Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[N:5]1[C:22](=[O:41])[CH2:23]/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:40])[O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])([CH3:3])[CH3:2].[Cl-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:54]=[C:55]([CH2:63][CH2:64][CH3:65])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57].C(O)(=O)C>O1CCCC1>[OH:54][C@@:55]([CH2:63][CH2:64][CH3:65])([C@@H:23]([C:22]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:7][C:6]1=[S:21])=[O:41])/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])=[O:40])[C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57]
Reactant: CCCC(=O)C(=O)OC(C)(C)C
Reactant: CC(C)[C@@H]1N(C(=O)C/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=S)OC1(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
2-Trimethylsilanyl-ethyl [(E)-9-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-9-oxo-non-6-enyl]-carbamate (400 mg, 0.672 mmol) and dried lithium chloride (114 mg, 2.69 mmol) were dissolved in tetrahydrofuran (3.2 mL), and the mixture was then cooled to −78° C. in a dry ice-acetone bath. Lithium hexamethyldisilazide (a solution of 1 M tetrahydrofuran, 1.51 mL, 1.51 mmol) was added in order, and the mixture was then stirred for 1 hour. A solution of tert-butyl 2-oxo-pentanoate (130 mg, 0.755 mmol) in tetrahydrofuran (2.4 mL) was added, and the mixture was then stirred at −78° C. for further 6 hours, and quenched with acetic acid (0.160 mL, 2.80 mmol). The dry ice-acetone bath was then removed. Ethyl acetate (30 mL) and water (10 mL) were added and the mixture was then separated. The organic layer was washed with a saturated aqueous solution (20 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 270 mg (0.352 mmol, 52% yield) of tert-butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate.
Reaction SMILES: Br[CH:2]([C:4]1([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)OCC(C)(C)CO1)C.[C:22]([O-:25])(=[O:24])C.[K+]>C(N)=O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH3:2])[C:22]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: CC(C)Cc1ccc(C2(C(C)Br)OCC(C)(C)CO2)cc1
Agent: [K+]
Solvent: NC=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
A mixture of 2-(1-bromoethyl)-5,5-dimethyl-2-(4-isobutylphenyl)-1,3-dioxane (3.55 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), formamide (50 ml) is heated at 170° C. under stirring for 2.5 h. The reaction mixture is worked up as described in Example 1a to give 2-(4-isobutylphenyl)-propionic acid (2.5 mmol; yield 25%), m.p. 74°-76° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)#N.C(O)(=[O:20])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:20]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C#N)c2C
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl (R)-(5-cyano-4-methyl-indan-1-yl)acetate (1.00 g, 4.36 mmol, from EXAMPLE 110, Step J) in pyridine (28 mL), acetic acid (15 mL), H2O (15 mL) and NaH2PO2 (3.07 g, 34.9 mmol) Rainey nickel was added (1.0 g) and the mixture was heated to 50° C. After 5 hr, the reaction was concentrated in vacuo and filtered through Celite®. The filtrate was concentrated in vacuo and partitioned between EtOAc (150 mL) and H2O (50 mL). The organic layer was washed with 5.0 N HCl (7×50 mL), sat. NaHCO3 (2×50 mL), brine (1×50 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/hexanes) to give 882 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.76-1.84 (m, 1H), 2.41-2.51 (m, 2H), 2.57 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.6 Hz), 2.81-2.87 (m 1H), 2.93-2.99 (m, 1H), 3.61-3.67 (m, 1H), 3.72 (s, 3H), 7.16 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, 7.8 Hz), 10.2 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1([CH3:23])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>ClCCl>[CH3:8][O:9][C:10]1([CH3:23])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(C)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
