Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][CH:4]=1
Reactant: Brc1cnc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(Br)cn1
Temperature: 115 °C
Yield: 8.6 %

Procedure:
A solution of 2,5-dibromopyrazine (238.0 mg, 1.0 mmol), ethyl acrylate (174.0 μL, 1.6 mmol), palladium(II) acetate (3.4 mg, 0.015 mmol), and tri(o-tolyl)phosphine (36.5 mg, 0.12 mmol) in DMF (1.4 mL) and diisopropylethylamine (0.7 mL) was heated at reflux (115° C. oil bath) for 4.4 h, cooled to room temperature, and then quenched with H2O. The suspension was extracted with EtOAc (300 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was purified on silica gel (11% EtOAc/hexane) to give 22 mg (8.5%) of ethyl(E)-3-(5-bromo-2-pyrazinyl)-2-propenoate as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)CCCBr
Reactant: COC(=O)c1[nH]c2ccncc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Br)c2cnccc2n1CCCS(C)(=O)=O
Temperature: 60 °C

Procedure:
A suspension of methyl 3-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 12-c (1000 mg, 3.92 mmol), 1-bromo-3-(methylsulfonyl)propane 12-b (804 mg, 3.92 mmol) and cesium carbonate (1277 mg, 3.92 mmol) in dry DMF (8 ml) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and poured into iced water. The product was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by column chromatography using a gradient starting from 0% to 10% MeOH/DCM. After evaporation and drying in vacuo, 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.23 (m, 2H) 2.97 (s, 3H) 3.13-3.22 (m, 2H) 3.95 (s, 3H) 4.65 (t, J=7.28 Hz, 2H) 7.75 (dd, J=6.02, 1.00 Hz, 1H) 8.47 (d, J=6.02 Hz, 1H) 8.88 (d, J=1.00 Hz, 1H); m/z=375 (M+H)+, Br pattern.
Reaction SMILES: C(O[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)CC=C>C1(C)C=CC=CC=1>[N+:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:11]=1)([O-:14])=[O:13]
Reactant: C=CCCOc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 4 h
Yield: 443.3 %

Procedure:
2.52 g of the 2-(3-butenyloxy)-4,4'-dinitrobiphenyl synthesized in Reference Example 1 was dissolved in 80 mL of dry toluene. To this was first added 100 microliters of a 3% chloroplatinic acid 2-propanol solution, and a solution in 20 mL dry toluene of 7.88 g of hydrogen-terminated polysiloxane (average value of n: 14.4) with the formula ##STR17## was then added dropwise. Heating was continued for 4 hours at 100° C. Purification by column chromatography yielded 8.68 g of the 4,4'-dinitrobiphenyl-terminated polysiloxane as a waxy light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O.B1([O-])O[O:20]1.O.O.O.O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:10]1[CH:11]=[C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:20])[CH:8]=[N:9]1
Reactant: [O-]B1OO1
Reactant: C1=C(c2cnn(C3CCCCO3)c2)CCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1c1cnn(C2CCCCO2)c1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of the 4-cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (775 mg, 3.34 mmol) prepared in Example 33a in THF (4 mL), a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added with cooling on ice, and the reaction solution was stirred for 30 minutes with cooling on ice. To the reaction solution, a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added again, and the mixture was stirred at room temperature for 90 minutes. To the reaction solution, water (5 mL) and subsequently sodium perborate tetrahydrate (1.00 g, 6.50 mmol) were added, and the mixture was stirred for 5 hours. To the reaction solution, sodium thiosulfate (2.0 g) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (dichloromethane/methanol=97:3) to yield the title compound (590 mg, 71%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][N:27]([CH3:43])[C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH3:26][N:27]([CH3:43])[C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][N:29]=1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N(C)C)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 50 mg, 0.125 mmol) and 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 38 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: tR 2.68 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.46 (s, 2H), 8.20 (s, 1H), 8.09-8.02 (m, 1H), 7.91-7.84 (m, 1H), 7.38 (s, 1H), 4.60-4.51 (m, 1H), 3.56 (s, 3H), 3.13 (s, 6H), 1.97 (s, 3H), 1.49-1.44 (m, 6H))
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1B1OC(C)(C)C(C)(C)O1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2C=O)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.48 g, 4.50 mmol), 2-formylfuran-3-boronic acid pinacol ester (1.00 g, 4.50 mmol), saturated aqueous sodium carbonate solution (20 ml), and tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) in ethylene glycol dimethyl ether (25 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (750 mg, 48.4%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])O)=[CH:5][CH:4]=1.COC1C=C2C(CCC2(C2C=CC=CC=2)O)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][CH:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1C)CC2
Agent: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Product: COc1ccc2c(c1)C(c1ccccc1C)C=C2

