Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[CH:32]=[CH:33][O:34]CC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:23][C:10]1[CH:11]=[C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:4]=[C:3]([NH:25][CH3:26])[C:2]([C:33](=[O:34])[CH3:32])=[CH:7][N:6]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1C(C)=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (100 mg, 0.24 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and tributylethoxyvinyltin (0.16 mL, 0.47 mmol) in toluene was stirred in a sealed tube at 110° C. for 1 hour. The reaction mix was filtered and concentrated. The reaction mixture was filtered through a pad of silica gel (eluted with 0-100% EtOAc in heptane) to give the crude product. Purification of the crude product was achieved by reverse phase HPLC (9 mg, 10%). Additional compounds made using the above procedure are shown in Table 4 above.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([C:19]2([CH3:22])[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:23][OH:24]>ClCCl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:23][OH:24])[CH2:15][C@H:16]([C:19]2([CH3:22])[CH2:21][CH2:20]2)[O:17][CH2:18]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC1([C@H]2C[C@@H](CO)[C@](N)(c3ccc(F)cc3F)CO2)CC1
Solvent: ClCCl
Product: CC1([C@H]2C[C@@H](CO)[C@](NC(=S)NC(=O)c3ccccc3)(c3ccc(F)cc3F)CO2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.98 g, 6.00 mmol) was added drop-wise to a solution of rel-[(2R,4R,5S)-5-amino-5-(2,4-difluorophenyl)-2-(1-methylcyclopropyl)tetrahydro-2H-pyran-4-yl]methanol (C58) (2.20 g, 5.00 mmol) in dichloromethane (60 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 1.1 g, 2.39 mmol, 48%.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1.CN(C)C=O>C(O)(C)C>[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: CC1CCCCN1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC1CCCCN1[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (R)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 14b, 20 mg, 0.050 mmol), 2-methylpiperidine (0.029 mL, 0.25 mmol), and N,N-dimethylformamide (0.01 mL) in isopropanol (0.50 mL) was heated at 150° C. under microwave irradiation for 15 minutes. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel chromatography (100:0 to 70:30 dichloromethane/ethyl acetate, then 98:2 to 92:8 dichloromethane/methanol). Fractions containing product were combined and concentrated under reduced pressure to give 4-(2-435)-3-(2-methylpiperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, CD2Cl2) δ ppm 1.06-1.12 (m, 3H), 1.37-1.45 (m, 2H), 1.54-1.61 (m, 1H), 1.67-1.77 (m, 2H), 2.01-2.16 (m, 2H), 2.19-2.29 (m, 1H), 2.35-2.51 (m, 1H), 2.63-2.70 (m, 1H), 2.81-2.95 (m, 1H), 3.36-3.50 (m, 1H), 3.50-3.79 (m, 5H), 7.55 (s, 2H), 7.72 (s, 4H), 7.88 (s, 1H); MS (ESI) m/z 403 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[C:17]([O:26][CH3:27])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(C)(=O)=O)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCOc1cc(CCC(=O)O)ccc1CCCc1ccc(OS(C)(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
600 mg (1.25 mmol) of methyl 3-{3-butoxy-4-[3-(4-methanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate are dissolved in 10 ml of tetrahydrofuran and 1.8 ml (1.8 mmol) of aqueous 1N lithium hydroxide solution are then added. The reaction medium is stirred for 15 hours at room temperature. After addition of water and acidification with acetic acid, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 480 mg (82%) of 3-{3-butoxy-4-[3-(4-methanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoic acid are obtained after crystallization from a 2/8 isopropyl ether/pentane mixture.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3csc4cncn34)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 203 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 4 ml of THF and 4 ml of 1/15 M phosphate buffer (pH 6.8) was added 152 mg of 10% Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 1 hour. The catalyst was collected by filtration on Celite, and washed with water. The filtrate was washed with ethyl acetate, and then the aqueous layer was purified by column chromatography on DIAION HP-20, followed by crystallization form 1 ml of water to give 32.8 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22](O)=[O:23])[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([CH2:22][OH:23])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(CO)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (70 mg, 0.174 mmol) in Tetrahydrofuran (THF) (5 mL) was added in LiAlH4 (19.85 mg, 0.523 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. Then LiAlH4 (19.85 mg, 0.523 mmol) was added in and the reaction mixture was stirred at rt for another hour. The reaction mixture was cooled to 0° C. and quenched with water (0.04 ml), NaOH (15%, 0.04 ml) then water (0.12 ml). After the resultant mixture was stirred at room temperature for 2 h, anhydrous MgSO4 was added and the reaction mixture was filtered through celite and washed with EtOAc. Evaporation of the solvent gave the crude product. The crude product was purified on a silica column (0˜4% MeOH/DCM) to give the solid (12 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 2.91-3.05 (m, 4H), 3.64-3.74 (m, 4H), 4.89 (d, J=5.56 Hz, 2H), 5.12 (t, J=5.81 Hz, 1H), 5.95 (s, 2H), 6.33 (d, J=6.82 Hz, 1H), 6.81 (d, J=2.02 Hz, 1H), 6.97 (d, J=1.77 Hz, 1H), 7.34 (t, J=7.71 Hz, 1H), 7.54-7.74 (m, 2H), 7.85 (d, J=8.08 Hz, 1H), 8.01 (d, J=7.58 Hz, 1H), 8.25 (d, 1H). MS (ES+) m/z 388.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[S:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:32][C:33]([CH3:37])=[CH:34][CH:35]=[O:36].C(=O)([O-])O.[Na+]>C1COCC1.CCOCC.C(O)(=O)C>[OH:36][CH:35]([CH:34]=[C:33]([CH3:37])[CH3:32])[CH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: CC(C)=CC=O
Reactant: Cc1nsc2cc(O)ccc12
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)=CC(O)Cc1nsc2cc(O)ccc12
Temperature: -78 °C

