Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[O:16])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.C[Si]1(C)CC[Si](C)(C)[N:32]1[CH2:38][CH2:39][CH2:40][Mg]Cl>C1COCC1>[NH2:32][CH2:38][CH2:39][CH2:40][C@:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[OH:16]
Reactant: Cc1cccc(-c2c(Cl)cccc2C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: C[Si]1(C)CC[Si](C)(C)N1CCC[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2c(Cl)cccc2[C@](O)(CCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-(6-chloro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate (800 mg, 1.94 mmol) in anhydrous THF (15 mL) cooled to −78° C. was added dropwise a solution of 2 M (3-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)propyl)magnesium chloride in THF (0.968 mL, 1.94 mmol). After addition, the reaction mixture was allowed to warm slowly to room temperature while stirring overnight. The mixture was quenched with satd aq NH4Cl (15 mL) and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated to give crude (R)-tert-butyl 3-((S)-4-amino-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carboxylate (900 mg), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:3]=1.O.[NH2:14][NH2:15].C(O)C>C1COCC1>[NH:14]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:3]=1)[NH2:15]
Reactant: OC1CN(c2cc(Cl)ncn2)C1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NNc1cc(N2CC(O)C2)ncn1
Reaction time: 1 h

Procedure:
960 mg (5.2 mmol) 1-(6-chloropyrimidin-4-yl)azetidin-3-ol and 2.5 ml (51.7 mmol) hydrazine hydrate are initially introduced into a mixture of 10 ml ethanol and 10 ml THF. The reaction is carried out at 130° C. for 1 h in a single mode microwave (CEM Explorer). The mixture is concentrated to approx. 20-50% of the original volume of liquid and is left to stand at RT for 48 h. The supernatant is decanted off from the solid formed and the solid is washed three times with 1.5 ml cold ethanol each time. It is dried under a high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:10][CH2:11][O:12][C:13]([CH:15]1[CH2:21][CH2:20][C:18](=[O:19])[CH2:17][CH2:16]1)=[O:14]>Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[OH:19][C:18]1([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:17][CH2:16][CH:15]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Fc1cccc(F)c1F
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Product: CCOC(=O)C1CCC(O)(c2cc(F)c(F)c(F)c2)CC1

Procedure:
Thus, 1-triisopropyloxytitanyl, 3,4,5-trifluorobenzene--prepared by transmetalation of 3,4,5-trifluorobenzenemagnesiumbromide using chlorotriisopropyloxytitanium--is reacted chemoselectively with ethyl cyclohexanone-4-carboxylate (1) on the carbonyl group to give ethyl 4-hydroxy-4(3,4,5-trifluorophenyl)cyclohexanecarboxylate. Elimination of water, catalytic hydrogenation over Pd/C, hydrolysis and epimerization using KOH/methanol give the pure trans 4-(3,4,5-trifluorophenyl)cyclohexanecarboxylic acid-(1). The latter is converted into the mixed anhydride using pivaloyl chloride and, using N,O-dimethylhydroxylamine, into the corresponding amide. The latter is reduced in high yield using LiAlH4 to give the aldehyde IIIa'.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][CH2:12][OH:13])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[CH:14]1[CH:19]=CC=CC=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)C.Cl>O>[CH3:1][C:2]1([CH2:11][CH2:12][O:13][CH2:24][CH2:25][N:20]2[CH2:14][CH2:19][O:23][CH2:22][CH2:21]2)[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[O:6]1
Reactant: c1ccccc1
Reactant: CC1(CCO)Oc2ccccc2O1
Reactant: C1COCCN1
Agent: CCCl
Agent: Cl
Solvent: O
Product: CC1(CCOCCN2CCOCC2)Oc2ccccc2O1

Procedure:
3.2 g. of 80% HaH are added a little at a time, with cooling, to 10 g. of 2-methyl-2-(β-hydroxyethyl)-1,3-benzodioxole dissolved in 180 cc. of anhydrous benzene. The mixture is refluxed for one hour and cooled. 15 g. of morpholine-ethyl chloride are added drop by drop, and the mixture is refluxed for three hours. The solvent is eliminated under vacuum, and the residue is dissolved in water, acidified with dilute HCl and extracted with ether. The aqueous phase is made alkaline, and again extracted with ether. The organic phase is separated, dried over Na2SO4, and evaporated.
Reaction SMILES: CC1(O)C=C[C:5]([CH2:6][N:7]2[CH2:12][CH2:11]C[CH2:9][CH2:8]2)=[CH:4][CH2:3]1.CS(O[CH2:21][CH2:22][C:23]#[CH:24])(=O)=O.[C:25](=[O:28])([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][C:22]1[CH:3]=[CH:4][C:5]([CH2:6][C:25]2([OH:28])[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][C:4]#[CH:3])[CH2:12][CH2:11]2)=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: C#CCCOS(C)(=O)=O
Reactant: CC1(O)C=CC(CN2CCCCC2)=CC1
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(Cc2ccc(C)cc2)CC1
Yield: 65 %

