Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].O>CS(C)=O>[CH2:24]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCCCCCCBr
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
This example illustrates a synthesis of 3-(11,10-Oxidoundecyl)-1-methylthymine (inventive compound no. 1932). Sodium hydride (95%) (168 mg, 7 mmol) was added to a solution of 1-methylthymine (700.5 mg, 5 mmol) in dimethylsulfoxide (15 mL). After 20 minutes of stirring, 1-bromundec-10-ene (1.165 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and saturated aqueous salt solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% ethyl acetate/hexane eluant to yield 1.22 g (83.7% yield) 3-(10-undecenyl)-1-methylthymine (inventive compound no. 1931).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[C:16]([CH3:18])[NH:15][C:14](=O)[CH:13]=1.N.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:17]=[C:16]([CH3:18])[N:15]=1
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]c(C)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: COCCOc1ccccc1-c1cc(Cl)nc(C)n1
Temperature: 5 °C
Yield: 87 %

Procedure:
A stirred suspension of 6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-3H-pyrimidin-4-one (0.17 g, 0.66 mmol) in POCl3 (2 mL) was heated at reflux for 1 h. The reaction mixture was cooled to about 5° C. and poured cautiously into 10 ml ice-water, ammonia (10 mL) was added and extracted with ethyl acetate (2×10 mL), organic layers were combined, washed with water (5 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent CHCl3-EtOAc, 10:1), yielding 0.16 g (87%) 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidine as colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Cl[CH:29]([CH3:33])[C:30](=O)[CH3:31]>CN(C)C=O>[CH3:33][C:29]1[N:26]=[C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)[S:27][C:30]=1[CH3:31]
Reactant: CC(=O)C(C)Cl
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: CN(C)C=O
Product: Cc1nc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 0.60 g (1.56 mmol) of the starting material I, 1.02 g (9.57 mmol) of 3-chloro-2-butanone and 8 ml of dimethylformamide was stirred at 90° C. for 3 h. After cooling the precipitated crystals were filtered off, dried and purified by recrystallization from dimethylformamide and water to yield 0.49 g (76%) of the title compound; Mp.: >260° C. (dec.).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)c(C)c3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)ccc1F
Yield: 89.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.035 g, 0.058 mmol) and LiOH (0.014 g, 0.579 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0298 g, 0.052 mmol, 89% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.12-7.17 (m, 2H), 7.04-7.12 (m, 2H), 6.95-7.01 (m, 3H), 5.96 (br. s., 1H), 4.16-4.28 (m, 2H), 3.60 (br. s., 1H), 3.09 (t, J=7.0 Hz, 2H), 2.80-3.01 (m, 1H), 2.66 (s, 3H), 2.30 (d, J=1.7 Hz, 3H), 2.19-2.32 (m, 1H), 2.22 (s, 3H), 1.97-2.15 (m, 1H), 1.25 (s, 9H), 0.87 (br. s., 3H), 0.68 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=577.3.
Reaction SMILES: [NH2:1][CH:2]([P:4]([CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH3:9])(=[O:6])[OH:5])[CH3:3].Cl.[CH3:14]O>>[NH2:1][CH:2]([P:4]([CH2:7][CH:8]([C:10]([O:12][CH3:14])=[O:11])[CH3:9])(=[O:5])[OH:6])[CH3:3]
Reactant: CC(CP(=O)(O)C(C)N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)CP(=O)(O)C(C)N

Procedure:
A solution of 100 mg of 1-aminoethyl-(2-carboxy-1-propyl)phosphinic acid in methanol (5 ml) was cooled to 0° C. and saturated with HCl gas. The sealed reaction mixture was then stirred 12 hours at room temperature whereupon the methanol was removed in vacuo to provide the title compound as a hydrochloride salt which was desalted via the procedure, in Example 2 using propylene oxide to provide the title compound. (80 mg).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=1>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:23]=1
Reactant: Oc1ccc(F)cn1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C(c1ccccc1)n1cc(F)ccc1=O
Temperature: 120 °C

Procedure:
1.2 g (4.36 mmol) of 2-bromo-1,2-diphenylethanone and 740 mg (6.54 mmol) of 5-fluoro-2-hydroxypyridine were intimately ground in a mortar, and the mixture was subsequently heated at 120° C. for 2 hours. The still hot, oily mass was dissolved in ethyl acetate. Cooling resulted in the 5-fluoro-1-(2-oxo-1,2-diphenylethyl)-1H-pyridin-2-one in crystalline form, 1.01 g (75%), which was immediately dissolved in 15 ml of methanol. After addition of 340 mg (9.03 mmol) of sodium borohydride, the mixture was left at room temperature for one hour and then diluted with water. The resulting mass of crystals was filtered off with suction. The product contains the diastereoisomeric pyrid-2-one alcohols in the ratio of about 1:2 and was not fractionated further.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]([CH3:10])[CH3:9])[S:4][C:3]=1[CH:11]=O.[C:13](=[N:26][NH2:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:13](=[N:26][N:27]=[CH:11][C:3]1[S:4][C:5]([CH2:7][N:8]([CH3:10])[CH3:9])=[CH:6][C:2]=1[Br:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CN(C)Cc1cc(Br)c(C=O)s1
Solvent: CCO
Product: CN(C)Cc1cc(Br)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Temperature: 65 °C

