Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1)#[N:2].[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a solution of 83 mg of (7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 80 mg of tert-butyl piperidin-4-yl-carbamate in 10 mL of chloroform, 24 μL of acetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 136 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 76 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][O:20][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][O:20][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCO3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Yield: 87.9 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.52 mL, 4.8 mmol) was added to a stirred solution of chloride 222 (359 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 223 (390 mg, 88%) as a yellow solid: mp (MeOH/DCM) 192-194° C.; 1H NMR δ 7.45 (s, 1H, H-9), 7.35 (br s, 1H, NH), 6.96 (s, 1H, H-5), 6.23 (s, 2H, H-7), 3.35-3.39 (m, 2H, CH2N), 2.42 (t, J=6.7 Hz, 2H, CH2N), 2.18 [s, 6H, N(CH3)2]; 13C NMR δ 158.9, 155.2, 148.7, 146.9, 125.3, 103.2, 101.6, 95.9, 57.8, 45.2 (2), 38.6. Anal. calcd for C12H15N5O3: C, 52.0; H, 5.5; N, 25.3. Found: C, 52.1; H, 5.5; N, 25.3%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30](O)=[O:31])[CH:3]=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]([NH:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=2)=[O:31])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)O)cccc34)cc(Cl)nc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)Nc5cccc(C(F)(F)F)c5)cccc34)cc(Cl)nc21
Yield: 88.4 %

Procedure:
5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (92 mg, 88% yield) was prepared as described for Example 11-D starting from 5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-1-naphthoic acid (80 mg, 0.17 mmol) and 3-(trifluoromethyl)benzenamine (55 mg, 0.34 mmol). MS m/z: 612 [M+1].
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[C:20]1=[O:29])[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[C:20]1=[O:29])[CH2:28]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C1C2CC3CC(C2)CC1(O)C3
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(CC(C3)C1=O)C2
Yield: 94 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-hydroxyadamantane-2-one was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-acryloyloxyadamantane-2-one (yield: 94%, white solid) was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([C:12]=1[CH3:13])[CH:10]=[O:11])(=[O:3])[CH3:2].[CH:19]([Mg]Br)([CH3:21])[CH3:20]>O1CCCC1>[C:1]([O:4][C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([CH:10]([OH:11])[CH:19]([CH3:21])[CH3:20])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 5-acetoxy-4-t-butyl-2-hydroxy-6-methylbenzaldehyde was dissolved in 10 ml of anhydrous tetrahydrofuran, 10 ml of isopropylmagnesium bromide (0.76M in tetrahydrofuran) was added dropwise and the mixture was stirred at room temperature for 30 minutes. After the reaction was quenched with distilled water, the reaction mixture was combined with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with saturated brine, then dried over anhydrous magnesium sulfate, and then concentrated to give 0.44 g of 4-acetoxy-5-t-butyl-2-(1-hydroxy-2-methylpropyl)-3-methylphenol as a yellow amorphous material (yield 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=O)=O)=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[S:33][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:9][N:10]=2)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCC1CCC(C(=O)NNC(=O)c2ccncc2)CC1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2nnc(-c3ccncc3)s2)CC1

Procedure:
A solution of 4-pentyl-cyclohexanecarboxylic acid N′-(pyridine-4-carbonyl)hydrazide (Preparation 19, 50 mg, 0.158 mmol) and Lawesson's reagent (127 mg, 0.32 mmol) in toluene (2 ml) was heated under reflux for 18 h. The solvent was evaporated and the residue purified by flash chromatography (IH-EtOAc, 4:1 then EtOAc) to afford the title compound: RT=5.02 min; m/z (ES+)=316.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br>Br.C(Cl)Cl.[OH-].[Na+]>[Br:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2ccccc2cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc2ccccc2c1Br
Temperature: 110 °C
Yield: 34.8 %

