Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:12])=[CH:16][CH:15]=1
Reactant: Clc1ccc(I)cc1
Reactant: C=CCCCCCCCCCO
Product: OCCCCCCCCCC#Cc1ccc(Cl)cc1

Procedure:
In a manner described in Example 18 above, 10-undecene-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound; NMR (CDCl3) δ1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H), 2.36-2.41 (m,2H), 3.61-3.66(m,2H), 7.16-7.31 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:35][C:36]([NH2:38])=[O:37]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: NC(=O)CBr
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CC(N)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 2-bromoacetamide were reacted to give 558. LCMS m/z: 252.7 (2M+H+)
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:10][CH:11]([O:13][C:14]([NH:16][CH2:17][C:18]1([CH2:24][C:25]([O:27]CC=C)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15])[CH3:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]>C(O)C.[Pd]>[C:5]([O:10][CH:11]([O:13][C:14]([NH:16][CH2:17][C:18]1([CH2:24][C:25]([OH:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15])[CH3:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred suspension of ammonium formate (3.4 g, 54 mmol) in ethanol (34 mL), was added compound (15) (10 g, 27 mmol) together with 10% Pd/C (1 g) under a nitrogen atmosphere. After one hour, the reaction mixture was filtered and the catalyst washed with ethanol (2×10 mL). The filtrates were combined and evaporated. The crude product was dissolved in diethyl ether (150 mL) and the organic phase was washed with 2N HCl (100 mL), water (100 mL) and brine (100 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give a viscous liquid that crystallized upon standing. The product was recrystallized using 1:10 ethyl acetate:heptane (100 mL) to give the product (11) as a white, crystalline solid (7.9 g, 88%), m.p 63–64° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])/[C:9]1=[O:30])=O)(C)(C)C.[CH3:31][C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])=[CH2:33]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:30])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH:27]([CH3:29])[CH3:28])[CH2:37][C:36](=[O:38])[NH:35][CH:34]3[C:32]([CH3:33])=[CH2:31])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(C)C=NC(=C)O[Si](C)(C)C
Reactant: CC(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OC(C)C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 63.3 %

Procedure:
In a manner similar to the method described in Example 41b, E/Z-6-Chloro-3-(5-chloro-2-isopropoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2 g, 4.47 mmol) was reacted with 1-(1-methyl-ethenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (22.37 mmol) in toluene to give title compound as a white solid (1.3 g).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrCC(OCC)=O>[Pd]>[CH:1]1([NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)CBr
Product: c1ccc(CNC2CCc3ccccc32)cc1

Procedure:
The amino acid was synthesized as described by Miyake, et al., Takeda Kenkyushoho 44: 171-185 (1985). [Chem. Abstr. 106: 156830 (1987)]. N-(1-indanyl)-benzylamine was prepared by reductive amination of 1-indanone with benzylamine, and alkylation of the amine by ethyl bromoacetate. The benzyl group was cleaved by hydrogenolysis over palladium. Saponification of the ethyl ester gave the amino acid, which was converted to the Boc derivative by the standard procedure described in Example III.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])(=[O:4])=[O:3].C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])[NH2:13])(=[O:4])=[O:3]
Reactant: Cc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(S(N)(=O)=O)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a heterogeneous solution of 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27) (0.5 g, 2 mmol) in of ethanol:water (50 mL, each) were added iron powder (1.08 g, 20 mmol), and ammonium chloride (1.08 g, 20 mmol) at room temperature. The resulting heterogeneous mixture was then stirred at 60° C. for 2 hours, filtered through celite (when hot), washed with ethanol (2×50 mL) and then the solvent was removed under reduced pressure. The residue upon dilution with water was extracted with ethyl acetate (3×50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 3-aminosulfonyl-4-fluoro-5-methylaniline (28). LCMS: purity: 85%; MS (m/z): 205 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4]([OH:22])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]1[OH:21].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C>C(O)C.O>[CH3:15][C@:14]12[CH2:16][CH2:17][C@H:18]3[C@@H:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([OH:22])[C:3]([OH:2])=[CH:20][C:19]=43)[C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[OH:21]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@@H]3c4cc(O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C