Procedure:
To 3-bromo-5-dimethylaminomethyl-thiophene-2-carbaldehyde [4.30 g, 17.3 mmol, Intermediate (2)] in ethanol (40 mL) is added benzophenone hydrazone (3.75 g, 19.0 mmol). The solution was heated at 65° C. for 5 hours. The solvent is removed under reduced pressure. The residue is chromatographed through silica gel (n-heptane-ethyl acetate. 90:10 as eluant) to produce [5-(Benzhydrylidene-hydrazonomethyl)-4-bromo-thiophen-2-ylmethyl]-dimethyl-amine] 5.57 g, 75%, Intermediate (3)] as an orange oil. LC/MS: RT=2.72 minutes, 426.05 m/e (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:39]=3)[CH:32]=2)C=CC=1>[Cu].C1(C)C=CC=CC=1>[O:37]([C:38]1[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=1)[O:44][C:45]1[CH:50]=[C:49]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:8]3[CH:21]=[CH:20][CH:19]=[C:10]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:13]=4)[CH:9]=3)[CH:3]=2)[CH:48]=[CH:47][CH:46]=1)[C:33]1[CH:32]=[CH:31][CH:36]=[CH:35][CH:34]=1
Reactant: Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(Oc4cccc(-c5cccc(Oc6cccc(Oc7ccccc7)c6)c5)c4)c3)c2)cc1

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser and Dean-Stark trap was charged with 59.8 g. (0.215 mole) of m-(m-phenoxyphenoxy)phenol, 50 ml. of toluene and 7.2 g. (0.129 mole) of potassium hydroxide. Water was azeotroped from the system and 100 ml. of diglyme added followed by dropwise addition of 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl over a 30 min. period. To this mixture 2.5 g. of cuprous chloride and 0.5 g. of copper powder was added. Diglyme was distilled from the system and the resulting mixture heated at 230°-240°C. for 18 hours. At the end of this time, 250 ml. of ether was added to the cooled mixture and the resulting slurry centrifuged to remove salts. The ethereal solution was washed thoroughly with aqueous base, water and then dried over anhydrous magnesium sulfate. The ether was removed under vacuum, and the resulting oil was distilled to give 24.4 g. of the desired product, bp 340°/ 0.05 mm., nD25 1.6510.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cnn(Cc2ccccc2)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(Cc4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-benzylpyrazole.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:25])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:29][C:28]1([CH3:30])[O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][CH:9](/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH2:19][CH3:20])[O:25]1
Reactant: COC(C)(C)OC
Reactant: CCCC[Sn](/C=C/C(O)CC(O)CC(=O)OC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC[Sn](/C=C/C1CC(CC(=O)OC)OC(C)(C)O1)(CCCC)CCCC

Procedure:
A mixture of E-methyl 3,5-dihydroxy-7-tributylstannyl-6-heptenoate (4.18 g), 2,2-dimethoxypropane (18 ml) and pyridinium p-toluene sulfonate (0.227 g) is stirred in anhydrous methylene chloride (4.5 ml) at room temperature for about 20 hours, diluted with ether, washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 10% ether in hexane to give the desired product.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[CH:17]=[CH:16][N:15]=1>>[CH3:31][N:29]([CH2:28][C:25]1[O:24][C:23]([CH2:22][S:21][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[C:19]=2[CH3:20])=[CH:27][CH:26]=1)[CH3:30]
Reactant: Cc1c(SCc2ccc(CN(C)C)o2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Product: Cc1c(SCc2ccc(CN(C)C)o2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-4-{[(5-dimethylaminomethyl-2-furyl)methyl]thio}-3-methylpyridine hydrochloride gives the title compound after chromatography on silica gel (dichloromethane/methanol/triethylamine 9:1:0.1 to 2:1:0.1).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH2:22]([N:29]=[C:30]=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:22]([NH:29][C:30](=[O:31])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)NCCCCCCC)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.67 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, heptyl isocyanate (644 mg/ml, 4 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to get 10b as creamish solid. Yield: 625 mg, 71.26%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>>[O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(CCOc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCOc2ccccc2)CC1

