Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CO)cc2)cc1
Yield: 357.3 %

Procedure:
A solution of 0.5 g (1.45 mmol) of the material from Example 45 and 0.055 g (1.45 mmol) of sodium borohydride in 5 mL of ethanol was stirred overnight at room temperature, then concentrated in vacuo. The residue was partitioned between 25 mL of water and 25 mL of ethyl acetate, the organic layer separated and the aqueous layer extracted three more times with 25 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 60% ethyl acetate/hexane) of the residue afforded 1.8 g (71%) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)s2)cs1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)s2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.9 %

Procedure:
In a water bath at about 20° C., to a suspension of N-(4-{2-[5-(hydroxymethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (500.0 mg, 1.771 mmol) in anhydrous chloroform (2.5 ml) was added dropwise thionyl chloride (0.77 ml, 10.6 mmol). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. Anhydrous chloroform (5 ml) was added to the residue and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove thionyl chloride azeotropically. The residue was dried under reduced pressure to give N-(4-{2-[5-(chloromethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (633.2 mg) as a pale-brown solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([N:21]([CH:23]2[CH2:25][CH2:24]2)[CH3:22])[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1.Cl>O.C1COCC1>[CH:23]1([N:21]([CH3:22])[C:10]2[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=[C:8]([CH2:7][CH2:6][C:5]([OH:26])=[O:4])[N:9]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)CCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nc(CCC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Reaction time: 3 h
Yield: 53.9 %

Procedure:
The LiOH (0.047 g, 0.0018 mol) dissolved in water (2 ml) was added to a solution of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid methyl ester (0.5 g, 0.0014 mol) in THF (3 ml), and the resulting solution was stirred at R.T for 3 hrs. The reaction mixture was diluted with water, acidified with dilute HCl (up to pH 5) and extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over Na2SO4, concentrated, and the crude was purified by preparative HPLC to give 0.25 g (54%) of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid. 1H NMR (400 MHz, CDCl3) δ ppm=0.53 (m, 2H), 0.87 (m, 2H), 1.76 (m, 2H), 1.92 (m, 2H), 2.84 (m, 7H), 3.1 (s, 3H), 3.22 (t, 2H), 14.75 (s, 1H). LC-MS: [M+H]=331.9.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:33](C(OC(C)(C)C)=O)[NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:49]1[CH:53]=[CH:52][NH:51][N:50]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58](O)(=O)[CH3:59]>>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:23][N:24]1[C:32]2[CH:31]=[CH:30][C:29]3[N:28]([C:58]([CH3:59])=[N:34][N:33]=3)[C:27]=2[CH:26]=[C:25]1[C:49]1[NH:50][N:51]=[CH:52][CH:53]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cc[nH]n3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12

Procedure:
A solution of di-tert-butyl 1-[1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-2-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (1.1 g, 1.4 mmol, from Step 3) in acetic acid (28 mL) was heated at 130° C. for 1.5 hours. Acetic acid was removed in vacuo, and the residue was dissolved in DCM and washed with saturated NaHCO3. The aqueous layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (0.66 g, 54%).
Reaction SMILES: [SH-].[Na+].N[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[C:6]([C:23]([F:26])([F:25])[F:24])[CH:5]=1.Cl.[I-:28].[K+]>>[F:24][C:23]([F:26])([F:25])[C:6]1[CH:5]=[C:4]([I:28])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Reactant: [I-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2ccc(I)cc2C(F)(F)F)c(C(F)(F)F)c1

