Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[O:6]([CH2:13][C:14]#[C:15][CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].S([O-])(=O)(=O)C.[I-:28].[Na+]>C(Cl)Cl.CC(C)=O.C(N(CC)CC)C>[I:28][CH2:16][C:15]#[C:14][CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [I-]
Reactant: OCC#CCOc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ICC#CCOc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
1.432 ml (2.12 g, 0.0185 mol) of methanesulfonyl chloride was added dropwise to a solution of 2 g of 4-phenoxybut-2-yn-1-ol and 2.77 ml of triethylamine in 30 ml of methylene chloride at such a rate to maintain the reaction temperature at 0° C. After addition, the resulting mixture was stirred for 30 minutes at 0° C. Then the reaction mixture was poured into 30 ml of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and the solvent removed by evaporation in vacuo and thus crude 4-phenoxy-but-2-yn-1-ol methanesulfonate was obtained. The foregoing crude mesylate was dissolved in 15 ml of acetone and treated with a solution of 5.55 g of sodium iodide and 1.049 g of sodium bicarbonate in 30 ml of acetone. The reaction mixture was stirred for 1 hour at room temperature and then the solvent was removed under reduced pressure. The residue was diluted with water (25 ml) and extracted with methylene chloride, (3×30 ml) the organic extracts were dried and the solvent removed by evaporation. The residue was purified by silica gelcolumn chromatography (50 g) using hexane:ethyl acetate (95:5) as eluant, to yield 2.3 g (62%) of 1-iodo-4-phenoxybut-2-yne. The product was stored in the refrigerator.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCCCC.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].Cl[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1>C(NCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:41]([C:38]1[CH:39]=[CH:40][C:35]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:36][CH:37]=1)([O-:43])=[O:42]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 89 %

Procedure:
0.005 mol % of Pd(OAc)2, 0.01 mol % of hexyldiadamantyl-phosphine and 1 mol % of Cu(I)I are added to a mixture of 12 mmol of trimethylsilylacetylene and 10 mmol of 4-chloronitrobenzene in 40 ml of diethylamine. The mixture is stirred under reflux until conversion is complete. The readily volatile constituents are then removed under vacuum. The residue is dissolved in toluene and washed with water. After chromatography on silica gel, 89% of 1-(4-nitrophenyl)-2-trimethylsilylacetylene is obtained.
Reaction SMILES: [CH:1]1([C:5]([N:7]2[CH2:18][CH2:17][C:10]3[N:11]=[N:12][C:13]([NH:15][NH2:16])=[CH:14][C:9]=3[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:22])=O>C(O)(=O)C>[CH:1]1([C:5]([N:7]2[CH2:18][CH2:17][C:10]3[N:11]=[N:12][C:13]([NH:15][N:16]=[C:20]([CH3:22])[CH3:19])=[CH:14][C:9]=3[CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: NNc1cc2c(nn1)CCN(C(=O)C1CCC1)C2
Reactant: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)C1CCC1)C2

Procedure:
A solution of 5.8 g of 6-cyclobutanecarbonyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 50 cc of acetone and 2 drops of glacial acetic acid is heated at reflux on a water bath for 30 minutes. The crude product obtained as a brown oil is crystallized with absolute ethanol. The title compound has a M.P. of 175°-178° (decomp., from acetone/ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: OC1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: COC(=O)c1cn(C)c2cc(N3CCC(O)CC3)ccc12
Temperature: 110 °C
Reaction time: 22 h
Yield: 59.1 %