Procedure:
1.5 g of 3-methyl-benzo[d]isothiazol-6-ol in 26 ml of THF are added to a LDA solution previously prepared from 3.9 ml of diisopropylamine and 16.0 ml of n-butyllithium (1.6M in hexane) in 23 ml of THF and the mixture is stirred at -78° C. 2.5 ml of 3-methyl-2-butenal in 40 ml of THF are added. The reaction mixture is thawed overnight and neutralized with 3.9 ml of acetic acid in 20 ml of ether. The mixture is added to sodium hydrogen carbonate solution, the inorganic phase is extracted with ethyl acetate and the organic phases are washed with sodium chloride solution and dried. The crude product is purified by chromatography (silica gel, ethyl acetate:hexane 1:1). 1.5 g of (RS)-3-(2-hydroxy-4-methyl-pent-3-enyl)-benzo[d]isothiazol-6-ol are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>>[C:12]1([CH:10]2[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccn1
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Product: Oc1ccccc1C1=NN(c2ccccn2)C(c2ccccc2)C1

Procedure:
Example 3 is prepared using 2-hydroxychalcone and 2-hydrazinopyridine following the procedure described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1>S(Cl)(Cl)=O>[NH:13]1[C:12]([NH:11][C:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])=[N:16][N:15]=[N:14]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ncccc1Cl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1ncccc1Cl
Yield: 39.3 %

Procedure:
0.53 g of 3-chloro-2-pyridinecarboxylic acid, 10 ml of thionyl chloride and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.28 g of N-(5-tetrazolyl)-3-chloro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(CCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1CCC(F)(F)F
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (700 mg, white solid) from 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone (850 mg, 3.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (668 mg, 5.51 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C(O)(=O)[C@@H](C1C=CC=CC=1)O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH:17]([NH2:19])[CH3:18]>C(O)(C)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C@H:17]([NH2:19])[CH3:18]
Reactant: COc1cccc(C(C)N)c1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)O
Product: COc1cccc([C@@H](C)N)c1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 14.0 g (92.0 mmol) of (R)-(-)- mandelic acid (Aldrich, 99+%), 14.0 g (92.7 mmol) of (±) 3-methoxy-α-methylbenzylamine and 500 mL of isopropanol was brought to reflux and gravity filtered while hot. The solution was then seeded at 50° C. with diastereomerically-pure seeds. After cooling to room temperature, the mixture was filtered to afford 10.9 g of a fluffy, white solid. This was recrystallized from 500 mL of isopropanol. The solids were collected then partitioned between ethyl acetate and saturated Na2CO3. The organics were washed with saturated NaCl, dried with Na2SO4, and concentrated to afford 5.8 g (83%) of a yellow oil. NMR analysis of the derived camphorsulfonamide (FIG. 6) indicated that the chemical is enantiomerically pure, to the limits of detection of NMR. This oil was distilled, b.p. 118°-120° C. at aspirator pressure, [α]D =+3.8° (c+1 in 2N HCl). Preliminary results suggest that this compound may form a carbonate upon exposure to air. It is therefore recommended that the chemical be stored under an inert atmosphere.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1>[Pd]>[CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: [Pd]
Product: C1CC2CCCC3CCC(C1)C23
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Acenaphthene was hydrogenated by the same procedure as in Example 1 except that the catalyst was replaced by a 5% Pd/C catalyst and reaction was effected at 160° C. for 6 hours. No substantial change was observed in the distribution of reaction products at the end of 4 hour reaction. Perhydroacenaphthene was finally obtained in a yield of 99.6%. The yields of Nos. 1 to 4 isomers were 33.5%, 11.8%, 24.5%, and 29.7%, respectively.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:31][C:28]3([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]3)[CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)no2)cc1

