Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([C:35](=[O:41])[CH2:36][C:37](=O)[CH2:38][CH3:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:38](/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:39]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.195 mmol) of Intermediate 46 and 34 mg (0.2 mmol) of Intermediate 16 to yield 32 mg of Example 8: TLC (DCM/MeOH, 4/1): Rf=0.63; 1H NMR (DMSO-d6, 300 MHz) δ11.57 (d, 1H, J=9.6), 7.97 (m, 2H), 7.86 (d, 1H, J=7.2), 7.42 (m, 5H), 7.18 (d, 2H, 8.4), 6.87 (d, 2H, J=8.4), 5.61 (s, 1H), 4.20 (t, 2H, J=6.6), 4.14 (m, 1H), 3.22 (m, 2H), 2.94 (t, 2H, J=6.6), 2.83 (dd, 1H, J=13.8, 9.3); low resolution MS (ES+)m/e 543 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:31]=1)=O)(C)(C)C>>[N:33]1[CH:34]=[CH:35][C:30]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:31][C:32]=1[C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2ccncc2)c1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[2,4′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K58) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (86 mg).
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[N:11][C:10]=1[CH3:17].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=1>CCOCC>[OH:25][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:26])=[CH:19][CH:20]=1)[CH2:17][C:10]1[C:9]([CH3:8])=[N:14][C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of phenyllithium in 150 milliliters 7:3 benzene-ether (0.1 mole) at 0° C. was slowly added a solution of 13.6 grams of tetramethylpyrazine (0.1 mole). The mixture was stirred at room temperature for 2 hours and heated under reflux for 1.5 hours. The mixture was cooled to 0° C., and a solution of 12.0 grams of p-tolualdehyde (0.1 mole) in 50 milliliters of ether was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then treated in the manner of Example I. The crude product was crystallized from ether to yield 10.7 grams of product (42%) as fine white needles, m.p. 99°-101° C. Analysis Calculated for C16H20N2O: C,74.96; H,7.86; N,10.93 Found: 75.19; 7.96; 10.88
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][C:4]([CH3:9])([CH3:5])[C:3]([OH:10])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: Oc1ccc(Cl)cc1OCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(Cl)cc1OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium hydroxide (0.253 g) was added to a stirred mixture of the product from step (i) (1.5 g) and 1,1,1-trichloro-2-methylpropanol (3.0 g) in acetone (40 ml) at 0° C. After stirring at RT for 1 h the mixture was cooled to 0° C. and a further portion of sodium hydroxide (0.253 g) added. After repeating for a third time, the mixture was stirred at RT overnight, then quenched with 2M hydrochloric acid and extracted with ethylacetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with diethylether:isohexane (1:1). Yield 1.4 g
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[OH:26][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCCC1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCCC3)ccc1OCC2

Procedure:
10-Bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 22.4 mg of 10-[2-(1-hydroxycyclopentyl)ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 338 (M)+. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=2.1 Hz, 1H), 7.84-7.71 (m, 1H), 7.54 (d, J=23.6 Hz, 1H), 7.29 (dd, J=8.5, 2.1 Hz, 1H), 7.10 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.28 (s, 1H), 4.49 (d, J=12.6 Hz, 4H), 1.94-1.84 (m, 4H), 1.82-1.62 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:10])[CH2:4][C:5]#[C:6][C:7]([CH3:9])=[CH2:8].[CH3:11][C:12]([C:19]#[CH:20])=[CH:13][CH2:14][CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:11][C:12]([C:19]#[C:20][CH2:9][C:7](=[CH2:8])[CH2:6][C:5]#[C:4][C:3]([CH3:10])=[CH2:2])=[CH:13][CH2:14][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: C=C(C)C#CCC(=C)CCl
Reactant: C#CC(C)=CCCC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C#CCC(=C)CC#CC(C)=CCCC(C)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.8 %

