Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Br[CH2:13][C:14]1[O:15][C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Commercially available 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (124 mg, 0.476 mmol) was added to a solution of 3-(bromomethyl)-4-phenyl-1H-isochromen-1-one (intermediate C1, 100 mg, 0.317 mmol) in DMF (1 mL). K2CO3 (65.8 mg, 0.476 mmol) was added and the resulting mixture was stirred at 50° C. for 2 hrs. The resulting crude was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 5%, formic acid 0.01%); Phase B ACN 95%, water 5%, formic acid 0.01%) to give the title compound (138 mg, 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamine and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°. uv λmax 222 nm (ε 22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/N+H 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3 - /CN 1335, 1320, 1275, 1200, 1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 314.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:33][CH:32]=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=CC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 4,4'-dichlorobenzophenone (25.1 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (144 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 23.8 g of essentially pure 3,3-bis(4-chlorophenyl)-2-propenal as an orange oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[N:34]=[C:35]=[O:36].C(N(CC)C(C)C)(C)C>C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[NH:34][C:35]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:9]3[NH:8][CH:12]=[CH:11][CH:10]=3)[CH:18]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Nc1ccc(-c2ccnc(-c3ccc[nH]3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc(-c4ccc[nH]4)c3)cc2)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline TFA salt (60 mg, 0.17 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (48 mg, 0.32 mmol) and N,N-diisopropylethylamine (40 mg, 0.31 mmol). After 1 hour, the reaction mixture was evaporated and purified by silica gel chromatography with 2-3% MeOH/CHCl3 to give 1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea as off-white solid. Yield: 28 mg.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([C:34](=[O:36])[CH3:35])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: CC(=O)N1CCNCC1
Agent: OC1CCNC1
Product: CC(=O)N1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-acetylpiperazine. A yellow solid 125 was obtained (0.010 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ 2.17 (s, 3H), 3.67-3.72 (m, 2H), 3.73-3.77 (m, 2H), 3.83-3.88 (m, 2H), 3.94-3.98 (m, 2H), 4.28-4.34 (m, 4H), 6.93 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.02 (d, J=5.8 Hz, 1H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 8.29 (d, J=6.2 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][NH:8][C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[S:10])=O.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]1[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([SH:10])=[N:8][N:7]=1
Reactant: COc1ccc(C(=O)NNC(=S)NCC(C)C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nnc(S)n2CC(C)C)c(OC)c1
Yield: 21.2 %

Procedure:
Ex-109C: A solution of 1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (Ex-109B, 0.5 g, 1.61 mmol) and sodium hydroxide (0.999M, 4.8 mL, 4.8 mmol) in ethanol (30 mL) was refluxed for one day. The solvent was removed under reduced pressure and the residue redissolved in ethyl acetate. The solution of ethyl acetate was washed with water and brine, dried over sodium sulfate, and concentrated to give 5-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole-3-thiol (0.1 g). Additional product (0.36 g, 98% overall) was obtained by extracting the water wash with dichloromethane and a mixture of isopropyl alcohol (33%, v/v, in dichloromethane). 1H NMR (CDCl3) δ 10.82 (bs, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.56 (dd, J=8.1, 2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.72 (d, J=6.7 Hz, 2H), 2.17–2.08 (m, 1H), 0.70 (d, J=6.7 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@@H:3]([CH3:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:22][CH2:21][C:13]3([CH2:20][CH2:19][C:16]4([O:18][CH2:17]4)[CH2:15][CH2:14]3)[C:12]2=[O:23])=[CH:7][CH:6]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:23]=[C:12]1[C:13]2([CH2:14][CH2:15][CH:16]([CH:17]=[O:18])[CH2:19][CH2:20]2)[CH2:21][CH2:22][N:11]1[C:8]1[CH:7]=[CH:6][C:5]([O:4][C@H:3]([CH3:24])[C:2]([F:25])([F:1])[F:26])=[CH:10][CH:9]=1
Reactant: C[C@@H](Oc1ccc(N2CCC3(CCC4(CC3)CO4)C2=O)cc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1ccc(N2CCC3(CCC(C=O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of 8-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one (50 mg, 135 umol, obtained in example 252, Step 2) in chloroform was added tosic acid (26 mg, 135 umol) and the reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (grad 0% to 80% EtOAc in heptane) to yield the title compound as a white solid (7 mg, 14%). MS (m/e): 370.1 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH:45][C:6]([C:4]2[CH:3]=[N:2][NH:1][CH:5]=2)=[O:8])[CH3:44])=[CH:39][CH:38]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=C(O)c1cn[nH]c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn[nH]c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5.0 g (44.6 mmol) 4-pyrazolecarboxylic acid in 100 mL DMF 15.2 mL (89.2 mmol) DIPEA and 15.7 g (49.1 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 8.9 g (44.6 mmol) (S)-1-(4-bromophenyl)ethylamine are added and stirring is continued over night. The mixture is poured on water and is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is triturated with DCM to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:32][CH:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 64.5 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (802 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (638 mg, 3.0 mmol) were coupled together in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (100 mL) followed by cooling to 0° C. and filtration to yield product as a red solid (900 mg, 65%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.15 (AA′XX′, J=8.6 Hz, 2H), 8.06 (AA′XX′, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 5.61 (d, J=7.5 Hz, 1H), 4.28 (m, 1H), 4.18 (dd, J=5.0, 7.2 Hz, 1H), 3.18 (s, 3H), 2.34 (s, 3H), 1.39 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:18][C:17]=2[O:23][CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(OCc3ccc(C#N)cc3)cc2OCc2ccc(C#N)cc2)CC1
Yield: 76.3 %

