Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1cc(F)cc(F)c1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 17.2 %

Procedure:
Prepared in 17.2% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,19-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.94 (br. s., 1H), 7.57 (t, J=7.5 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.34 (t, J=9.2 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 6.04 (br. s., 1H), 4.20 (br. s., 1H), 3.92 (t, J=10.6 Hz, 1H), 3.55 (t, J=11.2 Hz, 1H), 3.41 (br. s., 4H), 2.48 (s, 3H), 2.31 (s, 3H), 1.93 (d, J=13.6 Hz, 1H), 1.88-1.79 (m, 2H), 1.69 (d, J=12.5 Hz, 5H), 1.54 (br. s., 2H), 1.20 (s, 3H), 1.17 (s, 9H), 0.73 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 675.3.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[C:12](=O)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.C([SiH](CC)CC)C.CO.C(Cl)Cl>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c3ccccc3c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Reaction time: 96 h
Yield: 88.7 %

Procedure:
To a stirred suspension of 2 (40 g, 0.16 mol) in trifluoroacetic acid (2.5 L) was added triethylsilane (94 g, 0.8 mol) in small portions at room temperature and the reaction mixture was stirred for 96 h, during which time the reaction progress was monitored using TLC (eluent −5% MeOH/CH2Cl2). The reaction mixture was slowly poured on ice, filtered, washed with copious amounts of H2O and MeOH and dried in vacuo to provide the above-titled compound 6 (33.1 g, 88%), whose spectral data were identical to those of a sample of compound 6 that was obtained using Method I.
Reaction SMILES: CC1=C(C)[C:4]([O:6]C1=O)=[O:5].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])C1C=CC=CC=1.C(=O)=O.C=C>ClCCl.[Hg].C(O)(C)C>[CH3:23][C:18]12[C:10](=[O:17])[O:6][C:4](=[O:5])[C:21]1([CH3:22])[CH2:20][CH2:19]2
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C=C
Agent: O=C=O
Agent: [Hg]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC12CCC1(C)C(=O)OC2=O
Yield: 1201.2 %

Procedure:
In a low temperature exposure unit equipped with a 125 W mercury lamp in a cooled immersion bath, stirrer and gas inlet pipe, 15 g (0.12 mole) of dimethyl maleic anhydride and 1 g (0.0054 mole) of benzophenone are dissolved in 300 ml of dichloromethane, and the solution is cooled by means of an external cooling bath with a mixture of isopropanol and dry ice to -60° to -70° C. Ethylene gas is then introduced over 1 hour and the reaction mixture is subsequently irradiated at the above temperature for 12 hours while introducing a weak flow of ethylene. The solvent is then evaporated off and the crude product is recrystallised from dichloromethane/n-hexane, affording 10 g of 1,2-dimethylcyclobutane-1,2-dicarboxylic anhydride (54% of theory) in the form of white crystals with a melting point of 84°-86° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CC[N:15](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
To a solution of indole-2-carboxylic acid (1e: 1 mmol) in DMF (4 mL) was added DIPEA (2 eq.) followed by HATU (1.2 eq.). The mixture was stirred for 15 minutes before the desired amine (R6—NH2) was added. The mixture was left to stir at room temperature for 5-16 hrs before saturated NH4Cl solution was added. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified on CombiFlash® purification system (Teledyne Isco) using appropriate mixtures of ethyl acetate and cyclohexanes to obtain the desired product indole-2-carboxamide (I).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(N)c1
Yield: 55.4 %

Procedure:
A solution of the product from Example 5H (1.17 g, 7.0 mmol) in 25 mL of absolute EtOH and SnCl2 (3.58 g, 29.8 mmol) was stirred at room temperature for 16 h. Adjusted to pH 12 with 1N NaOH and extracted with EtOAc. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (835 mg, 82%) 1H NMR (300 MHz, CDCl3) δ ppm: 2.30 (2, 3H) 6.62 (d, J=8.83 Hz, 1H) 6.69 (s, 1H) 7.10 (m, 3H) 7.21 (m, 2H) 7.54 (d, J=7.72 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:16])=O)=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)cnc2-c2ccc(F)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)cnc2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 42.4 %

Procedure:
A mixture of 75 mg (0.20 mMol) of the product of Example 21 and 5 ml of POCl3 was heated to 100° C. for 2 hours, cooled to room temperature, poured into ice-water and extracted with dichloromethane (4×15 ml). The combined organic layers were extracted once with brine, dried over MgSO4 and evaporated to dryness to recover a colorless oil. Trituration with ether gave a colorless solid which was dried at 0.1 mm Hg at 50° C. to give 29.9 mg (42%) of solid: m.p. 178°-181.5° C.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)C.Cl[CH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2>O1CCCC1>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 11.4 g of magnesium shavings, 151.5 g of diethyl malonate and 300 ml of dry ethanol is warmed to 60° under argon over a period of 30 minutes. After the vigorous reaction has faded, the mixture is heated to boiling under reflux for an additional 1 hour and then concentrated in vacuo. The residue is treated twice with 300 ml of dry benzene each time and in each case evaporated well. The residue obtained is dissolved under argon in 350 ml of dry tetrahydrofuran. Thereto there is added dropwise at room temperature over a period of 20 minutes a solution of 195.5 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 500 ml of dry tetrahydrofuran. The mixture is heated to boiling under reflux overnight while stirring and then evaporated in vacuo. The residue obtained is partitioned between 2.0 l of toluene and 500 ml of ice-water. The organic phase is washed successively twice with 500 ml of 1N hydrochloric acid each time, twice with 500 ml of water each time, twice with 250 ml of saturated sodium bicarbonate solution each time and several times with water, dried over magnesium sulfate and evaporated in vacuo. Diethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonate is obtained as an orange oil.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:19][C:7]1[C:6]2[C:2]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)=[CH:3][S:4][C:5]=2[C:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COc1ccc(-c2cnc(N)c3c(Br)csc23)cn1
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: COc1ccc(-c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)cn1
Reaction time: 0.08 h