Procedure:
0.70 g. of 2-methoxy-1,3,5 (10)-estratriene-3,17β-diol is heated under reflux and nitrogen purging in 10 ml. of toluene with 18 ml. of diisobutylaluminum hydride (20% in toluene) for 22 hours. The reaction mixture is cooled to about 0° C. and then decomposed with 5 ml. of ethanol and then with 5 ml. of ethanol-water mixture (1:1). The mixture is further worked up as set forth in Example 3. After purification from methanol, 0.45 g. of 1,3,5(10)-estratriene-2,3,17β-triol is obtained; m.p. 181°-183° C.; ε286 = 3420.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=4[F:34])[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][C:37]([CH3:48])([CH3:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:35][CH2:36][C:37]([CH3:48])([CH3:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:30])=[CH:27][C:26]=4[F:34])[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoic acid (200 mg, 0.42 mmol) in DCM (3 mL) was added tert-butyl 3-amino-2,2-dimethylpropylcarbamate (98 mg, 0.48 mmol), HATU (229 mg, 0.60 mol) and iPr2NEt (0.35 mL, 2.00 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=20% to 40%) to give tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamate (270 mg, 100%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(N(C)C)=O>[CH3:1][C:2]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccccc2n1-c1ccccn1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 71.3 %

Procedure:
To a stirred solution of 2-methyl-1H-benzimidazole (6.61 g, 50 mmol) in dimethylacetamide (40 ml) at room temperature under a nitrogen atmosphere was added sodium hydride (2.40 g, 60 mmol) in portions during 15 min. At the point where the reaction mixture was too viscous to stir, the reaction was diluted with 100 ml of dimethylacetamide. After 50 min., a solution of 2-fluoropyridine (5.83 g, 60 mmol) in dimethylacetamide (30 ml) was added during 15 min. The resulting mixture was heated at 100° C. for 2 h and then to reflux for about 4 h. Volatiles were removed by evaporation under reduced pressure. The residue was dissolved into ethyl acetate (200 ml) and washed consecutively with water (3×100 ml) and brine (100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 300 g; n-hexane/ethyl acetate (17/3)) yielded 7.46 g (71%) of the titled compound as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH3:19])[C@@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20]I>CN(C=O)C.O>[CH3:20][O:12][C:11](=[O:13])[C@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: CI
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](OS(C)(=O)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
Jones reagent was prepared by mixing chromium (VI) oxide (2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10 min. The solution was used directly, and was added dropwise to a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g, 4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was added and the mixture was concentrated. Water was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give the crude acid. To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO3 (1.44 g, 14.4 mmol) and MeI (0.90 mL, 14.4 mmol). After 12 h, the mixture was diluted with water and extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography to give 1.13 g (69% over 2 steps) of the desired product. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.3, 1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7, 1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].C(N(CC)CC)C.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:5][CH:3]([CH2:4][S:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[O:1]
Reactant: C=C(C)C=O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C=O)CSc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 51.4 g (0.733 mole) of methacrolein and 2 g (0.018 mole) of triethylamine at 0-5° C. is added 80.8 g (0.733 mole) of benzenethiol slowly. The addition rate is such that the temperature was under 10° C. The reaction mixture is stirred at 0-5° C. for one hour. The mixture is placed on a rotary evaporator to remove triethylamine.
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH:4]([CH2:6][OH:7])[OH:5]>>[OH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:6]([C@@H:4]([CH2:3][OH:2])[OH:5])[OH:1])[OH:7])[OH:5]
Reactant: O
Reactant: OCC(O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A gel vehicle containing about 25-28% water (apart from water provided as humectant solvent), about 10-12% of 99.5% glycerine solution and about 30-35% of 70% sorbitol solution can readily provide a refractive index of about 1.43 to 1.46 and permit formation of a clear gel dentifrice in which the refractive index of the polishing agent is about 1.41 to 1.47 and within 0.02 of the refractive index of the liquid vehicle.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16](=[CH:19]OCC)[C:17]#[N:18])[CH3:13]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][CH:19]=[C:16]([C:17]#[N:18])[C:15]([O:14][CH2:12][CH3:13])=[O:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccc2ccccc2n1
Product: CCOC(=O)C(C#N)=CNc1ccc2ccccc2n1

Procedure:
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958) reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolylaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:14]1([N:24]=[C:25]=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:25]([NH:24][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:26])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc2ccccc2cc1N
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: COc1cc2ccccc2cc1NC(=O)Nc1cccc2ccccc12
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 2-amino-3-methoxynaphthalene (0.253 g, 1.50 mmol) in CH2Cl2 (3 mL) at room temp. was added a solution of 1-naphthyl isocyanate (0.247 g, 1.50 mmol) in CH2Cl2 (2 mL) and the resulting mixture was allowed to stir overnight. The resulting precipitate was separated and washed with CH2Cl2 to give the desired urea as a white powder (0.450 g, 90%): mp 235-236° C.; 1H-NMR (DMSO-d6) δ 4.04 (s, 3H), 7.28-7.32 (m, 2H), 7.38 (s, 1H), 7.44-7.72 (m, 6H), 7.90-7.93 (m, 1H), 8.05-8.08 (m, 1H), 8.21-8.24 (m, 1H), 8.64 (s, 1H), 9.03 (s, 1H), 9.44 (s, 1H); FAB-MS m/z 343 ((M+H)+). B1f. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]([Cl:28])([Cl:27])[C:24](Cl)=[O:25]>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:24](=[O:25])[C:23]([Cl:28])([Cl:27])[Cl:22])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 9a) (8.5 g, 29.9 mmol) in anhydrous dichloromethane (33 ml) was added trichloro-acetyl chloride (16.3 g, 89.7 mmol). The resulting mixture was stirred overnight at room temperature, after which a second portion of trichloro-acetyl chloride (3 ml) was added. The resulting mixture was stirred for 6 h at 40° C., and then at 25° C. over 2 days, evaporated to dryness. Methyl tert-butyl ether (60 ml) was added and the mixture was stirred. The product precipitated, was filtered off, washed with a small amount of methyl tert-butyl ether and dried in vacuo to give 9.8 g (76%) of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.34 min; m/z=429.01 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[CH3:21][N:18]1[CH2:19][CH2:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:17]1
Reactant: CN1CCC(CN2CCN(Cc3ccccc3)CC2)(c2ccccc2)CC1
Solvent: CO
Product: CN1CCC(CN2CCNCC2)(c2ccccc2)CC1