Procedure:
1-(2-Phenoxyethyl)-4-piperidone oxime is prepared from 1-(2-phenoxyethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][N:2]=[C:3]([C:9]1([O:12][CH2:13][CH2:14][O:15]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C1(CCl)OCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-hydroxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 0.5 g) in dried acetone (5 ml) was added potassium carbonate (0.29 g), and then dimethyl sulfate (0.265 g) was added dropwise thereto at ambient temperature with stirring. The mixture was stirred for 7 hours at ambient temperature and then filtered. The filtrate was evaporated to give ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer).
Reaction SMILES: CO[C:3](=[O:29])[C@H:4]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:5][C:6]1[C:7]([CH2:16]Cl)=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:22]([O:21][C:19](=[O:20])[NH:18][C@H:4]1[C:3](=[O:29])[N:33]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH2:16][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[C:13]([Cl:15])=[CH:14][C:6]=2[CH2:5]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
A mixture of 2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)propionic acid methyl ester (525 mg, 1.20 mmol) [Chaturvedula et al. WO 2006/052378], trifluoroethylamine (1.0 g, 10.2 mmol), and K2CO3 (499 mg, 3.61 mmol) in CH3CN (15 mL) was heated at 40° C. in a sealed vessel for 45 h. Additional trifluoroethylamine (1.0 g, 10.2 mmol) was added and the mixture was heated at 40° C. for a further 48 h and then allowed to cool to ambient temperature. The reaction mixture was filtered through a 0.45 μm PTFE membrane and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (10 mL) and AcOH (1 mL) and the mixture was heated at reflux for 6 h, allowed to cool to ambient temperature, and partitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=467.
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[N:16]=2)[CH:8]=[CH:9][C:10]=1[OH:11].Br[CH:30]([CH3:32])[CH3:31]>>[F:28][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:30]([CH3:32])[CH3:31]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OCC(F)F)c2)n1
Reactant: CC(C)Br
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(C)C)c(OCC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 317 and 2-bromopropane, white powdery 3-{2-[3-(2,2-difluoroethoxy)-4-isopropoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [CH:1]#[CH:2].C(=O)=O.CO.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])=[O:17]>O1CCCC1>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:16]([C:10]1[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])([OH:17])[C:1]#[CH:2]
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2C)c(C)c1
Reactant: C#C
Agent: O=C=O
Solvent: CO
Solvent: C1CCOC1
Product: C#CC(O)(c1ccc(C)cc1C)c1ccc(C)cc1C
Reaction time: 8 h

Procedure:
0.5 g of Fe(NO3)3.9H2O and 49 g of sodium are added to liquid ammonia (1.5 ) to produce sodium amide. Then acetylene gas is introduced into the reaction mixture at a temperature of -40° C. to -65° C. (whilst cooling using dry ice-methanol) for one hour while stirring. Then, an anhydrous tetrahydrofuran solution containing 476 g of di-(2,4-dimethylphenyl) ketone is added dropwise to the reaction mixture while cooling and stirring. After further stirring for 2 hours, the mixture is left at room temperature overnight. After removal of ammonia from the reaction solution by evaporation, 3N diluted HCl (300 ml) is added to the solution. After extraction with ether, the ether layer is washed with water and dried. After removal of ether by evaporation, 1,1-bis(2,4-dimethylphenyl)-2-propyn-1-ol is obtained as colourless oily product with a yield of 450 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[S:11][CH:12]=1)[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=1)[CH3:2]
Reactant: CCc1cnn(C)c1-c1csc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnn(C)c1-c1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (192 mg, 0.77 mmol) in Tetrahydrofuran (THF) (4 mL). 6N NaOH (4 mL, 24.0 mmol) was added slowly, the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl3 and H2O and the pH of the aqueous layer adjusted to pH ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na2SO4 and solvent removed affording the title compound (181 mg, quant.) used without further purification: LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:5][C:4]=1[CH2:23][S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].[N:37]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:27]1([S:24]([C:23]2[C:4]3[C:3](=[CH:22][CH:21]=[C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[CH:5]=3)[NH:2][N:37]=2)(=[O:25])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethanol (430 mL) in two portions and 1 N hydrochloric acid (200 mL) were added to toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester (6.5 g, 13 mmol). A solution of sodium nitrite (1.5 g, 22 mmol) in water was then added to the reaction mixture. The reaction was heated to aid in solubility. After stirring at ambient temperature for 2 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred at ambient temperature for one hour. It was then solvent evaporated and partitioned in water and ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform. Drying at 63° C. in vacuo yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester a buff-colored foam (3.9 g, 59%); Mass Spectrum (+EI, [M+H]+) m/z 523. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.76 (d, 1H, J=8.78 Hz), 8.52-8.55 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.64-7.74 (m, 3H), 7.55-7.63 (m, 2H), 7.50 (d, 1H, J=9.15 Hz), 7.27 (d, 2H, J=8.05 Hz), 7.14 (d, 1H, J=2.20 Hz), 6.94 (dd, 1H, J=9.15 Hz and 2.44 Hz), 4.32-4.34 (m, 2H), 4.18-4.20 (m, 2H), 2.25 ppm (s, 3H). Elemental Analysis for C26H22N2O6S2: Calcd: C, 59.76; H, 4.24; N, 5.36; Found: C, 59.69; H, 4.28; N, 5.14.