Procedure:
According to the procedure of Preparation 10 (a), except substituting 6-methoxy-1-(2-methylphenyl)-1-indanol for the 6-methoxy-1-phenyl-1-indanol, the title compound was obtained as a colorless oil following silica gel chromatography (3% EtOAc/hexanes): MS (ES) m/e 237.2 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])C.[Mg+2:5].[C:6]([O-:9])(=[O:8])C>O>[C:1](=[O:3])([OH:8])[O-:4].[Mg+2:5].[C:6](=[O:8])([OH:3])[O-:9]
Reactant: CC(=O)[O-]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O
Temperature: 50 °C

Procedure:
A magnesium bicarbonate solution was prepared from hydromagnesite (15.0 g) and magnesium acetate (17.0 g) in water (circa 1000 mL) by bubbling carbon dioxide through the aqueous suspension overnight. [Minor residual undissolved solids derived from the hydromagnesite used were not removed by filtration.] The resulting solution was heated to 50° C. with magnetic stirring and aqueous KOH was added while continuing the magnetic stirring. Five different experiments were run, and in each case, the amount of KOH was varied and the final pH was measured and is shown in Table II. The precipitate was filtered and dried in an oven at about 110° C., resulting in a solid material which was examined by TGA to determine the hydromagnesite/magnesium hydroxide ratio, and by SEM to determine the morphology and size of product. The materials were also evaluated for their ease in filtration. These results are summarized in Table II. The X-ray powder pattern of brucite was not observed in the X-ray powder patterns (XRD) of the samples with pH<10.6, indicating that the magnesium hydroxide has a very small crystalline size, i.e., <50 Å. The XRD of the sample at pH=10.61 showed broad brucite peaks. SEM analysis of these samples showed neither spheres nor rosettes, due to the agitation during the base addition.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][OH:16]>>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Product: O=[N+]([O-])c1ccncc1OCc1ccc(Cl)cc1Cl
Yield: 68.2 %

Procedure:
In accordance with the same procedures as in Steps 3 and 4 of Preparation 1, except for using 3-bromo-4-nitropyridin-N-oxide prepared in Step 2 of Preparation 1 and 2,4-dichlorobenzyl alcohol, the titled compound was obtained (Yield: 68.2%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:43]([CH:48]1[C:57]2[N:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH2:51][CH2:50][CH2:49]1)[CH2:44][CH2:45][CH2:46][NH2:47]>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.O>[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:43]([CH:48]1[C:57]2[N:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH2:51][CH2:50][CH2:49]1)[CH2:44][CH2:45][CH2:46][NH:47][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccn1
Yield: 47.7 %

Procedure:
To a stirred solution of picolinic acid (36.7 mg, 0.30 mmol) in anhydrous DMF (3 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.6 mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6 mg, 0.36 mmol) and N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (100 mg, 0.30 mmol). The resultant solution was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (40 mL), brine (15 mL) and H2O (5 mL) and the two layers mixed vigorously for 15 minutes. The layers were separated and the organic layer washed with brine (5×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the beige foam by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 50:1:1) gave the free base of the title compound (63.0 mg, 48%) as a white foam.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[S:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:1](=[S:2])[NH2:3])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Yield: 37.9 %

Procedure:
The title compound (1.5 g) was prepared from 3.01 g (16.91 mmol) of thiocarbonyldiimidazole and 3.0 g (16.12 mmol) of 1-tert-butoxycarbonyl-piperazine according to the method of Intermediate 53 followed by purification via trituration with diethyl ether: low resolution MS (ES) m/e 246 (MH+).
Reaction SMILES: [F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].O.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[CH2:16]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:27]([F:38])=[CH:28][CH:29]=[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1)[CH3:17]
Reactant: C=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(CC)c3c2)c1F
Reaction time: 1 h
Yield: 37.6 %

Procedure:
2,6-Difluoro-N-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0093 g, 0.017 mmol) was dissolved in MeOH (1.0 mL). 10% Pd/C (2.0 mg) was added and followed by stirring under a balloon of H2 for 1 hour. Water (0.3 mL) and K2CO3 (0.0235 g, 0.170 mmol) were added, and the reaction mixture was stirred at 50° C. for 18 hours. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:2 hexane/EtOAc) giving N-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (2.7 mg, 37.6%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 10.84 (s, 1H), 9.79 (br s, 1H), 8.32-8.34 (m, 2H), 7.51-7.57 (m, 1H), 7.24-7.27 (m, 2H), 3.10-3.14 (m, 2H), 2.67-2.73 (m, 2H), 1.74-1.80 (m, 2H), 1.25-1.28 (m, 2H), 0.98-1.01 (m, 3H); m/z (APCI-neg) M−1=421.2.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>C1COCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 44.4 %

