Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 5-methyl-2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 225, step B) (53 mg, 0.18 mmol), and p-toluenesulfonicacid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.092 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) d ppm 10.23 (s, 1H), 9.40 (s, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.50 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=8.07 Hz, 1H), 7.73 (d, J=9.17 Hz, 1H), 7.61 (t, J=7.70 Hz, 1H), 7.53 (s, 1H), 7.45-7.51 (m, 1H), 7.36-7.44 (m, 1H), 7.20 (t, J=8.07 Hz, 2H), 7.00 (t, J=6.97 Hz, 1H), 6.83 (s, 1H), 6.51 (d, J=5.13 Hz, 1H), 3.81 (s, 3H), 3.23-3.30 (m, 4H), 2.95-2.99 (m, 4H), 2.94 (s, 3H), 2.17 (s, 3H); MS (ESI): 725 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(C)=[O:34].[OH-].[Na+].Cl>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:34])[NH:28][CH:27]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CS(C)=O
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(=O)[nH]c2)cc(OC)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), prepared using procedures similar to those described above in Example 8, DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100° C. overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H2O and the pH was adjusted to 7.0 with 1N HCl. The resulting solid was filtered, washed with H2O, and air-dried. The solid was then sonicated in EtOAc, filtered, washed with EtOAc, and dried under high vacuum to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (190 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 12.10 (br s, 1H), 8.97 (s, 1H), 8.23 (s, 1H), 7.95 (m, 2H), 7.59 (m, 1H), 7.37 (m, 4H), 6.43 (d, 1H), 6.25 (s, 1H), 3.77 (s, 6H). MS (EI) m/z for C21H19N5O5S: 454.0 (MH+).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:30][C:31]1[N:32]=[C:33]([Sn](CCCC)(CCCC)CCCC)[S:34][CH:35]=1.[Li+].[Cl-]>O1CCOCC1.C(Cl)Cl.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>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:33]4[S:34][CH:35]=[C:31]([CH3:30])[N:32]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3nc(C)cs3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a suspension of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (40 mg, 0.0808 mmol, example 58) in dioxane (1.5 ml) was added a solution of 4-methyl-2-(tributylstannyl)-thiazole (38 mg, 0.0970 mmol) in dioxane (0.5 ml) and argon was bubbled through the resulting mixture for 10 minutes. Then LiCl (10 mg, 0.242 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.00404 mmol) were added and the mixture was stirred at reflux for 3.5 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM and filtered through a pad of silica gel. The filtrate was evaporated and the remaining light brown solid was purified by silica column chromatography (DCM/EtOAc 4:1) to obtain a white solid (15 mg) which was triturated with ether to obtain the title compound (9 mg, 22%) as a white solid.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:28]([C:26]2[S:27][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:30])=[O:29])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.53 g NaH (60%) with 40.0 ml THF is cooled down to −30° C. and 3.1 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition it is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 5.0 g of 5-bromothiophene-2-sulfonylchloride is added by −30° C. The mixture is stirred at ambient temperature for 24 h. The NaH is hydrolyzed with water and the solution is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 4.5 g of colorless crystals are obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:7]([CH3:9])[CH3:8])(Cl)[Cl:5])[CH3:3].[F:10][C:11]([F:21])([F:20])[S:12]([O:15][Si](C)(C)C)(=[O:14])=[O:13].C[Si](C)(C)Cl.FC(F)(F)S(O)(=O)=O>>[F:10][C:11]([F:21])([F:20])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][N:2]([C+:4]([N:7]([CH3:9])[CH3:8])[Cl:5])[CH3:3]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CN(C)[C+](Cl)N(C)C
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
0.5 g (2.92 mmol) of bis(dimethylamino)dichloromethane are added at room temperature to 0.86 g (3.87 mmol) of trimethylsilyl trifluoromethanesulfonate, prepared by reaction of 0.42 g of trimethylchlorosilane with 0.58 g of trifluoromethanesulfonic acid at room temperature. The reaction mixture is stirred for 5 minutes, and all volatile products are subsequently removed under reduced pressure. The residue is dried under reduced pressure at 7 Pa and 50° C., giving 0.82 g of bis(dimethylamino)chlorocarbenium trifluoromethanesulfonate, corresponding to a yield of 98.7%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH3:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25].N12CCCN=C1CCCCC2>C1COCC1>[C:8]([C:7]1[C:2]([NH:32][C@@H:29]2[CH2:28][CH2:27][C@H:26]([C:24]([NH:23][CH3:22])=[O:25])[CH2:31][CH2:30]2)=[N:3][C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Reactant: CNC(=O)C1CCC(N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1CC[C@@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C#N)CC1
Temperature: 60 °C