Procedure:
A mixture of 1-benzyl-4-((1-methyl-4-phenylpiperidin-4-yl)methyl)piperazine (1.5 g, 4 mmol) and 20% PdOH/C in methanol (50 ml) was shaked in the hydrogenation bar under H2 50-60 psi for 18 hours. The mixture was then filtered and the solvent removed in vacuo to afford desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16]2([C:33]([NH:35][OH:36])=[O:34])[CH2:21][CH2:20][N:19]([C:22]([C:24]3([CH3:32])[CH2:29][O:28]C(C)(C)[O:26][CH2:25]3)=[O:23])[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16]2([C:33]([NH:35][OH:36])=[O:34])[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]([CH2:25][OH:26])([CH3:32])[CH2:29][OH:28])[CH2:20][CH2:21]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)NO)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)NO)CCN(C(=O)C(C)(CO)CO)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 694.2 %

Procedure:
A mixture of 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide (0.106 g, 0.2 mmol) and 2 mL of 1N HCl in 2 mL of THF was stirred at room temperature for 4 h. The reaction was diluted with EtOAc, washed with H2O, saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether to provide 0.67 g (71%) of the desired product as an off white solid. Electrospray Mass Spec: 483.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](Cl)=[O:33]>C1COCC1.ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:33]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a stirred solution of 10.8 g (40.8 mmol) 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 17.3 ml (102 mmol) N-ethyldiisopropylamine in 500 ml THF at 5° C. was added dropwise over 90 minutes a solution of 7.90 g (44.9 mmol) 2-chloro-isonicotinoyl chloride in 250 ml dichloromethane and stirring continued at room temperature for 16 h. The reaction mixture was then quenched by addition of 30 ml methanol and concentrated in vacuo. The residue was then resuspended in ethyl acetate and washed sequentially with saturated sodium bicarbonate solution, 0.5 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in Vacuo to ca 100 ml. The resulting suspension was then left standing at room temperature for 72 h and then 100 ml ether was added and the suspension stirred for 1 hour at room temperature. The crystals were collected by filtration and dried in vacuo to afford 9.79 g (59%) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a brown crystalline solid. ES-MS m/e (%): 429 (M{37Cl}+Na+, 11), 427 (M{35Cl}+Na+, 30). 407 (M{37Cl}+H+, 30), 405 (M{35Cl}+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2OC(=O)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:15][C:16]([F:25])([CH3:24])[C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].ClC1C=CC=C(Cl)C=1>>[F:15][C:16]([C:17]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:25])[CH3:24]
Reactant: CCc1ccc(-c2nsc(=O)o2)cc1
Reactant: CCOC(=O)C#CC(C)(F)F
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(C)(F)F
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Into a 10-mL sealed tube, was placed 5-(4-ethylphenyl)-2H-1,3,4-oxathiazol-2-one (227 mg, 1.10 mmol, 1.00 equiv), ethyl 4,4-difluoropent-2-ynoate (357 mg, 2.20 mmol, 2.01 equiv), 1,3-dichlorobenzene (3 mL). The resulting solution was stirred for 16 h at 150° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 0.191 g (54%) of ethyl 5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate as orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].OOS([O-])=O.[K+].[Na+].[Br-:22].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[C:11]([Br:22])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Reactant: [Br-]
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a stirred solution of 2-(4-Amino-phenyl)-propionic acid ethyl ester (3.16 g) in acetone and water was added OXONE (10.0 g) and NaBr (6.75 g) at room temperature. After stirred for 2 minutes at room temperature, the reaction mixture was diluted with EtOAc and poured into 5% aq. Na2S2O3 solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=6:1) to afford the product as white solid. (49.6%)