Trifluoroacetic acid (2.54 mL, 32.97 mmol) was added dropwise to tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate (22) (756 mg, 3.30 mmol) in dichloromethane (10 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 15 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the desired compound as an oil (235 mg, 55.2%); 1H NMR (400.132 MHz, CDCl3) δ 1.15 (3H, s), 1.41-1.49 (2H, m), 1.68-1.74 (2H, m), 2.76 (2H, dt), 2.93 (2H, dt), 3.19 (3H, s), 3.49 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([NH:32][C:33]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)=[O:34])[CH:30]=[CH:31][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 2.58 min, MH+ 526. NMR: δH [2H6]-DMSO 11.64, (1H, b), 10.14, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.91, (1H, s), 7.79-7.75, (2H, m), 7.65, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 3.77, (2H, s), 2.67-2.24, (11H, m), 2.16, (3H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]2[C:9](=[O:30])/[C:10](=[CH:12]/[C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15](COCC[Si](C)(C)C)[N:14]=3)/[O:11][C:7]=2[C:6]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](/[CH:12]=[C:10]2\[O:11][C:7]3[C:6]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:36][CH2:35]4)=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:32]=[CH:31][C:8]=3[C:9]\2=[O:30])=[N:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.100 g, 0.154 mmol) obtained in Step 3 in THF (1 mL) was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.54 mL, 1.54 mmol), and the mixture was refluxed for 3 hours by heating. The reaction mixture was cooled to room temperature, and then added with water (20 mL), the mixture was extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-(2-hydroxyethoxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0440 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([Cl:26])=[CH:10][C:11]([O:24][CH3:25])=[C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=1.CCN(CC)CC.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[Cl:26][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:13][C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:37])[CH:35]=[CH2:36])[CH2:20][CH2:19]2)=[O:17])=[C:11]([O:24][CH3:25])[CH:10]=1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of the crude 2-(5-(2-Chlorophenyl)-4-chloro-2-methoxyphenylamino)-1-(piperazin-1-yl)ethanone (0.304 mmol) and Et3N in DCM (5 mL) at 0° C., acryloyl chloride (27.5 mg, 0.304 mmol) was slowly added and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (80 mg, 58.7% yield, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.52 (m, 1H), 7.45-7.39 (m, 2H), 7.32-7.29 (m, 1H), 6.97 (s, 1H), 6.80 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.12 (dd, J=2.0, 16.8 Hz, 1H), 5.70 (dd, J=2.0, 10.4 Hz, 1H), 5.35 (bs., 1H), 3.93 (d, J=4.0 Hz, 2H), 3.89 (s, 1H), 3.55-3.49 (m, 8H). ESI-MS m/z: 448.2[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[CH2:77]([C:74]1([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:68]=[CH:69][C:70]1=2)[CH3:78]
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (113 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([C:6]#[N:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(C#N)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C#N)cc21

Procedure:
Methanesulphonyl chloride (1.0 ml) was added to a stirred suspension of 7-cyano-3-hydroxy-1-methyl-4quinolone (0.4 g) and triethylamine (2.0 ml) in dry dichloromethane (200 ml) at 0 to 5° and the resultant solution stirred for 2 hours. The solution was washed with water (2×50 ml), dried over magnesium sulphate and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (40:1) followed by trituration with diethyl ether (10 ml) to give the novel compound 7-cyano-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 268°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Reaction time: 0.37 h
Yield: 70.8 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1973 g, 0.90 mmol) is added to a slurry of pentane-washed NaH (0.0286 g, 0.72 mmol) in DMF (1 mL) and, after stirring for 22 min, p-fluorobenzyl bromide (0.14 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0166 g, 0.42 mmol) and DMF (1.8 mL) are added. The mixture is stirred for 1 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.2088 g (71%) of the title compound; mp 166-166.5° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1639, 1607, 1510, 1485, 1449, 1426, 1413, 1226, 1189, 1157, 1108, 1095, 830, 790, 734 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.84, 5.78, 6.97, 7.19, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found: C, 69.44; H, 4.55; N, 4.34.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (77.0 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (87 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-20% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off white foam. 1H-NMR (CDCl3) δ 7.88 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.38 (s, 1H), 5.18 (br s, 1H), 3.81 (s, 3H), 3.10 (br s, 2H), 2.72 (s, 3H), 2.68-2.49 (m, 6H), 2.18-2.00 (m, 2H), 1.82-1.69 (m, 2H), 1.40-1.18 (m, 4H), 1.07 (t, J=7 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CCN(C)CC2)c2nccc(C)c2c1