Procedure:
A mixture of 4-methyl-4-hydroxybenzylpiperidine hydrocholoride (1.3 g, 5.4 mmol), 1-butyn-4-yl methanesulfonate (0.96 g, 6.5 mmol), potassium carbonate (2.5 g, 18 mmol) in 50 mL of acetonitrile was allowed to reflux for 12 hrs. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). Evaporation of solvents gave a residue, which was purified by flash chromatography (50% EtOAc in hexane), giving 0.90 g (65%) of the title compound as a pale yellow oil. 1H NMR (CDCl3) 1.258 (m, 2 H), 1.883 (m, 2 H), 1.962 (m, 3 H), 2.040 (m, 2 H), 2.342 (s, 3 H), 2.399 (m, 2 H), 2.611 (m, 3 H), 2.708 (m, 2 H), 7.060-7.135 (m, 4 H).
Reaction SMILES: C(Cl)(=O)C.[C:5]1([N:11]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12](=[O:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]([CH2:41][CH:42]=O)[CH2:30][N:31]([CH3:40])[C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:26][C:27]=1[Cl:28].C([BH3-])#N.[Na+]>CO.O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]([CH2:41][CH2:42][N:18]2[CH2:17][CH2:16][CH:15]([N:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:12](=[O:14])[CH3:13])[CH2:20][CH2:19]2)[CH2:30][N:31]([CH3:40])[C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)N(c1ccccc1)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccccc1)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a flask containing methanol (0.5 mL) at 0° C. was added acetyl chloride (0.085 mL), and the resulting solution was allowed to stir for 20 minutes. 4-(N-Phenylacetamido)piperidine (0.327 g) in methanol (1 mL) was added, followed by N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.350 g) in methanol (2.5 mL) and, 15 minutes later, sodium cyanoborohydride (0.038 g). After being stirred at room temperature for 4 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed (water), dried, and evaporated. The resulting material was chromatographed, with ethyl acetate:methanol (5:1) as the eluent, to give the title compound (0.253 g) as a white solid; MS: m/z=552(M+1). Analysis for C31H35Cl2N3O2.0.8 H2O: Calculated: C, 65.67; H, 6.51; N, 7.41; Found: C, 65.76; H, 6.37; N, 7.48.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Yield: 55.6 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 248 mg of 4-methoxy-benzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then agitation is carried out at ambient temperature for approximately one night. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. After chromatography on silica eluting with methylene chloride/CH3CN in a proportion of 70/30, 250 mg of expected product is thus obtained in the form of a beige solid.
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)C(C)C)(C)C.C1COCC1.[C:28](=O)([O:34]C(C)(C)C)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CCOC(C)=O>[C:30]([O:29][C:28](=[O:34])[NH:1][C@H:2]([CH2:3][OH:4])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: N[C@@H](/C=C/c1ccc(Br)cc1)CO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/c1ccc(Br)cc1)CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
(E)-(S)-2-amino-4-(4-bromo-phenyl)-but-3-en-1-ol (7.8 g) and N,N-diisopropylethylamine (11.1 ml) were combined with THF (150 ml) to give a colourless solution. The reaction mixture was cooled to 0° C. and di-tert-butyl carbonate (7.17 g) was added. The reaction mixture was stirred at room temperature overnight to afford a yellow solution. The reaction mixture was then poured into EtOAc and washed sequentially with 1 M aq. HCl, 1 M aq. NaOH and saturated brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was then stirred over charcoal (2 g) for 30 min. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford [(E)-(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-allyl]-carbamic acid tert-butyl ester as an off-white solid (10.8 g, 98%). MS (ISP): 344.0 ([{81Br}M+H]+), 342.0 ([{79Br} M+H]+), 287.9 ([{81Br}M+H—C4H8]+), 286.0 ([{79Br} M+H—C4H8]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.C([O-])(=O)C.[NH4+:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:14]3[C:13](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:25][C:10]([CH3:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=CC(c2ccc(Cl)cc2)C2=C(CCCC2=O)N1
Yield: 34 %