Procedure:
Using a modification of the procedure suggested by T. Jeffery, Tetrahedron Lett., 30, 2225 (1989), a mixture of 175 mg (1.13 mmoles) of 6-chloromethyl-2-methyl-1,6-heptadien-3-yne (produced in accordance with Example XII), 139 mg (1.02 mmoles) of 6-methyl-5-octen-7-yn-2-one (produced in accordance with Example II), 220 mg (1.6 mmoles) of anhydrous potassium carbonate, 50 mg (0.50 mmole) of cuprous chloride, and 30 mg (0.13 mmole) of benzyltriethylammonium chloride in 1.00 mL of acetonitrile (HPLC-grade) was stirred vigorously at room temperature for 21 hours, during which time the mixture was maintained under a nitrogen atmosphere. Isolation of the product as described in the procedure of Example III afforded, after fractional evaporative distillation, 207 mg (80% yield) of the named unsaturated ketone: boiling point 122°-135° C. (bath temperature, 0.25 mm). The identity and purity of this compound were ascertained by highfield (300 MHz) proton NMR analysis. The proton NMR spectrum of the named ketone exhibited singlets at δ1.77 and 1.86 (two vinyl CH3 's), a singlet at δ2.12 (CH3C=O), a triplet (J=7.3Hz) at δ2.47 (CH2C=O), two singlets at δ3.08 and 3.09 (4H's, hydrogens bonded to C-9 and C-11), a singlet at δ5.15 (3 vinyl H's), a singlet at δ5.21 (one vinyl H), and a triplet at δ5.70 (vinyl hydrogen bonded to C-5).
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[C:7]3[CH2:14][CH2:13][O:12][C:8]3=[CH:9][CH:10]=2)[CH:5]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:4]1)=O.Cl.C(O)C>C(O)C>[CH2:14]1[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[C:8]2[O:12][CH2:13]1)[NH:3][CH2:4][CH:5]3[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)NCCC1CN(C=O)c2ccc3c(c21)CCO3
Agent: Cl
Solvent: CCO
Product: CCC(=O)NCCC1CNc2ccc3c(c21)CCO3
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-[2-(6-formyl-1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide (0.18 g, 0.62 mmol.) in ethanol (5 mL) was added saturated hydrogen chloride/ethanol (15 mL). The mixture was stirred for 1.5 hours at 80° C. and then cooled. The solvent was removed in vacuo to afford the title compound as an amorphous product.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7](O)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si]([C:20]#[N:21])(C)C>C1C=CC=CC=1.[Zn+2].[I-].[I-]>[C:20]([CH:7]1[S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=2[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]1=2)#[N:21]
Reactant: OC1Sc2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: N#CC1Sc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6H-dibenzo[b,d]thiopyran-6-ol (2.6 g; 12 mmol) was dissolved in anhydrous benzene (50 ml). Trimethylsilylcyanide (4.5 ml; 36 mmol) and a catalytic amount of ZnI2 were added to the solution, then the reaction mixture was stirred for 20 hours at room temperature. The solution was washed with 1N NaOH, dried and evaporated. The residue was crystallized from diethyl ether to give 6-cyano-6H-dibenzo[b,d]thiopyran as white solid (2.3 g; 10 mmol); m.p. 114°-116° C. By proceeding analogously the following compounds were obtained:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[C:35]1([C:41]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:46][CH2:45][CH2:44][NH:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:47]1([C:41]2([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:46][CH2:45][CH2:44][N:43]([C:32](=[O:34])[CH2:31][N:15]3[CH2:16][CH2:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]3=[O:13])[CH2:42]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: c1ccc(C2(c3ccccc3)CNCCO2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.060 g, 0.313 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.059 g, 0.198 mmol) and 2,2-diphenylmorpholine (0.050 g, 0.209 mmol, CAS 77373-34-3) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.43 (s, 20H), 4.15 (s, 2H), 4.09 (s, 2H), 3.39-3.44 (m, 2H), 3.28-3.33 (m, 2H), 3.27 (t, J=6.4 Hz, 2H), 2.57 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 517 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH:13]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C1C=CC=CC=1.CCOCC.[BrH:35]>C(O)(=O)C>[BrH:35].[NH2:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH:13]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1C(=O)Nc2ccccc2SC1c1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1C(=O)Nc2ccccc2SC1c1ccccc1

Procedure:
5.4 g of the compound obtained in Example 2 was dissolved in a 25% solution of hydrogen bromide in acetic acid. After the lapse of 2 hours, 15 ml of acetic acid was added to the solution and the resulting mixture was stirred for an hour. After the addition of ether, the precipitated crystals were separated by filtration and washed with ether to obtain 4.0 g of the desired compound.
Reaction SMILES: Br[C:2]1[N:3]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:23])[CH:5]=2.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.CC([O-])=O.[K+]>COCCOC.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]>[Cl:23][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:32]3[CH2:34][CH2:33]3)[N:3]2[C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)=[CH:8][CH:7]=1
Reactant: OB(O)C1CC1
Reactant: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: CCCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 85 °C
Reaction time: 7 h
Yield: 47.1 %

Procedure:
To a stirred solution of ethyl 3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate 1 (Example 2, Step 3; 100 mg, 0.19 mmol) in DME (20 mL) under inert atmosphere were added cyclopropyl boronic acid (16.6 mg, 0.19 mmol), KOAc (56.8 mg, 0.58 mmol) at RT and degassed for 15 min. To this, was added Pd(dppf)Cl2 (28.3 mg, 0.038 mmol), heated to 85° C. and stirred for 7 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography using 8-10% EtOAc/Hexanes to afford 43 mg of compound 2 with 51% purity. The impure material was further purified by preparative HPLC to afford pure compound 2 (25 mg, 27%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.83 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.26-7.22 (m, 2H), 7.14-7.08 (m, 2H), 4.34 (q, J=7.5 Hz, 2H), 4.21 (t, J=7.0 Hz, 2H), 2.03-1.98 (m, 2H), 1.76-1.75 (m, 1H), 1.05-1.01 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 1.00 (t, J=7.0 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 89.7%; m/z 480.5 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.83 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.[Pt]=O>[CH:19]1([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Reactant: O=C1CCCC1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC2CCCC2)cc1OC
Yield: 100 %