Yield: 53.7 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.8 g (0.018 mole) of N-methylpiperazine in 70 ml of benzene was heated under reflux for 20 hr, treated with 2 ml of triethylamine, and heated for an additional 24 hr. The mixture was allowed to cool, filtered and the filtrate was washed with water, dried and concentrated to dryness in vacuo. The residue was recrystallized twice from n-hexane containing a little toluene and then dried in vacuo at 68° to afford 3.1 g (53%) of the title compound, mp 104°-107°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (1.38 g, 7.41 mmol) in acetonitrile (10 mL) was stirred with triethylamine (2.07 mL, 14.8 mmol) and methyl 2-bromoacetate (1.02 mL, 11.1 mmol) at room temperature for 4 hours and then filtered. The filtrate was concentrated, and after addition of saturated aqueous ammonium chloride, extracted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 83%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1CCO[CH:19]1[C:23]1[C:31]2[O:30][C:29]([CH3:33])([CH3:32])[CH:28]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:27]=2[C:26]([CH3:41])=[C:25]([N:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)[C:24]=1[CH3:56]>CC(C)=O.O>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([N:45]2[CH2:46][CH2:47][N:42]([C:25]3[C:24]([CH3:56])=[C:23]([CH:19]=[O:18])[C:31]4[O:30][C:29]([CH3:33])([CH3:32])[CH:28]([C:34]5[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[C:27]=4[C:26]=3[CH3:41])[CH2:43][CH2:44]2)=[CH:53][CH:52]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C4OCCO4)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C=O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 80.4 %

Procedure:
Pyridinium p-toluenesulfonate (20 mg, 80 mmol) was added to a solution of 1-(7-(1,3-dioxolan-2-yl)-2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (1.41 g, 2.67 mmol) obtained in Example 93 in acetone (15 ml) and water (1 ml) and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to obtain 1.04 g (yield 81%) of the title compound. mp. 175–177° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-fluorobenzoic acid (1.1 g, 5.2 mmol) in SOCl2 (11.8 g, 99 mmol) was warmed to 90° C. and was stirred for 2 h. The mixture was cooled to ambient temperature and was concentrated under reduced pressure. The residue was diluted with toluene (5 mL) and was concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to remove excess SOCl2. The crude acid chloride was carried on without purification or characterization.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:34])[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)[CH3:34])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Reactant: CC(CN)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NCC(C)c2ccc(Cl)cc2)c(NS(=O)(=O)c2cccc3nsnc23)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid was coupled with (±)-2-(4-chloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=10.22 min. MS (ESI−): mass calcd. for C23H21ClN4O3S2, 500.07; m/z found, 499 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.48 (s, 1H), 8.31 (dd, J=7.0, 1.0, 1H), 8.18 (dd, J=8.8, 1.0, 1H), 7.67 (dd, J=8.8, 7.0, 1H), 7.47 (s, 1H), 7.33-7.27 (m, 2H), 7.16-7.10 (m, 2H), 6.90 (d, J=8.0, 1H), 6.71 (d, J=8.0, 1H), 5.75-5.70 (m, 1H), 3.73-3.64 (m, 1H), 3.30-3.21 (m, 1H), 3.05-2.94 (m, 1H), 2.26 (s, 3H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O.O>[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: Oc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 18.9 g of 3-mercaptophenol (0.150 moles), 32.9 g of 2-nitro-5-bromo-p-xylene (0.143 moles) and K2CO3 (0.143 moles) in 95 ml of N,N-dimethylformamide is stirred at room temperature for 2 hours. A solution of HCl at 10% is added under stirring; the mixture is diluted with H2O and extracted with ethyl acetate. The organic phase is washed again with water, anhydrified on sodium sulfate, filtered and evaporated. 20 g of solid product are obtained, which is used as such for the subsequent reaction.