Procedure:
4-(4-Chlorophenyl)-3-butene-2-one (2.83 g), 1.3-cyclohexanedione (1.81 g), and ammonium acetate (2.60 g) were combined in ethanol (125 mL) and heated at reflux for 5.5 h. The solvent was evaporated, and the residue was taken up in water and extracted with ethyl acetate. The combined organic extracts were washed (water, brine), dried, and evaporated to yield a residue which was chromatographed, eluting with hexane:ethyl acetate (1:1) to yield the title compound as a pale yellow solid (1.46 g); mp 184°-187° C.; MS: 273 (M); NMR: 1.73 (s,3, CH3), 1.75-1.98 (m,2, CH2), 2.15 (m,2, CH2), 2.43 (t,2, J=6.0, CH2), 4.39 (d,1, J=4.7, CH), 4.58 (d,1,J=4.8, CH), 7.14 (d,2, J=8.4, Ar), 7.26 (d,2, J=8.4, Ar), 8.48 (s,1, NH); Analysis for C16H16ClNO: Calculated: C, 70.20; H, 5.89; N, 5.12; Found: C, 70.21; H, 5.67; N, 5.02.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([OH:13])=O)[O:4][CH2:3][CH2:2]1.C[O-].[Na+].S(Cl)([Cl:19])=O>CO.C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([Cl:19])=[O:13])[O:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCCC12OCCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCCCC12OCCO2
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decane-6-carboxylic acid (2.42 g, 13 mmol) in methanol (6 mL) was added a 5.4 N solution of sodium methoxide in methanol (2.41 mL). The mixture was stirred at 20° C. for 20 min and the solvent was then evaporated under reduced pressure. Toluene (20 mL) was added to the residue and the solvent was evaporated under reduced pressure. The white solid obtained (2.5 g) was suspended in toluene (13 mL) and thionyl chloride (1 mL, 13.8 mmol) was added to the stirred solution at 20° C. over 10 min. Stirring was continued at 40° C. for 1 h when gas evolution stopped to give a ca 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene.
Reaction SMILES: CC(N(C)C)=[O:3].CC1[C@@H](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:24][C@:20]2([OH:47])C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H:18]([C@@H:19]2[O:48]C(C2C=CC=CC=2)=O)[C@:17]2([O:59]C(C)=O)[CH2:57][O:58][C@@H]2C[C@@H]1O)=O.[OH2:69].[Na+].[Cl-]>O>[O:69]=[CH:24][C@@H:20]([C@H:19]([C@@H:18]([C@@H:17]([CH2:57][OH:58])[OH:59])[OH:3])[OH:48])[OH:47]
Reactant: CC(=O)N(C)C
Reactant: O
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
Agent: [Cl-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 5 %

Procedure:
The DMA-paclitaxel mixture was diluted in normal saline or 5% dextrose in water to yield drug concentrations of 1 mg/ml and 5 mg/ml.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:3](=[O:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCc1cccnc1
Reactant: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 102 °C

Procedure:
21.6 g (131 mmol) 3-(3-pyridyl)-propionic acid methyl ester, 35.1 g (109 mmol) 4-(1-diphenylmethyl-piperidin-4-yl)-butylamine and 9.8 g (54.5 mmol) 30% sodium methylate solution in methanol are heated to boiling in 480 ml toluene for five hours. Subsequently, 30 ml of solvent is distilled off, sodium methylate precipitates thereby, and the temperature of the suspension increases under heavy foaming to 102° C. The mixture is cooled to 70-80° C. and extracted twice with 45 ml and 30 ml water. The organic phase is azeotropically dried in a moisture separator and cooled to ca. 0° C. The resulting precipitate is filtered and crystallized from 190 ml toluene. Colorless crystals with an MP of 139° C.; yield 46.3 g (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:26]Br.O>C(O)(=O)C>[Br:26][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[S:16][C:17]([F:18])([F:20])[F:19]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-nitro-5-[(trifluoromethyl)thio]pyrrole (0.35 g, 0.0011 mol) and sodium acetate (0.11 g, 0.0013 mol) in acetic acid is treated with a solution of bromine (0.21 g, 0.0013 mol) in acetic acid, stirred for one hour, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.25 g, mp 160°-165° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:54]=[N+:55]=[N-:56].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][N:54]=[N+:55]=[N-:56])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCO)n2COCP(=O)(OC(C)C)OC(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN=[N+]=[N-])n2COCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 36 (1.00 g, 1.48 mmol) in pyridine (20 mL) is treated with methanesulphonyl chloride (539 mg, 97%, 3.00 mmol) and the mixture is stirred for 20 h at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL), washed with water (2×) and brine and the organic layer dried over MgSO4 followed by filtration and concentration. The residue containing 37 is dissolved in DMF (9 mL), treated with sodium azide (260 mg, 3.96 mmol) and the mixture stirred for 4 h at 100° C. The reaction mixture is diluted with ethyl acetate (300 mL), washed with water (2×) and brine and the organic layer dried over MgSO4. After filtration, the filtrate is concentrated and the residue was purified on a silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent to give 458 mg (44%, two steps) of product as a colorless film: 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.89 (s, 1H), 7.40-7.18 (m, 13H), 6.79 (d, J=8.8 Hz, 2H), 4.87-4.76 (m, 1H), 4.73-4.60 (m, 2H), 4.19-3.68 (m, 4H), 3.77 (s, 3H), 3.41-3.32 (m, 1H), 3.22-3.10 (m, 1H), 2.47-2.32 (m, 1H), 2.24-2.12 (m, 1H), 1.29 (d, J=6.0 Hz, 6H), 1.24 (d, J=6.7 Hz, 6H). IR (neat, cm−1) 3017, 2103, 1605 and 1216. HRMS Calcd for C36H43N8O5P (M+H)+ 699.3172. Found: 699.3152.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][C:21]1([CH3:24])[CH2:23][O:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][C:21]([CH3:24])([OH:22])[CH3:23])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC1(C)CO1
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 36.4 %