Procedure:
500 mg of N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-propanediamine and 0.21 ml of cyclopentanone were dissolved in 5 ml of ethanol, followed by the addition of 10 mg of platinum oxide to carry out hydrogenation at a room temperature under 1 atm for 6 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under a reduced pressure to obtain 660 mg of the title compound as a yellow oil (yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)[CH:20]=[O:21]>S(Cl)(Cl)=O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:20](=[O:21])[C:12]([CH3:13])=[CH2:11])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.2 g of 4-(E)-ethyloxycarbonyloxycinnamic acid in 20 ml of thionyl chloride and 0.05 ml of N,N-dimethylformamide was heated under reflux for 3 hours. Subsequently, excess thionyl chloride was distilled off. 3.3 g of 4-hydroxybutyl methacrylate were added dropwise to a solution of the resulting 4-(E)-ethyloxycarbonyloxycinnamoyl chloride in 15 ml of pyridine while stirring at 0° C. within 15 minutes. The reaction mixture was stirred at room temperature for a further 12 hours, then poured into water and extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification on silica gel with hexane/ethyl acetate (vol. 7:3) gave 3 g of 4-methacryloyloxybutyl (E)-3-(4-ethoxycarbonyloxyphenyl)acrylate, m.p. 54°-56° C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(C(=O)c2ccco2)CC1
Agent: Cl
Product: O=C(CN1CCN(C(=O)c2ccco2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 35.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(furan-2-carbonyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 223, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(furan-2-carbonyl)piperazin-1-yl)acetamido)propanamide (17 mg, 35.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.22 (s, 1H), 8.04 (d, 1H), 7.84 (s, 1H), 7.61 (d, 2H), 7.26-7.31 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 5H), 6.63 (dd, 1H), 4.71 (m, 1H), 4.53 (s, 2H), 3.73-3.77 (m, 2H), 3.65 (s, 2H), 3.06 (m, 2H), 2.51-2.54 (m, 4H). MS (EI) for C33H33FN4O6. found 601.6 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg, 3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53 mL) was subjected to MW irradiation at 140° C. for 30 min. The RM was treated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, brine and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=462.1-464.0 [M+H]+, m/z=460.1-462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84 (dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz, 2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH2:29][CH3:30])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C@H:31]1([NH2:38])[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1>>[NH2:37][C@H:34]1[CH2:35][CH2:36][C@H:31]([NH:38][C:2]2[CH:9]=[C:8]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:13]4[C:12]([CH2:29][CH3:30])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:32][CH2:33]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CCc1cn(-c2ccc(C#N)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-aminocyclohexylamino)-4-{3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (41h) instead of compound (1e) and using trans-cyclohexane-1,4-diamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), a compound (the second stage yield: 57%) was prepared as a white solid using 2-(trans-4-aminocyclohexylamino)-4-{(3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8]C(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:26][C:27]([CH3:46])([CH3:45])[CH2:28][O:29][C:30]1[N:35]=[C:34]([C:36]([OH:38])=O)[CH:33]=[N:32][C:31]=1[N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.N[C@H](CO)CC(C)C>>[OH:1][CH2:2][C@@H:3]([NH:8][C:36]([C:34]1[CH:33]=[N:32][C:31]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:30]([O:29][CH2:28][C:27]([CH3:26])([CH3:46])[CH3:45])[N:35]=1)=[O:38])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)(C)COc1nc(C(=O)O)cnc1N1CCOCC1
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCOCC2)c(OCC(C)(C)C)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2,2-dimethyl-propoxy)-5-morpholin-4-yl-pyrazine-2-carboxylic-acid and (S)-leucinol (commercially available). m/z (ES+): 395.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[CH:14][N:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:10]2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH:14]1[N:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:10]2[C:11]=1[CH2:12][CH2:13][NH:8][CH2:9]2
Reactant: CCOC(=O)Cn1cc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1cc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 2 ml of methylene chloride was dissolved 0.11 g (0.36 mmol) of ethyl 5-t-butoxycarbonyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-acetate, and under ice-cooling, 0.4 ml of CF3CO2H was added to the residue and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:38]1[CH:42]=[C:41]([CH2:43][C:44](O)=[O:45])[N:40]=[CH:39]1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:44](=[O:45])[CH2:43][C:41]2[N:40]=[CH:39][NH:38][CH:42]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 4-imidazoleacetic acid hydrochloride (19.5 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.