Procedure:
A re-sealable tube is charged with 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (850 mg, 1.00 equiv, 3.17 mmol), 4-hydroxypiperidine (491 mg, 1.5 equiv, 4.76 mmol), copper(I) iodide (60.379 mg, 0.1 equiv, 0.32 mmole), proline (73 mg, 0.2 equiv, 0.64 mmol) and potassium carbonate (885 mg, 2 equiv, 6.34 mmol) and purged with nitrogen. Anhydrous dimethyl sulfoxide (2 mL) is added. The tube is closed and the mixture is stirred at 110° C. for 22 h. The mixture is allowed to reach room temperature and aqueous saturated NH4Cl is added. The mixture is extracted with EtOAc (2×). The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified via chromatography (40 g silica) eluting with a gradient of 20% to 100% ethyl acetate/hexane to provide the title compound (540 mg, 59%) as a white solid. ES/MS m/z 289.0 (M+1)
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(#N)C.[N-:11]=[N+:12]=[N-:13].[Na+]>O>[N:11]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 490 g. (4 moles) of ethyl chloroacetate in 1500 ml. of acetonitrile were added 260 g. (4 moles) of sodium azide, and the mixture was heated at the reflux temperature for 20 hours. After heating, the reaction mixture was poured into 1 liter of water with stirring for 1/2 hour. The organic phase was separated from the aqueous phase and evaporated in vacuo to dryness. The yellow residual oil was dissolved in 1200 ml. of diethyl ether and the solution was dried over magnesium sulfate. Evaporation of the diethyl ether in vacuo gave 391 g. (76% yield) of ethyl azidoacetate.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH2:15])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][NH:12][C:13](=[O:14])[NH:15][CH2:8][P+:3]([CH2:1][NH:15][C:13]([NH:12][CH3:11])=[O:14])([CH2:4][NH:15][C:13]([NH:12][CH3:11])=[O:14])[CH2:6][NH:15][C:13]([NH:12][CH3:11])=[O:14]
Reactant: CNC(N)=O
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)NC[P+](CNC(=O)NC)(CNC(=O)NC)CNC(=O)NC
Yield: 100.2 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with N-methylurea (14.82 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 20.78 g (100%) of tetrakis(3-methylureidomethyl)phosphonium chloride (I, R=R'=H, R"=CH3, X=Cl) as a brittle amber glass.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH2:11][CH2:12][CH2:13][CH3:14])=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:31][NH:32][NH2:33]>C(O)C>[NH2:10][C:6]1[NH:33][N:32]([CH2:31][C:30]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=2)[C:4](=[O:3])[C:5]=1[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NNCc1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C(=O)OCC)=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCc1c(N)[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 2 h

Procedure:
To a solution of 41.1 g α-n-butyl-β-amino-β-ethoxyacrylic acid ethyl ester and a spatula tipfull of p-toluenesulphonic acid in 100 ml ethanol were added dropwise, under nitrogen, 36.5 g 3,4-dichlorobenzylhydrazine. After the mixture had been stirred afterwards for two hours, it was left to stand overnight. The solvent was distilled off, a mixture of ether/petroleum ether (1:1) was added to the residue; the product crystallized through.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22]#[N:23])([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH3:17])([CH3:12])([CH3:11])[CH3:10]>CCO.O>[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22](=[NH:23])[NH:7][OH:8])([CH3:17])[CH2:18][CH:19]1[CH2:20][CH2:21]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C#N)(CC1CC1)NC(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Temperature: 80 °C
Yield: 65.5 %

Procedure:
Sodium bi carbonate (0.204 g, 2.9 mmol) was dissolved in EtOH (10 mL) and water (10 mL). Hydroxylamine hydrochloride (0.204 g, 2.9 mmol) was added at 25° C. A solution of (cyano-cyclopropylmethyl-methyl-methyl)-carbamic acid tert-butyl ester (3) (0.7 g, 2.67 mmol) in ethanol (5 mL) was added thereto and the resulting reaction mixture was heated at 80° C. for 12 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (30 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (Combi-Flash, 40 g, 5:95 ethyl acetate/n-hexane) to give the title compound (0.45 g, 65%) as white solid; LC-MS (ELSD peak area, ESI) 100%, 258.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.S(Cl)([Cl:23])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:19][C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=S(Cl)Cl
Reactant: Oc1nc2ccccc2nc1-c1nc2ccccc2s1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2nc1-c1nc2ccccc2s1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(benzo[d]thiazol-2-yl)quinoxalin-2-ol (251 mg, 0.900 mmol) in toluene (4500 μl) was added thionyl chloride (131 μl, 1.800 mmol) followed by DMF (69.7 μl, 0.900 mmol). The green mixture was stirred at 110° C. for 3 hr. The reaction mixture was evaporated under reduced pressure and the resulting solid was diluted with CHCl3 (30-40 ml) and the insoluble solid filtered and rinsed with CHCl3. The filtrate was evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (eluted with chloroform, then dichloromethane) to provide the title compound as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1
Reactant: OCC(O)CN1CCNCC1
Reactant: Clc1ncccn1
Solvent: C1COCCO1
Product: OCC(O)CN1CCN(c2ncccn2)CC1