Procedure:
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.95 g, 2.71 mmol) and 4-bromomethyl-benzonitrile (2.12 g, 10.84 mmol) and other reagents as described in Example 75(a) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (5H, m), 1.4 (9H, m), 1.75 (4H, m), 3.6 (1H, m), 5.3 (4H, s), 6.7 (1H, s), 6.85 (1H, s), 7.35 (2H, d), 7.5 (1H, s), 7.75 (4H, d), 7.9 (4H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]5[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 72 %

Procedure:
The title compound (64 mg, 64%) was synthesized as a greenish yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (42.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 7:6 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=5.2 Hz, 2H), 8.34 (d, J=8.4 Hz, 1H), 8.26 (d, 1H), 8.22 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.93 (d, 1H), 7.89 (d, J=16.8 Hz, 1H), 7.72 (t, J=4.8 Hz, 2H), 7.55 (d, J=16.0 Hz, 1H); MS ESI 444.3 [M+H]+, calcd for [C22H14BrN5O+H]+ 444.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](OB(O)O)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:27]2[CH2:28][CH2:29][C:25](=[O:30])[CH2:26]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OB(O)O)cc1
Reactant: O=C1C=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc([C@H]2CCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Under an argon stream, [4-(3-ethoxy-3-oxopropyl)phenyl]boric acid (2.33 g, 15 mmol) and Rh[(S)-BINAP(nbd)]BF4 (226 mg, 0.25 mmol) was dissolved in a solvent mixture of 1,4-dioxane (30 mL) and water (5 mL), followed by degassing with ultrasonic waves. Then, triethylamine (2.1 mL, 13 mmol) and cyclopentenone (1.1 mL, 13 mmol) were sequentially added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane: 15/85-25/75) to give the title compound (2.76 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[Br:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[O:23][CH3:24]>>[CH3:22][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([O:23][CH3:24])[CH:16]=1)[CH:13]=[N:12][C:11]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH:20]2.[Br:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[O:23][CH3:24]
Reactant: N#Cc1cnc(N)cn1
Agent: COc1cc(OC)c2cnc(Br)cc2c1
Product: COc1cc(OC)c2cnc(Nc3cnc(C#N)cn3)cc2c1

Procedure:
The title compound was prepared according to the method described in Synthesis 4-1-B from 2-amino-5-cyanopyrazine and 3-bromo-6,8-dimethoxyisoquinoline. The 3-bromo-6,8-dimethoxyisoquinoline was prepared as described in White et al., 1967. 1H NMR (d6-DMSO, 400 MHz) δ 10.98 (s, 1H), 9.12 (s, 1H), 8.80 (s, 1H), 8.72 (s, 1H), 8.34 (s, 1H), 6.86 (s, 1H), 6.57 (s, 1H), 3.98 (s, 3H), 3.92 (s, 3H). LCMS (2) Rt=2.88 min; m/z (ESI−) 306 (M−H); (ESI+) 308 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:2]([NH:1][C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (4.8 mmol) of methyl(S)-2-amino-3-(4-methoxyphenyl)propionate (cf. preparation 2-1) is diluted in 30 mL of dichloromethane. The solution is cooled in a bath of cold water, and 1.4 g (7.2 mmol) of 4-nitrophenyl chloroformate and 1.2 mL (7.2 mmol) of diisopropylethylamine are then added. After warming to room temperature, the reaction medium is stirred for 2 hours. The solution is poured into water and then extracted with dichloromethane. The organic phase is dried and then evaporated. The crude product obtained is used in the following step without further purification.
Reaction SMILES: [CH2:1]([CH:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O)[CH2:2][CH3:3].[BrH:14].S(=O)(=O)(O)O>O>[Br:14][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH3:3]
Reactant: CCCC(CCC)CCCCCO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCC(CCC)CCCCCBr
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To a 50 mL flask containing 6-propylnonan-1-ol (4,92 g, 26,4 mmol) was added hydrobromic acid 48% (12 mL, 105,6 mmol, 4 eq.) and conc. sulfuric acid (1,4 mL, 26,4 mmol, 1 eq.) and the mixture was heated to reflux (95 ° C.) for 14 h. The reaction was cooled to room temperature before adding H2O (40 mL). The mixture was extracted with dichloromethane (3×120 mL) and the combined organic phases were washed with aqueous sodium bicarbonate (40 mL, 1 M). Drying over magnesium sulfate and evaporation gave 1-bromo-6-propylnonane (5,87 g, 89% yield) as a brown liquid. 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,40 (t, J=6,8 Hz, 2H); 1,86 (tt, J=6,8 Hz, J=6,8 Hz, 2H); 1,45-1,35 (m, 2H); 1,34-1,15 (m, 13H); 0,88 (t, J=6,8 Hz, 6H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 36,9; 36,0 (2C); 34,0; 33,5; 33,9; 28,7; 25,8; 19,8 (2C); 14,5 (2C).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1.C(N(CCCC)CCCC)CCC>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: Clc1ccc(Cl)nc1
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cn4)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine (0.2 ml) were heated at 160° C. for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 427.98 (C23H30CIN5O); MS (ESI): 428 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Fc1cccc(CCl)c1
Product: COc1ccc(O)c(Cc2cccc(F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][CH2:9][C@@H:10]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN(C(=O)[O-])C(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)nc1
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl{(2S)-2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-pyridinyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part c) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 30 min., the solution was concentrated and neutralized through a plug of silica (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
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].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[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:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]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[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

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), 1-methylpiperazine (9.80 μL, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (3 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 purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% 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′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (29 mg, 46.4%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).