Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH3:42])[S:30]([C:33]1[S:34][C:35]([Cl:41])=[C:36]([N+:38]([O-])=O)[CH:37]=1)(=[O:32])=[O:31]>>[Cl:41][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[N:29]([CH2:28][CH2:27][OH:26])[CH3:42])=[CH:37][C:36]=1[NH:38][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CN(CCO)S(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.21) according to general procedure II.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[CH:6]/[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C(C)(C)c1ccc(Cl)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.1 g (85.23 mmol) of ethyl-E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate is mixed in 228 ml of ethyl acetate with 2.41 g of palladium on carbon (10%), and it is stirred overnight at room temperature under hydrogen atmosphere. The catalyst is removed by filtration through a glass-fiber filter, and the residue that remains after concentration by evaporation (24.1 g=99.1%) is incorporated in crude form into the next stage.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]=[N+]=[N-])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3]1
Reactant: Cn1cc(NS(=O)(=O)c2ccc(CN=[N+]=[N-])cc2)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(NS(=O)(=O)c2ccc(CN)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 270.4 %

Procedure:
To a solution of 1-methyl-3-[4-(azidomethyl)phenylsulfonylamino]indole (674 mg, 1.97 mmol), prepared as in step 1, in 8:2 THF/H2O (10 mL) was added triphenylphosphine (1.03 g, 3.9 mmol) and the reaction mixture was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-methyl-3-[4-(aminomethyl)phenylsulfonylamino]indole (1.68 g) as a yellow-orange foam.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:15]1([OH:39])[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[S:31](=[O:33])(=[O:32])[N:30](C(C)(C)C)[C:29](=[O:38])[CH:28]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O.C([SiH](C(C)C)C(C)C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:15]1([OH:39])[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[S:31](=[O:32])(=[O:33])[NH:30][C:29](=[O:38])[CH:28]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CN3CCC(O)(Cc4ccccc4)CC3)s2)S1(=O)=O
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(c2ccc(CN3CCC(O)(Cc4ccccc4)CC3)s2)S(=O)(=O)N1
Yield: 61 %

Procedure:
To 4.12-B in a microwave vial was added TFA (1.9 mL) and triisopropylsilane (0.06 mL). The reaction was microwave irradiated at 130° C. for 15 min. The solvents were evaporated and crude purified by reverse phase HPLC to afford 4.12-C (11 mg, 61%). 1H NMR (500 MHz, DMSO-d6): δ 9.24 (br s, 1H), 7.52 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.23 (m, 2H), 7.17 (m, 1H), 7.14 (m, 2H), 6.67 (s, 1H), 4.80 (br s, 1H), 4.55 (d, J=7 Hz, 2H), 3.18 (m, 2H), 3.08 (m, 2H), 2.67 (s, 2H), 1.63 (m, 2H), 1.56 (m, 2H); LCMS found for C20H22N2O4S2 (M+H)+: m/z=419.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.O[CH2:25][C:26]1[CH:30]=[C:29]2[C:31]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=3[NH:95][C:96](=[O:101])[C:97]([CH3:100])([CH3:99])[CH3:98])=[C:32]3[N:36]=[C:35]([C:37]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=4[NH:82][C:83](=[O:88])[C:84]([CH3:87])([CH3:86])[CH3:85])=[C:38]4[NH:42][C:41](=[C:43]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=5[NH:69][C:70](=[O:75])[C:71]([CH3:74])([CH3:73])[CH3:72])[C:44]5[CH:45]=[CH:46][C:47](=[C:49]([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=6[NH:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:27]=1[NH:28]2)[N:48]=5)[CH:40]=[CH:39]4)[CH:34]=[CH:33]3.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:25][C:26]2[CH:30]=[C:29]3[C:31]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=4[NH:95][C:96](=[O:101])[C:97]([CH3:100])([CH3:99])[CH3:98])=[C:32]4[N:36]=[C:35]([C:37]([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=5[NH:82][C:83](=[O:88])[C:84]([CH3:87])([CH3:85])[CH3:86])=[C:38]5[NH:42][C:41](=[C:43]([C:63]6[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=6[NH:69][C:70](=[O:75])[C:71]([CH3:72])([CH3:73])[CH3:74])[C:44]6[CH:45]=[CH:46][C:47](=[C:49]([C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=7[NH:56][C:57](=[O:62])[C:58]([CH3:59])([CH3:60])[CH3:61])[C:27]=2[NH:28]3)[N:48]=6)[CH:40]=[CH:39]5)[CH:34]=[CH:33]4)=[O:15])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: O=C(O)CCCCCCCn1ccnc1
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(CO)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(COC(=O)CCCCCCCn4ccnc4)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 0.17 h
Yield: 89 %