Procedure:
Grams 3.2 of 1-(2,3-dihydroxypropyl)piperazine and 1.14 g of 2-chloropyrimidine in 50 ml dioxane were refluxed for two and a half hour. The reaction mixture was then settled and the solution evaporated to dryness. The residue obtained was extracted with hot acetone and filtered to remove all impurities. After resting 1.1 g of 3-[4-(pyrimidin-2-yl)piperazin-1-yl]propane-1,2-diol were separated, which melted at 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@@H:11]([C:12]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=2)[C@H:24]([OH:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 36.3 %

Procedure:
The crude material (intermediate 3b from the preceding reaction) N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (183 mg, 0.47 mmol) was added to THF (30 mL) and stirred at room temperature. PS-BEMP (645 mg, 14.20 mmol base) was added to the solution followed by slow addition of p-TSCl (108 mg, 0.57 mmol). The reaction mixture was stirred for 3 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to get the purified product (63 mg): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.99 (d, J=9 Hz, 2H), 7.56 (m, 1H), 7.51 (m, 2H), 7.40 (d, J=9 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 5.32 (d, J=9 Hz, 1H), 4.85 (m, 1H), 4.42 (m, 1H), 2.34 (s, 3H), 1.38 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:12][O:11]2)=[CH:4][N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[N:23]1[CH2:30][C@H:29]2[NH:31][CH2:32][C@@H:24]1[CH2:25][CH:26]=[CH:27][CH2:28]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:12][N:31]2[CH2:32][C@H:24]3[N:23]([C:14]4[CH:15]=[CH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:13]=4)[CH2:30][C@@H:29]2[CH2:28][CH:27]=[CH:26][CH2:25]3)=[CH:6][CH:7]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: Cc1ccc(OC[C@@H]2CO2)cn1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3C/C=C\C[C@H]2CN3c2ccc3ccccc3c2)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3CC=CC[C@H]2CN3c2ccc3ccccc3c2)cn1
Temperature: 95 °C

Procedure:
(S)-2-Methyl-5-oxiranylmethoxy-pyridine (13 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was removed and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3]>CCO.[Pd]>[OH:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C#N)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
3-Allyl-4-hydroxybenzonitrile (20.0 g, 126 mmol) (Example 28) was dissolved in EtOH (320 mL) under argon. Pd/C (80 mg, 10%, Fluka) was added, and the reaction mixture was stirred under a hydrogen atmosphere (1 atm) at rt for 20 h. The catalyst was filtered off, and then the reaction mixture was concentrated under reduced pressure, yielding 20.2 g (99%) of the title compound as a slightly greenish oil. 1H NMR (400 MHz, CDCl3): 0.95 (t, 3H), 1.63 (m, 2H), 2.56 (m, 2H), 6.86 (d, 1H), 7.30 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[O:17])[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].CCOCC>C1COCC1.ClCCl>[C:31]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[O:17])[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.5 ml of absolute THF and 1.0 ml of absolute dichloromethane, and 0.02 ml of absolute pyridine is mixed with acetic anhydride (0.015 ml, 0.164 mmol). The mixture is stirred at room temperature overnight. Addition of ether and crystallization affords the product. Yield: 30 mg (87% of theory),
Reaction SMILES: C(O[C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([Br:15])[C:8]=1[OH:16])C.C([O-])([O-])=O.[K+].[K+].C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]2[C:8](=[C:9]([Br:15])[CH:10]=1)[O:16][C:4](=[O:17])[CH:5]=[CH:6]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C=C/c1cc(OC)cc(Br)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3ccccc3)cc(Br)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Dissolve preparation 2 (66.5 g, 275.89 mmol) in 1.5 L of dry DMF. Add finely powdered (325 mesh) K2CO3 (91.56 g, 662.13 mmol) followed by benzyl bromide (56.63 g, 331.07 mmol). Stir rapidly at room temperature overnight. Add 2 L of EtOAc, wash with H2O (1×2 L), 10% LiCl (3×, 4 L total volume) and brine. Dry over Na2SO4, filter and civ to yield a brown solid. Dissolve in hot EtOAc (2 L), filter off an insoluble brown solid, add hexane (˜500 mL) and allow to cool slowly, overnight. Filter off the resultant brown solid. This yields 50.3 g of a dark brown material. A second crop crashes out of the filtrate. This yields 8.1 g of a tan solid. Reduce the filtrate volume to ˜500 mL and placed on a plug of silica gel (1 kg, eluted with 1:1 EtOAc/hexane) to yield an additional 14.9 g of a darker brown solid. The total combined yield is 73.3 g (80%) of preparation 3. NMR (DMSO-d6) δ 7.96 (d, J=9.2 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.45-7.32 (m, 6H), 6.53 (d, J=9.7 Hz, 1H), 5.15 (s, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCNC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCn1nnnc1S
Yield: 43.2 %