Procedure:
6-Bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 100 mg, 0.27 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 115 mg, 0.25 mmol) were dissolved in THF (5 mL) and degassed then bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.025 mmol) was added. The reaction mixture was stirred at reflux temperature for 21 hrs then allowed to cool before washing with cesium fluoride (saturated aqueous solution) and extracting with EtOAc (2×30 mL). The combined organic extracts were filtered and the filtrate was concentrated in vacuo. The resultant residue was subjected to preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to afford 51 mg of an impure title compound (containing 25% starting material) which was dissolved in THF (3 mL) with 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 4.72 g, 0.103 mmol) and degassed before addition of bis(triphenylphosphine)palladium (II) dichloride (10 mg, 0.014 mmol). The reaction mixture was heated at 75° C. for 6.5 h then purified using an SCX-2 cartridge (loading in MeOH/eluting with 2 N NH3 in MeOH). The resultant residue was taken up in MeOH (5 mL) and treated with 3-mercaptopropylethyl sulfide silica (PhosphonicS SPM 32, 0.5 eq by weight) and stirred at 50° C. for 1 hr then filtered and evaporated. The resultant residue was dissolved in DCM then filtered and evaporated in vacuo before further purification by preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (25 mg).
Reaction SMILES: OC1C=CC=CC=1[C:8]1[C:16]2[N:15]=[N:14][NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.OC1C=CC(C)=CC=1C1C2N=NNC=2C=CC=1.OC1C(C(C)(C)C)=CC(C)=CC=1C1C2N=NNC=2C=CC=1Cl>>[NH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:16]=2[N:15]=[N:14]1
Reactant: Oc1ccccc1-c1cccc2[nH]nnc12
Agent: Cc1cc(-c2c(Cl)ccc3[nH]nnc23)c(O)c(C(C)(C)C)c1
Agent: Cc1ccc(O)c(-c2cccc3[nH]nnc23)c1
Product: c1ccc2[nH]nnc2c1

Procedure:
For example, (2′-hydroxyphenyl)benzotriazole, (2′-hydroxy-5′-methylphenyl)benzotriazole, (2′-hydroxy-5′-methylphenyl)benzotriazole, (2′-hydroxy-3′-tertiary-butyl-5′-methylphenyl)-5-chorobenzotriazole, or the like may be used.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([F:44])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[F:44])[CH3:43]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1ccc(OB([O-])[O-])cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-ethoxy-3-fluorophenyl borate (117 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 24 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:4) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-(4-ethoxy-3-fluorophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 50) (137 mg).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C1CCC(NC2CCCCC2)CC1.OS(O)(=O)=O>CN(C=O)C.C(O)(=O)C.C(N(CC)CC)C>[CH2:20]([O:19][C:17]([NH:1][C@H:2]([C:7]([NH:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of Z-Leu-OSu (122.5 g, 0.338 mol) in DMF (1.2 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Lys(Boc)-OH (83.26 g, 0.338 mol) was added and the solution stirred at 0° for 15 min. Triethylamine (47.6 mL, 0.338 mol) was added and the reaction mixture stirred at 0° for 30 min and 25° for 3 h. Additional triethylamine (20 mL) was added to maintain the pH at 8 and the reaction mixture stirred for an additional 20 h. At the end of this time, tlc showed some unreacted H-Lys(Boc)-OH and the reaction mixture was stirred for an additional 24 h (pH 8). The reaction mixture was cooled (0°), acidified with glacial acetic acid (160 mL) and evaporated in vacuo. The residue (oil) was dissolved in EtOAc (1.5 L) and washed with 1M citric acid (2×600 mL) and 10% NaCl (2×700 mL), dried (MgSO4), filtered and concentrated in vacuo. The oily residue was dissolved in anhydrous ether (4 L) and dicyclohexylamine (70.7 mL) added followed by the addition of 1 L of ether. After standing in the cold room for 72 h, the white salt was collected and dried to yield 210.8 g (90%); m.p. 125°-128° (recrystallization of an analytical sample increased the m.p. to 143°-146°); [α]D25 -4.17 (c 1, MeOH); Rf 0.39 (CHCl3 :MeOH:AcOH; 85:10:5). The free acid was generated from the DCHA salt in the following manner: Z-Leu-Lys(Boc)-OH.DCHA (201.9 g, 0.291 mol) was stirred in EtOAC:0.5N H2SO4 (2 L:727 mL) until all the solid dissolved. The organic layer was separated, washed with 0.5N H2SO4 (730 mL), dried (MgSO4) and evaporated in vacuo. Yield: 150.6 g (100%); [α]D25 +3.38° (c 1, CHCl3); Rf 0.64 (CHCl3 :MeOH:AcOH; 85:10:5).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH:17]([F:19])[F:18]>>[F:19][CH:17]([F:18])[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9](=[O:20])[CH2:6][C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccccc1OC(F)F
Product: N#CCC(=O)c1ccccc1OC(F)F

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis from 1.5 g (7.4 mmol, 1.0 eq) of 2-Difluoromethoxy-benzoic acid methyl ester (route A1bis). The crude product was used directly for the next step.