Procedure:
8-Imidazol-1-yloctanoic acid hydrochloride (90.1 mg, 0.37 mmol) and triethylamine (TEA, 0.1 ml, 0.74 mmol) were dissolved in dry DMF (4 ml) and stirred for 10 min. After removing TEA under reduced pressure, 2-hydroxymethyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin, 76 mg, 73 μmol), 4-(N,N-dimethylamino)pyridine (DMAP, 4.5 mg, 37 μmol) and dicyclohexylcarbodiimide (DCC, 75.4 mg, 0.37 mmol) were added to the solution and stirred for 84 hours at room temperature in darkness. The mixture was chromatographed on a silica gel flash column using CHCl3 --MeOH (30/1 v/v) as the eluent. The residue was dried at room temperature in vacuo to give a purple product, 2-(8-imidazol-1-yloctanoyloxymethyl)-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin (80 mg, 89%).
Reaction SMILES: C1(CO[CH2:9][CH:10]2[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]2)C=CC=CC=1.C[Si]([I:23])(C)C>C(Cl)(Cl)Cl>[I:23][CH2:9][CH:10]1[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]1
Reactant: C[Si](C)(C)I
Reactant: CC(=O)SC1CSC(COCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: CC(=O)SC1CSC(CI)C1
Reaction time: 2 h

Procedure:
A 0° C. mixture, under argon, of 0.44 g of product from Example 139 in 5 ml of dry chloroform is treated with 0.55 ml of trimethylsilyl iodide. The reaction is stirred, in the dark, for 2 hours. The reaction is quenched with 100 ml of saturated sodium sulfite, extracted with methylene chloride and the layers separated. The organic layer is dried, filtered and concentrated in vacuo. The residue is purified by. chromatography (silica gel: 0-100% methylene chloride/hexane) to give 0.31 g of the product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[C:30](F)=[N:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>CS(C)=O>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:30]2[C:29]([Cl:28])=[CH:34][C:33]([C:35]([F:38])([F:36])[F:37])=[CH:32][N:31]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2c2ncc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a vial containing (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.212 g; 0.731 mmol) in dimethylsulfoxide (2 mL) is added N,N-diisopropylethylamine (0.127 mL; 0.731 mmol) and 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.096 mL; 0.731 mmol). The mixture is heated at 100° C. for 1 hour in an oil bath and then cooled to room temperature. The crude mixture is filtered and purified by preparative HPLC chromatography. Product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 433 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:49]4[CH:48]=[N:47][N:46]([CH2:45][C:44]5[CH:60]=[CH:61][CH:62]=[C:42]([F:41])[CH:43]=5)[CH:50]=4)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 87.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(3-fluoro-5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66R) (170 mg, 0.251 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (113 mg, 0.376 mmol) using sodium carbonate (80 mg, 0.753 mmol) and Pd(dppf)Cl2 (9.7 mg, 0.012 mmol) in toluene/ethanol/water (20/10/4 mL) to afford 160 mg (88% yield) of the titled compound after purification by column (Silica gel 60/120) using 37% ethyl acetate in hexane as eluent. MS: m/z=726.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:7][N+:8]([O-:10])=[O:9].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:7]([N+:8]([O-:10])=[O:9])[C:21]([NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=1)(=[O:19])=[O:18])=[O:22]
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)C(=C2NCCN2C)[N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A solution of 1.43 g of 1A in 20 ml of methylene chloride was treated with 1.99 g of p-tolylsulfonyl isocyanate at room temperature. After a brief period of exothermicity, the mixture was held at room temperature overnight. The mixture then was diluted with 20 ml of dry ether and filtered to give 1, as a white powder, m.p.: 155°- 157°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31][CH3:32])=[O:30]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[O:23]
Reactant: COC(=O)C(C)(C)CN
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Solvent: CO
Product: COC(=O)C(C)(C)CNC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O

