=[N:19]1)(C(C)(C)C)(C)C>ClCCl>[CH3:29][C:27]1[CH:28]=[C:23]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][CH2:16][OH:15])[CH:22]=2)[CH:24]=[C:25]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:26]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CCO)c2)c1
Reaction time: 0.5 h

Procedure:
TFA (24 μL, 0.31 mmol) was added to a solution of N-{3-[1-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethyl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine in dichloromethane (2 mL), and the reaction was allowed to stir for 30 minutes. The competed reaction was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% formic acid modifier to afford 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]ethanol. MS ESI calcd. for C17H17F3N5O [M+H]+ 364. found 364. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.79 (d, J=4.9, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.31 (s, 1H), 7.23 (d, J=4.9, 1H), 7.05 (s, 1H), 4.92 (t, J=5.2, 1H), 4.14 (t, J=5.6, 2H), 3.73 (q, J=5.6, 2H), 2.27 (s, 3H).