Procedure:
4-Chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (1.0 equiv.) was placed in a sealable flask with (1s,4s)-4-amino-N-methylcyclohexanecarboxamide (1.0 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up afforded cis-4-((5-cyano-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidin-4-yl)amino)-N-methylcyclohexanecarboxamide (48.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (d, J=5.08 Hz, 1H), 8.64-8.69 (m, 1H), 8.29 (t, J=5.66 Hz, 1H), 8.21 (s, 1H), 7.72 (d, J=5.08 Hz, 1H), 7.53-7.66 (m, 1H), 7.00-7.12 (m, 1H), 4.62-4.73 (m, 2H), 3.69 (br. s., 1H), 2.53-2.61 (m, 3H), 2.15-2.30 (m, 1H), 1.70-1.97 (m, 2H), 1.42-1.62 (m, 3H), 1.15-1.27 (m, 3H). MS (ESI) m/z 434.3 [M+1]+
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CCOCC>[C:33]([O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CCN2C[C@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
Mixture of 660 mg (1.53 mmol) of (+)-5,11-dihydro-5-[[(2R, 4R) -4-hydroxy-1-(4-methoxyphenethyl) pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine, 1.04 g (3.98 mmol), 486 mg (3.98 mmol) of benzoic acid, and 693 mg (3.98 mmol) of DEAD in tetrahydofuran (15 ml) was stirred for 20 hours at room temperature. The mixture was diluted with ether and the solution was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate: n-hexane=1:1 ) to give 680 mg (83.3%) of (+)-5-[[(2R, 4S)-4-benzoyloxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as pale yellow amorphous.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:59][C:60]([F:71])([F:70])C1C=CC(C(Cl)=O)=CC=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([C:60]([F:71])([F:70])[F:59])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O

Procedure:
The compound of example 101 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-trifluoromethylbenzoyl chloride. The compound of example 101 was used directly without isolation for the preparation of compound of example 102.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([B-](F)(F)F)=[CH2:17].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:13][C:12]([F:15])([F:14])[O:11][C:4]1[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C=C[B-](F)(F)F
Reactant: O=C(O)c1ccc(Br)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(C(=O)O)c(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 46.9 %

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1.[Na].[CH3:28][OH:29]>C(Cl)Cl>[CH3:28][O:29][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1Cl
Reactant: CO
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1OC

Procedure:
The ester from Step 3 (7.76 g) was added to a solution of sodium (920 mg) in anhydrous methanol (50 ml) and the resulting suspension was refluxed under an argon atmosphere for 75 minutes. The mixture was cooled, diluted with CH2Cl2 (200 ml), washed with water (3×50 ml) and reduced to dryness to provide the title compound, m.p. 133°-134.5°.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:11]=1[CH3:27]>C1COCC1>[CH3:16][C:14]1[N:13]=[C:12]([NH:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[C:11]([CH3:27])=[C:10]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:15]=1
Reactant: OC1CCOC1
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc(C)nc(OC3CCOC3)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-hydroxy-tetrahydrofuran (0.5 ml) and sodium hydride (60% in oil, 53 mg, 1.33 mmol) in dry THF was stirred at room temperature for 5 minutes, (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (107 mg, 0.388 mmol) was added. The mixture was heated at reflux for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give 48 mg of the title compound as off-white crystals, mp 126–128° C. 1H NMR (CDCl3) δ 6.89 (s, 2H), 5.60 (brs, 2H), 3.84.0 (m, 4H), 2.27 (s, 6H), 2.13 (s, 6H), 2.1–2.25 (m, 2H), 1.93 (s, 3H) ppm.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][CH:5]=1.O1CCCC1.C([Li])CCC.O>CCCCCC>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]#[CH:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CCc1ccc(C=C(Br)Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(CC)cc1
Temperature: 25 °C