Procedure:
Methyl 4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (49.0 mg, 0.14 mmol) and methyl 3-amino-2,2-dimethylpropanoate (114.0 mg, 0.87 mmol) in MeOH (3 mL) were heated at 150° C. in a microwave for 4 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 15 mg. 1H NMR (CDCl3, 200 MHz): δ=13.10 (s, 1H), 8.40-8.28 (m, 2H), 8.10 (d, 1H, J=9.0 Hz), 7.30 (d, 2H, J=6.6 Hz), 7.05 (d, 1H, J=9.0 Hz), 6.92-6.80 (m, 3H), 5.14 (s, 1H), 4.38 (s, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.59 (d, 2H, J=6.6 Hz), 1.28 (s, 6H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.C(Cl)(=O)C(Cl)=O.[F:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][C@H:31]([CH3:35])[CH2:30]2)=[CH:26][CH:25]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[F:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:1](=[O:5])[CH2:2][OH:3])[C@H:31]([CH3:35])[CH2:30]2)=[CH:26][CH:25]=1
Reactant: O=C(O)CO
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a solution of glycolic acid (0.70 g, 9.2 mmol), 4-dimethylaminopyridine (catalytic) and pyridine (1.52 mL, 18.6 mmol) in dry dichloromethane (20 mL) was added trimethylsilylchloride (2.39 mL, 2.05 mmol) dropwise. The reaction was stirred at ambient temperature for 4 hours. The reaction was then cooled to 0° C. and catalytic dimethylformamide (3 drops) was added followed by addition of oxalyl chloride. The reaction was stirred at 0° C. for one hour and then 30 minutes at ambient temperature. The reaction was cooled back to 0° C. and (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (2.11 g, 10.12 mmol) was added as a solution in pyridine (2.45 mL, 30.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was neutralized with 1N hydrochloric acid and extracted with dichloromethane (2×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.84 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH2:74])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]>ClCCl>[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH:74][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reaction time: 1.5 h
Yield: 121.5 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (30 g, 66.3 mmol) in a 1 L round-bottom flask in dichloromethane (DCM) (300 mL) was added triethylamine (46.2 mL, 331 mmol) giving a solution to which was added TBTU (31.9 g, 99 mmol). The mixture became cloudy and was then stirred at room temperature under nitrogen for 5 min when 1-[3-bromo-4-(methyloxy)phenyl]methanamine hydrochloride (18.42 g, 72.9 mmol) was added. After 1.5 h the reaction was worked up. The mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 52.41 g (121%) of a golden foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 20-100% of {1% MeOH in EtOAc) in dichloromethane over 12 column volumes. The fractions were checked by HPLC and product fractions were combined and solvent evaporated to give 30.15 g (˜65%) of a cream foam that lab HPLC showed to be 97.2% pure (ret time 2.11 min) LC-MS m/z 650, 652 (M+H)+, 1.03 min (ret time).
Reaction SMILES: OC[C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12](C(OC(C)(C)C)=O)[CH2:13][C@H:14]([O:23][Si](CC)(CC)CC)[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.Cl.[C:41]([O:44][CH2:45]C)(=[O:43])[CH3:42]>>[OH:23][C@H:14]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][NH:12][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:45][O:44][C:41](=[O:43])[CH3:42])=[CH:4][C:5]=2[CH2:11]1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)OCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
A solution of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (188 mg) in ethyl acetate (2 ml) was treated with 4N hydrogen chloride in ethyl acetate (2 ml) for 3 hours. The mixture was evaporated in vacuo and washed with diethyl ether three times. The residue was triturated in diisopropyl ether, and precipitated powder was collected by filtration to afford 6-[(2S)-2-hydroxy-3phenoxypropyl]amino-3-acetyloxymethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene (113 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][C@H:56]([CH3:60])[CH2:55]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:54]5[CH2:59][CH2:58][NH:57][C@@H:56]([CH3:60])[CH2:55]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (R)—N′-Boc-2-methyl-piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (30 mg, 48.1%). LC-MS m/z 707 (M+H)+, 0.74 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J=6.27 Hz, 3H) 1.20 (t, J=7.53 Hz, 3H) 1.29-1.36 (m, 7H) 1.40-1.64 (m, 3H) 1.84-1.92 (m, 3H) 2.17 (s, 3H) 2.60-2.67 (m, 4H) 2.73-2.78 (m, 1H) 2.83 (q, J=7.36 Hz, 2H) 3.46 (s, 2H) 3.52 (td, J=11.36, 2.13 Hz, 2H) 3.80-3.87 (m, 2H) 4.04-4.11 (m, 1H) 4.21-4.44 (m, 6H) 6.74 (d, J=7.78 Hz, 1H) 7.04 (d, J=1.76 Hz, 1H) 7.07-7.11 (m, 1H) 7.14-7.21 (m, 3H) 7.26 (d, J=7.78 Hz, 1H) 7.34-7.38 (m, 1H) 7.99 (s, 1H) 8.43 (t, J=5.77 Hz, 1H) 9.02 (t, J=5.77 Hz, 1H).
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12](C)=CC=1)(=O)=O)CC#C.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>CCOCC>[C:16]([NH:20][CH2:9][CH2:14][C:13]#[CH:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: C#CCCNC(C)(C)C

Procedure:
A solution of toluene-4-sulfonic acid but-3-ynyl ester (1.57 g, 7.1 mmol) in tert-BuNH2 (3.54 g. 48 mmol) was heated to reflux for 18 h. The reaction mixture was diluted with Et2O (20 mL), filtered, and concentrated to afford the title product. 1H NMR (CDCl3) δ 2.74 (t, 2H), 2.38 (td, 2H), 2.00 (t, 1H), 1.12 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:35])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:27](=[O:28])[CH2:26][O:25][C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:23]3)=[CH:17][CH:16]=2)[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:35])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:27](=[O:28])[CH2:26][O:25][C:24]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:23]3)=[CH:17][CH:16]=2)[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)CCc1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)CC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1

Procedure:
A solution of 175 mg (0.31 mmol) of ethyl 3-{2-methyl-3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]phenyl}propanoate (Example 151A) in 5.5 ml of THF and 1.2 ml (1.2 mmol) of 1 N aqueous sodium hydroxide solution was stirred at 60° C. overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 165 mg (0.30 mmol, 99% of theory) of the title compound as a mixture of isomers.