Procedure:
Starting materials useful in the manufacture of substituted-quaterphenylene polyamides of the invention can be prepared by resort to a variety of organic synthetic routes. Preferred polyamides of the invention can be prepared, for example, by reaction of terephthaloyl chloride and/or trans-p,p'-stilbene dicarbonyl chloride with the diamino compound, 4,4'"-diamino-2,2',3",2'"-tetrakis(trifluoromethyl)-1,1':4',1'"-quaterphenyl. This novel diamine can be prepared, for example, from 2-bromo-5-nitro-benzotrifluoride by resort to the following reactions: (a) an Ullmann coupling of 2-bromo-5-nitrobenzotrifluoride utilizing active copper and dimethylformamide to provide 2,2'-bis-(trifluoromethyl)-4,4'-dinitro-1,1'-biphenyl; (b) a partial reduction utilizing aqueous sodium hydrosulfide to 4-amino-2,2'-bis-(trifluoromethyl)-4'-nitro-1,1'-biphenyl; (c) a diazotization of the resulting amine utilizing aqueous sodium nitrite and hydrochloric acid and a Sandmeyer reaction of the resulting diazonium salt with potassium iodide to provide 2,2'-bis-(trifluoromethyl)-4-iodo-4'-nitro-1,1'-biphenyl; (d) an Ullmann coupling of the resulting biphenyl compound utilizing active copper for production of 4,4'"-dinitro-2,2',3",2'"-tetrakis-(trifluoromethyl)-1,1':4',1":4",1'"-quaterphenyl; and (e) a reduction utilizing stannous chloride and hydrochloric acid for production of the desired diamine starting material. The production of this diamine starting material is illustrated by the following reaction sequence: ##STR32##
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.COCC(O)C.[NH2:61][C:62]1[CH:67]=[CH:66][C:65]([N:68]2[CH2:73][CH2:72][N:71]([CH2:74][C:75]([NH2:77])=[O:76])[CH2:70][CH2:69]2)=[C:64]([F:78])[CH:63]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:61][C:62]4[CH:67]=[CH:66][C:65]([N:68]5[CH2:73][CH2:72][N:71]([CH2:74][C:75]([NH2:77])=[O:76])[CH2:70][CH2:69]5)=[C:64]([F:78])[CH:63]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CN1CCN(c2ccc(N)cc2F)CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCN(CC(N)=O)CC5)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.092 g, 0.26 mmol), N-Phenylbis(trifluoromethanesulphonimide) (0.112 g, 0.314 mmol), N,N-Diisopropylethylamine (0.139 mL, 0.797 mmol) and 1-Methoxy-2-propanol (4.0 mL, 41 mmol) were combined in a tube and stirred at room temperature for 18 hours. 2-[4-(4-Amino-2-fluoro-phenyl)-piperazin-1-yl]-acetamide (0.087 g, 0.34 mmol) was added and the reaction was stirred at room temperature for 4 days to yield an orange solid, 2-(4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-fluoro-phenyl}-piperazin-1-yl)-acetamide; compound with 2 trifluoroacetic acids (35 mg, 16%). LCMS: m/z=581.25 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 8.33 (d, 1H, J=7.9 Hz), 7.95 (s, 1H), 7.80 (d, 1H, J=7.8 Hz), 7.66 (m, 2H), 7.54 (m, 3H), 7.14 (d, 1H, J=4.7 Hz), 7.07 (m, 1H), 6.96 (d, 1H, J=4.7 Hz), 3.95 (s, 2H), 3.5 (m, 2H), 3.31 (m, 4H), 3.09 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1Br)(=[O:3])[CH3:2].[CH3:15][O:16][C:17](=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 75 °C

Procedure:
N-Acetyl-2-bromo-6-nitroaniline, as described above in Step A, (6.3 g, 24.3 mmol), acrylic acid methyl ester (4.4 mL, 48.64 mmol), triethylamine (4.2 mL, 30.4 mmol) and palladium (11) acetate (275 mg, 1.22 mmol) were dissolved in acetonitrile (75 mL) and heated to 75° C. for 18 hours. The cooled reaction mixture was poured into saturated aqueous Na2CO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from MeOH—H2O to yield the above-titled compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(C#N)cc1)C(=O)O