Procedure:
To a solution of methyl N-(2-acetamidoethyl)dithiocarbamate (12.6 g.) in dioxane (40 ml.) was added a solution of sodium azide (6.4 g.) in water (40 ml.), and the mixture was heated under reflux for 4 hours. After dioxane was removed from the resultant mixture under reduced pressure, the residue was washed with ether (350 ml.) and adjusted to pH 1 with 10% hydrochloric acid. After the resultant solution was extracted with ethyl acetate (1.5 l.), the extract was dried over magnesium sulfate and the solvent was evaporated to dryness to give 1-(2-acetamidoethyl)-1H-tetrazole-5-thiol (5.3 g.) having m.p. 137.5° to 139.5° C.
Reaction SMILES: [F:1][C:2]([F:23])([CH:21]=[CH2:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].[C:24](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH:21]1([C:2]([F:1])([F:23])[CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[OH:4])[CH2:24][CH2:22]1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 365 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol in 10 ml pyridine were added 5 ml acetic acid anhydride. The ice bath was removed and the reaction mixture stirred at room temperature for one hour. The ice was added and the reaction mixture diluted by addition of 100 ml dichloromethane. The organic layer was separated and washed with 50 ml water, 1 M HCl, saturated NaHCO3 solution and brine. Then the organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting residue was dissolved in 30 ml diethyl ether (flask 1). 246 mg palladium, (II) acetate were added and the mixture cooled in an ice bath. In a second flask 4.0 g N-methyl-N-nitroso-p-toluenesulfonamide were suspended in 30 ml ethanol. An argon current was bubbled permanently through flask 2 and afterwards through flask 1. 2N NaOH was added dropwise to flask 2 until dissolution of N-methyl-N-nitroso-p-toluenesulfonamide, then the argon current was stopped. The reaction mixture (flask 1) was stirred at 0° C. for an additional hour. Then 10 ml acetic acid were added and the reaction mixture diluted by addition of 80 ml ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting residue was dissolved in 20 ml methanol, 1 ml sodium methylate solution (30%) were added and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was then neutralized by addition of acetic acid, the solvent was removed in vacuo and the residue purified by reversed phase HPLC to obtain 120 mg 2-Cyclopropyl-2,2-difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as lyophilisate.
Reaction SMILES: [NH:1]1[C:6](=O)[CH:5]=[CH:4][CH:3]=[C:2]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[N:1]=[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: O=c1cccc(-c2ccccn2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccccn2)n1
Temperature: 25 °C

Procedure:
To 100 ml of phosphorus oxychloride, cooled in an ice bath, was added 5.3 g of [2,2'-bipyridin]-6(1H)-one. The mixture was warmed to room temperature and then heated on a steam bath for 18 hours, then concentrated under vacuum. Crushed ice was added to the residual oil and the solution was basified with solid potassium carbonate. This mixture was extracted with methylene chloride, the extract was dried and evaporated in vacuo to a solid This solid was dissolved in ethyl acetate and placed on a silica gel column. The column was eluted with ethyl acetate and the obtained solid recrystallized from heptane, giving 6'-chloro-2,2'-bipyridine as white crystals, mp 60°-62° C., which was then treated as described in Example 1, giving the desired product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11](OCC)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CC1Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCC1Cc2ccccc2C1
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of ester 148 (68.8 g, 337 mmol) in dry THF (250 mL) was added to dropwise to a suspension of LiAlH4 (20.0 g, 501 mmol) in dry THF (500 mL) at 0° C. and the resulting mixture was stirred for 1.5 h. EtOAc was added to quench excess LiAlH4 and then aqueous H2SO4 solution (10%, 1 L) was added and the organic fraction separated. The aqueous solution was extracted with EtOAc (3×250 mL), and the combined organic fraction dried and the solvent evaporated to give alcohol 149 (54.5 g, 100%) (lit. Tanaka, et. al., J. Med. Chem. 1994, 37, 2071-2078) as a yellow oil: 1H NMR δ 7.16-7.25 (m, 2H, Harom), 7.09-7.14 (m, 2H, Harom), 3.74 (t, J=6.8 Hz, 2H, CH2O), 3.03-3.10 (m, 2H, CH2), 2.53-2.66 (m, 3H, CH2, CH), 1.82 (q, J=6.8 Hz, 2H, CH2), OH not observed.