Procedure:
A mixture of Example 215 (1.0 eq) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was reacted with N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-indole-2-carboxamide (1.2 eq), Na2CO3 (2.4 eq), and Pd(PPh3)4 (0.06 eq) at 95° C. for 18 hours. The organic solvent was removed in vacuo and the mixture was extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile/0.1M ammonium acetate isocratic for 5 minutes, then 40-100% acetonitrile/0.1M ammonium acetate over 30 minutes, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:14]O)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:45])C(=O)C1>C(Cl)Cl>[Br:45][CH2:14][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CO)cc1Oc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CBr)cc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
To a solution of 3-(3-chloro-phenoxy)-4-methoxy-phenyl]-methanol (13) (315 mg, 1.2 mmol) and triphenylphosphine (390 mg, 1.5 mmol) in methylene chloride (5 ml) was added NBS (0.250 mg, 1.4 mmol) in portions at 0° C. under nitrogen. After 10 min of stirring at 0° C., the mixture was allowed to warm to room temperature, and continued to stir for 16 h. After the solvent was removed, the residue was purified by silica gel column chromatography with ether/hexane as eluent to give 360 mg (85% yield) of product (14).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (83 mg, 0.37 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (109 mg, 0.37 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (127 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(CC(=O)O)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
A solution of borane dimethyl sulphide complex in tetrahydrofuran (11.7 mL, 23.32 mmol, 3.0 eq) is added dropwise within 10 minutes at −5° C. to a stirred solution of (4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (2.0 g, 7.77 mmol, 1.0 eq) in tetrahydrofuran (50 mL). The reaction mixture is stirred at −5° C. for 20 minutes then at room temperature for 3 hours. Methanol (10 mL) is cautiously added to the reaction mixture that is then evaporated and repeatedly treated with methanol and concentrated to dryness to afford [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (1.89 g, 99.5% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:14]3[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:3]=[C:2]([C:49]5[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[CH:13]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
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: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)c1
Yield: 67.2 %

Procedure:
N-[(3-Bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (0.825 g, 1.302 mmol), (3-formylphenyl)boronic acid (0.195 g, 1.302 mmol), potassium carbonate (0.540 g, 3.91 mmol), and Pd(Ph3P)4 (0.075 g, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude residue. The residue was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (584.1 mg, 0.875 mmol, 67.2% yield)) as a white solid. LC-MS m/z 659.6 (M+H)+, 1.01 min (ret time); mp 109-112° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Cl>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([N:30]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(S(=O)(=O)N2CCOCC2)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of compound 1 (300 mg, 0.68 mmol) in dry DMF (5 mL) was added NaH (60%, 60 mg, 1.50 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. 2-chloro-1-(2-chloroethoxy)ethane (97 mg, 0.68 mmol) and KI (113 mg, 0.68 mmol) was added and then this mixture was stirred overnight at rt, quenched with water and extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=4/1) to give compound 44 (70 mg, 21%) as a white solid. 1H-NMR (CDCl3, 300 MHz) δ: 0.60-0.70 (2H, m), 0.95-1.03 (3H, m), 1.23-1.40 (3H, m), 1.36 (18H, s), 1.49-1.52 (3H, m), 2.52 (3H, s), 3.02-3.05 (4H, m), 3.73-3.78 (6H, m), 6.35 (1H, s), 7.15 (2H, d, J=1.8 Hz), 7.41 (1H, t, J=1.8 Hz). MS Calcd.: 514; MS Found: 515 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([SH:15])=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(C(C)=O)C>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([S:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: O=C(O)CCCCCCBr
Reactant: CCCc1c(CSc2nnc(S)s2)ccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(CSc2nnc(SCCCCCCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 0.20 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1,3,4-thiadiazole obtained in Example 8, 0.15 g of 7-bromoheptanoic acid, 0.18 g of anhydrous potassium carbonate and 5 ml of methyl ethyl ketone was added a catalytic amount of tetra-n-butylammonium bromide. The mixture was stirred at 60° C. for 1 hour. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to perform fractionation. The aqueous phase was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (2:1) gave 0.20 g of 7-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]heptanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([Cl:40])[CH:42]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(Cl)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 3-chloroaniline (56 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (193 mg) as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=O)=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[N:6]([CH:13]=[N:12][CH:11]=2)[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:24]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(I)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 37.6 %

Procedure:
To a suspension of 5-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.7 g, 6.2 mmol) in toluene (20 mL) was added phosphorous oxychloride (1.1 mL, 12.2 mmol). The reaction mixture was heated at 95° C. for 30 minutes. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate, then brine. The organic phase was isolated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford the title compound as a yellow solid (1.0 g, 39%). LCMS (method B): RT=3.97 min, [M+H]+=430.