Procedure:
In analogy with Example 1i), 0.50 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(p-cyanophenyl)methyl]dihydrofuran-2-(3H)-one in 19 ml of dimethoxyethane and 10 ml of water is hydrolysed with 4.8 ml of a 1M lithium hydroxide solution to form the title compound: TLC Rf (B)=0.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1.ClCCl>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:16][CH:15]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: OB(O)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A round bottom flask equipped with a drying tube was charged with 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol), cupric acetate (0.34 g, 1.9 mmol), 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol), pyridine (0.20 mL, 2.5 mmol) and dichloromethane (5 mL, 80 mmol). The blue suspension was stirred open to the air for 6 days at room temperature. Water (25 mL) was added to the green-brown suspension and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (40 g) and 0%→8% methanol: dichloromethane solvent gradient. 4-[1-(4-Bromo-phenyl)-piperidin-4-yl]-morpholine was isolated as a tan solid (0.168 g, 41%). MP=146-149° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.5 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 3.76-3.71 (m, 4H), 3.68 (d, J=12.8 Hz, 2H), 2.71 (t, J=12.3 Hz, 2H), 2.60-2.54 (m, 4H), 2.37-2.27 (m, 1H), 1.93 (d, J=11.3 Hz, 2H), 1.69-1.58 (m, 2H). MS=325, 327 (MH)+. 49b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-[1-(4-bromo-phenyl)-piperidin-4-yl]-morpholine (65.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.044 g, 48%). MP=253-254° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.3 Hz, 1H), 8.23 (d, J=7.5 Hz, 2H), 8.08 (d, J=8.2 Hz, 2H), 7.63 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.1 Hz, 2H), 7.01-6.95 (m, 3H), 6.68 (s, 1H), 3.77-3.72 (m, 4H), 3.69-3.62 (m, 2H), 3.10 (s, 3H), 2.74-2.65 (m, 2H), 2.62-2.57 (m, 4H), 2.36-2.28 (m, 1H), 1.98-1.92 (m, 2H), 1.75-1.63 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O.O=[C:22]([CH3:33])[CH2:23][CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl[Si](C)(C)C>CN(C=O)C>[CH3:33][C:22]1[C:23]([CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]2[C:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C:5]=3[S:11][C:2]=2[N:1]=1
Reactant: CCCC(CC(C)=O)C(=O)OCC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCN(C)C3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Temperature: 100 °C

Procedure:
To a solution of (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol) in dry DMF (8 mL) under nitrogen atmosphere was added chlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. An extra volume of chlorotrimethylsilane was added (0.100 mL) and the reaction mixture was stirred at 100° C. for 48 h. The volatiles were removed under reduced pressure and the residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane to furnish the title compound as a dark oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:36][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCC1
Product: N#CC(=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 85 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in cyclobutylamine (0.70 ml) at 60° C. for 20 h. Work up as described in Example 1, 2) gave 354 mg (85%) of the title compound as white crystals. Mp 190.5-193° C. 1H NMR (300 MHz, CDCl3): δ=1.5 (m, 2H), 1.72 (m, 1H), 2.0 (m, 3H), 3.63 (sextet, 1H), 7.42 (s, 2H), 7.48 (d, 2H), 7.67 (s, 1H), 7.79 (d, 2H); MA calc for C21H16ClF6N3O2S: C, 48.15%; H, 3.08%; N, 8.02%. Found: C, 48.38%; H, 3.09%; N, 7.96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[C:6]2[CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([CH3:14])=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]nc(C)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nnc(C)c2c1
Temperature: 120 °C
Yield: 100 %

Procedure:
A solution of 6-methoxy-4-methyl-2H-phthalazin-1-one (6) (2.0 g, 10.5 mmol) in POCl3 (20 mL) is heated at reflux (120° C.) for 4 h and then cooled to room temperature. Unreacted POCl3 is removed at reduced pressure, followed by azeotroping with toluene (2×10 mL). The residue is diluted with sat. NaHCO3 (75 mL) and extracted with dichloromethane (150 mL, 2×60 mL, and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is dried under high vacuum to give 2.2 g (100%) of 7 as a yellow solid, mp 123-126° C. IR 2991, 1611, 1403, 1290, 1234 cm−1; 1H NMR (CDCl3) δ 2.95 (s, 3H, CH3), 4.05 (s, 3H, CH3O), 7.25 (d, J=1.2 Hz, 1H, 5-PhthH), 7.55 (dd, J=6.0, 1.2 Hz, 1H, 7-PhthH), 8.21 ppm (d, J=6.0 Hz, 1H, 8-PhthH).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:1][C:2]1[O:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(C)oc(C)c1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1oc(C)c(CO)c1C
Yield: 100.7 %