Procedure:
To a solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (1.35 g, 4.15 mmol) and 2,2-dimethyloxirane (0.755 mL, 8.30 mmol) in DMA (20 mL) in a sealed tube was added potassium carbonate (1.72 g, 12.5 mmol), and the reaction was heated to 80° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate, and washed twice with water and once with brine. It was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel loaded and eluted with 35% ethyl acetate/hexanes to yield pure 1-(6-bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (0.60 g, 36.4% yield).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH:27]3[CH2:29][CH2:28]3)[C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][CH:24]=[N:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CN1CCCC1=O>[CH:27]1([N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([NH:33][CH:30]([CH3:32])[CH3:31])[N:6]=3)[CH2:8][CH2:9]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:29][CH2:28]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nsc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of N-[1-(3-chloro-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-N-cyclopropyl-4-oxazol-5-yl-benzamide (43 mg) and isopropylamine (0.50 mL) in N-methyl-2-pyrrolidinon (1.50 mL) is stirred at 120° C. for two days. The mixture is concentrated in vacuo and the residue is purified by HPLC on reversed phase (MeOH/H2O/NH4OH). LC (method 5): tR=1.95 min; Mass spectrum (ESI+): m/z=453 [M+H]+.
Reaction SMILES: O.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[Cl:25][C:26]1([Cl:35])[CH:33]2[CH:28]([CH2:29][CH2:30][CH:31]=[CH:32]2)[C:27]1=[O:34]>C(O)C>[Cl:25][C:26]1([Cl:35])[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH:31]=[CH:32]2)[C:27]1=[O:34].[Cl:25][C:26]1([Cl:35])[C@H:33]2[C@H:28]([CH2:29][CH2:30][CH:31]=[CH:32]2)[C@@H:27]1[OH:34]
Reactant: O=C1C2CCC=CC2C1(Cl)Cl
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCO
Solvent: O
Product: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Product: O[C@H]1[C@H]2CCC=C[C@H]2C1(Cl)Cl
Temperature: 32 °C

Procedure:
A mixture of 3 liters of water, 150 g of an active Bakers Yeast, 15 g of edible yeast and 10 g of sucrose were stirred at 32° C. A solution of 24 g of 8,8-dichloro-bicyclo[4.2.0]oct-2-en-7-one in 170 ml of ethanol was added dropwise over a 15 minute period, followed by a further 5 g of sucrose. After stirring for 45 minutes the reaction mixture was centrifuged to remove the yeast, which was washed with acetone and the washings combined with the aqueous product from the centrifuge. The combined product was washed several times with ethyl acetate, the organic washings combined filtered and the solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel, eluting with 5% acetone in hexane, initially and gradually increasing the proportion of acetone to 100%, giving 4.0 g of (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one (4) as a liquid, [α]D =-78.7° (C=0.8, CHCl3), and 8.8 g of crude (1R,6S,7S)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-ol (5), which was recrystallized from hexane to give 6.4 g of pure (5), m.p.=86°-7° C., [α]D =-217.1° (C=0.6, CHCl3).