Procedure:
The title compound is prepared from 5-(4-cyano-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 4): tR=1.34 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>O1CCCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][NH:33][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:39]
Reactant: CCOC(=O)CN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The ethyl glycinate (2.65 g, 0.019 mole) and triethylamine (1.92 g, 0.019 mole) were added dropwise and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC([O-])=O.[K+].[Br:18]Br>CC(O)=O>[Br:18][C:5]1[CH:6]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(F)c(N)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 2-fluoro-4-methylsulfonyl-aniline (22.76 mmol) and KOAc (22.7 mmol) in AcOH was stirred at room temperature. The mixture was cooled to 0° C. and Br2 (22.7 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C. The mixture was concentrated and the residue was taken up in EtOAc. The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3), dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4](OC)=[O:5].[CH3:14][NH:15][CH3:16]>C(O)C>[CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4]([N:15]([CH3:16])[CH3:14])=[O:5]
Reactant: CNC
Reactant: COC(=O)C(OC)c1ccccn1
Solvent: CCO
Product: COC(C(=O)N(C)C)c1ccccn1

Procedure:
A mixture of 18.1 g. of methyl 2-methoxy-2-(2-pyridyl)acetate and 10 g. of dimethylamine in ethanol is stirred at room temperature for 26 hours. The mixture is concentrated, dissolved in chloroform and extracted with brine. The organic phase is dried over magnesium sulfate and filtered and the solvent is removed under reduced pressure to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][Si:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[N:29][C:28](C(O)(C#C)C)=[N:27]1>>[F:19][C:18]1[C:2]([C:3]#[C:4][C:5]([OH:6])([C:30]2[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:20])([CH3:36])[CH3:37])[N:27]=[CH:28][N:29]=2)[CH3:17])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC(C)(O)c1ncn(COCC[Si](C)(C)C)n1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ncnn1COCC[Si](C)(C)C

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with and 2-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,4-triazol-3-yl)but-3-yn-2-ol to give 8-fluoro-9-(3-hydroxy-3-(1((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide. A solution of crude give 8-fluoro-9-(3-hydroxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide (150 mg, 0.28 mmol, 1.00 equiv) and hydrofluoric acid (2 mL) in CH3CN (4 mL) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 10 with saturated NaHCO3 (10 mL). The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#pre-HPLC-006(waters)): Column, sunfire prep C18 19*150 mm 5 um; mobile phase, Water with 0.5% CF3COOH and CH3CN (10% CH3CN up to 45% in 12 min, up to 100% in 3 min, down to 10% in 2 min); Detector, UV 220/254 nm. 10 mg of product was obtained. This was treated by strong anion exchange resin (cleanert SAX-SPE). This resulted in 7.2 mg (6%) of the titled compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:28]Cl)[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1>CC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:28][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: ClCc1cc(Cl)cc2c1OCOC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCc1cc(Cl)cc2c1OCOC2

Procedure:
To a solution of 2-nitrophenol (1.27 g, 9.13 mmol) in acetone (100 mL) was added solid potassium carbonate (1.27 g, 9.13 mmol) followed by 6-chloro-8-(chloromethyl)benzo-1,3-dioxan (1.0 g, 4.57 mmol) and the solution was refluxed for 16 hours. Solvent was evaporated and the residue was purified by column chromatography to give 1-[(6-chloro(2H,4H-benzo[e]1,3-dioxin-8-yl))methoxy]-2-nitrobenzene, a compound of formula (3).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C(=O)(O)[O-].[Na+]>O>[F:10][C:11]([F:21])([F:20])[C:12]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:4][C:14](=[O:15])[CH:13]=1
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
A slurry of 2-methylresorcinol (12.4 g, 0,100 mole) and ethyl 4,4,4-trifluoroacetoacetate (18.4 g, 0.100 mole) was added slowly to 100 ml of ice cold sulfuric acid with vigorous stirring. After completion of addition, the solution was allowed to warm to room temperature and was subsequently stirred for 24 hours. The reaction mixture was then slowly added to 500ml of ice water (300 g ice and 200 ml water) with vigorous stirring. The desired product precipitated from the solution as a light pink solid. The solid was then isolated by vacuum filtration, transferred to a 500 ml beaker, 200 ml of water was added to achieve a slurry and the pH was adjusted to 6 with sodium bicarbonate. The solid was then filtered and recrystallized from ethanol-water to yield 19.5 g (80%) of the desired product. The melting point of the product was 197°-198 ° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:10][CH3:11])=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+]>>[CH2:10]([C:6]1[CH2:7][CH2:8][CH2:9][CH:4]([NH2:1])[CH:5]=1)[CH3:11]
Reactant: CCC1=CC(N=[N+]=[N-])CCC1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC1=CC(N)CCC1

Procedure:
The title amine was generated from 3-azido-1-ethyl-cyclohexene (2.27 g, 15.00 mmol), triphenyl phosphine (4.00 g, 15.20 mmol) and KOH (0.85 g, 15.20 mmol) according to the protocols as outlined in general procedure I. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 0.99 (t, J=7.62 Hz, 3H), 1.09-1.34 (m, 2H), 1.48-1.62 (m, 1H), 1.69-1.79 (m, 1H), 1.83-1.98 (m, 6H), 3.26-3.40 (m, 1H), 5.29-5.38 (m, 1H).