Procedure:
2,4,5-Trimethyl-3-carbethoxyfuran (40 g.) prepared in accordance with Helv. Chim. Acta., v. 15, 1112 (1932), was dissolved in ether (200 ml.) and added to a cooled slurry of lithium aluminum hydride (10 g.) in ether (200 ml.) After stirring a further 16 hours at room temperature a saturated, aqueous solution of sodium sulfate was added followed by the addition of magnesium sulfate (50 g.). The solids were filtered off and the solvents were concentrated to give crude alcohol, 2,4,5-trimethyl-3-hydroxymethyl furan (31 g.). A solution of this alcohol (4.2 g.) in dichloromethan (10 ml.) was added to a cooled slurry of triphenylphosphine hydrobromide (10 g.) in dichloromethane (40 ml.) and then left at room temperature for 15 minutes. Ether was then added and the solids formed were crystallized from a 1:5 parts by volume mixture of methanol and ethylacetate to give pure (2,4,5-trimethyl-3-furyl) methyl triphenylphosphonium bromide (10.2 g.) m.p. 223°-224°.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8](F)=[C:9]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:13])=[O:12])[CH:10]=1.[CH3:27][O-:28].[Na+].Cl>CO.O>[Br:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([O:28][CH3:27])=[C:9]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:13])=[O:12])[CH:10]=1
Reactant: O=S(=O)(c1cc(Br)c(Cl)cc1F)N1CCCCc2ccccc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of DCM (8 mL) containing 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (2.35 g, 5.6 mmol) was added 25% sodium methoxide in methanol (7.5 mL). The resulting suspension was stirred at rt for 3 hrs, followed by repartitioning with DCM (45 mL) and water (50 mL). A 6 N HCl solution was added dropwise until the aqueous layer pH was 7. The organic layer was separated, washed with water (2×30 mL), dried over MgSO4, and evaporated to afford 1-(5-bromo-4-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as the pale yellow foam (2.38 g). MS: 430.0 (M+H)+; tR=6.21 min (method 4). NMR (CDCl3), δ, 8.070 (1H, s), 7.130-7.219 (3H, m), 7.025-7.082 (1H, m), 6.761 (1H, d, J=7.5 Hz), 3.868 (3H, s), 3.733 (2H, m), 2.808-2.845 (2H, m), 1.902-1.940 (2H, m), 1.568-1.667 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Product: COC(=O)c1ccc(Cl)c(N)c1Cl

Procedure:
This material was prepared by chlorination of methyl 3-amino-4-chlorobenzoate with N-chlorosuccinimide. The product was isolated as a solid, mp 50°-52° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([O-:20])(=O)=[O:18])[CH:11]=[CH:10]2.O>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([Cl:3])(=[O:20])=[O:18])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (0.7 g) was added to a solution of sodium 6-hydroxynapthalene-2-sulfonate (9 mmol) in water (20 ml). Dimethyl sulfate (1.1 eq.) was added to this solution at 50-55° C. over 1 h, followed by sodium chloride (3.3 g). The solid that was formed was filtered off, washed with saturated NaCl solution and toluene and dried. Yield: 75% 2. Thionyl chloride (0.25 ml) was added to a cooled solution of 6-methoxynaphthalene-2-sulfonate (2 mmol) in dry DMF (1 ml) under N2. The reaction mixture was stirred for 3 h at 0° C. Iced water (20 ml) was added to the mixture, the solid was filtered off and washed with iced water. The solid was taken up in DCM (25 ml), the solution dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 75%
Reaction SMILES: [OH:1][C@H:2]([C:20]1[CH:21]=[CH:22][C:23]([NH:26]C(=O)C)=[N:24][CH:25]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C@@H:2]([OH:1])[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1ccc([C@@H](O)CNCCOc2ccc(-c3csc(C)n3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCNC[C@H](O)c3ccc(N)nc3)cc2)cs1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
In a round-bottomed flask, (R)-N-[5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide (74 mg, 0.18 mmol) was dissolved in 1.0 mL of ethanol, and 1.0 mL of 2 M sodium hydroxide was added to the solution. The reaction mixture was then heated to about 80° C. for about twenty minutes, and was then diluted with water and adjusted to about pH 11. The aqueous phase was extracted with four portions of methylene chloride, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (methylene chloride to 20% methanol/methylene chloride) to afford 49 mg (74%) of the desired product. LRMS ([M+1]+): 371.2.