Procedure:
1,1-Dibromo-2-(4-ethylphenyl)ethylene (1.1 g., 3.69 mmol.) is dissolved in 20 ml. of dry tetrahydrofuran and maintained under a nitrogen atmosphere. The solution is cooled to -78° and 3.9 ml. of a 1.9 M solution of butyl lithium in hexane is added with stirring. The reaction mixture is stirred 1 hour at -78°, then warmed to ambient temperature and stirred an additional hour. Water is added, the mixture is extracted with petroleum ether, the extracts are combined, dried (MgSO4) and concentrated to give 4-ethylphenylacetylene.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22]C=C)[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:31]([O:33]CC)=[O:32].ICCCC(F)(F)C(F)(F)F.C(OCC)(=O)CC(OCC)=O.ICCCCCCC=C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:48])[C:44]([F:45])([F:46])[F:47])[C:31]([OH:33])=[O:32])[C@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1
Agent: C=CCCCCCCI
Agent: FC(F)(F)C(F)(F)CCCI
Solvent: CCOC(=O)CC(=O)OCC
Product: C[C@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@H]1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3S,4S)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochroman prepared in Example 3 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from 1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and 1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or 3 was repeated to give 11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][O:11][C:12]2[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cc2)nc1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
To an acetic acid (20.0 mL) solution of 6-(4-fluoro-benzyloxy)-pyridine-3-carbaldehyde (2.23 g, 9.64 mmol) described in Manufacturing Example 58-1-2 were added nitromethane (2.94 g, 48.2 mmol) and ammonium acetate (1.49 g, 19.3 mmol) under nitrogen atmosphere, which was stirred for 2.5 hours at 105° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure to obtain the title compound (2.60 g) as a crude product.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>>[N+:20]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:3][CH:4]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(CC2CCCCCN2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(CC2CCCCCN2)cc1
Temperature: 25 °C

Procedure:
Add (drop by drop while stirring at -10° ) 10 g of 2-benzylperhydroazepine to 43 ml of concentrated sulfuric acid. Then, at the same temperature, add 33 ml of concentrated nitric acid to the thus-prepared reaction mixture and allow it to heat slowly to room temperature. Stir it for a further hour. Pour the resulting admixture into 500 g of ice, alkalize it with 6 N caustic soda solution and then extract it with diethyl ether. Dry the organic phase over sodium sulfate and distil off the solvent from the dried organic phase to obtain 12.0 g (97% of theory) of the title compound as a red oil.
Reaction SMILES: [ClH:1].[N:2]1([C:8]2[S:9][CH2:10][C:11](=[NH:13])[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=N)[NH:16]1>CO>[ClH:1].[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[C:10]2[S:9][C:8]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[N:12][C:11]2=[NH:13])[NH:16]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(N2CCCCC2)=N1
Agent: Cl
Solvent: CO
Product: N=C1N=C(N2CCCCC2)SC1=C1NC(=N)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of 21.9 parts of 2parts of 2-piperidino-4-imino-2-thiazoline hydrochloride in 240 parts of methyl alcohol there was added 14.5 parts of 1,3-diiminoisoindoline. The resultant mixture was heated at reflux for 6 hours, then chilled to 0° C. and filtered. The collected solid was washed with methyl alcohol and dried at 50° C. to obtain 27 parts of 1-imino-3-(2-piperidino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride melting at 320°-321° C. (dec). The assigned chemical structure was completely corroborated by a concordant nuclear magnetic resonance spectrum. The hydrochloride salt is readily converted to the free base, a colorless solid melting at 226°-227° C., by treatment with dilute ammonium hydroxide. This compound, which corresponds to Formula VIII wherein R, R1, R2 and R3 are each hydrogen and N=B is piperidino, was found on testing in vitro by standard serial dilution procedures to be bacteriostatic versus: Staphylococcus aureus 209 at a minimal concentration of 6.3 parts per million; Esherichia coli at 62.5 parts per million; Pseudomonas aeruginosa 211 at 125 parts per million; and fungicidal versus Tricophyton mentogrophytes at 62.5 parts per million; Aspergillus niger at > 125 parts per million; and Candida albicans at 125 parts per million.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:25]([NH:24][CH3:23])=[O:26]
Reactant: CN=C=O
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (0.5 g, 1.8 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.5 mL, 3.5 mmol), followed by methyl isocyanate (0.121 g, 2.2 mmol), and the reaction was stirred at room temperature under N2 for 30 minutes. The mixture was worked-up with CH2Cl2 and H2O, and the residue was purified by silica gel chromatography to give the title compound.