Procedure:
In a 40 mL screw-top vial with a stirbar was added 3-methyl-isoquinoline (6.00 g, 41.9 mmol) in hydrobromic acid (6 mL), followed by the dropwise addition of bromine (2.2 mL, 42.7 mmol, 1.02 eq). The entire suspension was heated at 100-120° C. for 24 hr. The reaction mix was cooled and diluted with DCM (100 mL) and 1N NaOH added slowly to neutralize the reaction. The organic layer was collected and dried over Na2SO4 and concentrated to a dark orange oil. The crude reaction was purified using Biotage MPLC system (40M column size, 0-15% Ethyl Acetate/Heptane over 30CV) giving a tan crystalline solid as the desire product (3.48 g, 14.57 mmol, 34.8%). 1H NMR (CDCl3, 400 MHz): δ 9.01 (s, 1H), δ 8.12-8.10 (d, 1H), δ 7.87-7.85 (d, 1H), δ7.72-7.68 (dt, 1H), δ 7.54-7.50 (dt, 1H), δ 2.80 (s, 3H); LRMS (m/z): 224, 222 (M+H).
Reaction SMILES: CI.[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([OH:16])[CH:8]=1)=[O:6].[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c2cc[nH]c2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c2cc[nH]c2c1
Yield: 49 %

Procedure:
Methyl iodide (0.72 mL, 11.5 mmol, 1.1 equiv.) was added dropwise, over 10 minutes, to a stirred solution of 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (2 g, 10.5 mmol, 1 equiv.) and potassium carbonate (1.3 g, 15.7 mmol, 1.5 equiv.) in acetone (20 mL) at room temperature and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, the residue dissolved in ethyl acetate (20 mL) and washed with saturated aqueous solution of NaHCO3 (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and the solvent removed under vacuum to afford 4-methoxy-1H-indole-6-carboxylic acid methyl ester, 1.1 g (49% yield). LC @215 nm; Rt 1.23: 91%, m/z (ES+): 206 (M+H+.); δH (400 MHz; MeOD) 7.74 (1H, s), 7.15 (1H, m), 7.03 (1H, d), 6.46 (1H, m), 3.86 (3H, s), 3.80 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: COC(=O)c1ccccc1CSc1ccc(F)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(F)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 54.8 %

Procedure:
Following General Procedure B, the title compound (1.6 g, 55%) was prepared from methyl 2-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (1.8 g, 6.19 mmol) and benzofuran-2-sulfonyl chloride (1.3 g, 6.19 mmol) in pyridine (10 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:28]([C:36](O)=[O:37])[C:27](=[O:39])[N:26]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:36]([C:28]2[C:27](=[O:39])[N:26]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:25]([CH3:24])[C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:37])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cn1c(-c2ccncc2)c(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(-c5ccncc5)n(C)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (628.9 mg, 2.001 mmol) and 1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (520 mg, 1.76 mmol) (1.679 g of a ˜30% by weight solution of acid in DMF) was dissolved in DCM (20 ml) and HATU (1.042 g, 2.740 mmol) was added. The reaction was stirred under nitrogen at room temperature overnight, and then filtered. The filtered solid was washed with dichloromethane, and the filtrate was concentrated and purified on silica gel (DCM→50:1→25:1→10:1 DCM/MeOH). The fractions with product were collected, concentrated, and purified on silica gel (30:1→20:1→10:1 DCM/MeOH). Fractions with product collected, concentrated, and purified again on silica gel (25:1→20:1 DCM/MeOH). Fractions with pure product collected and concentrated to give desired N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide (225.9 mg, 0.382 mmol, 22% yield). MS (ESI pos. ion) m/z: 592 (MH+). Calc'd exact mass for C33H26FN5O5: 591. 1H NMR (400 MHz, CDCl3): 10.96 (s, 1H), 8.88 (d, J=4.0 Hz, 2H), 8.48 (d, J=6.0 Hz, 1H), 7.83 (d, J=12 Hz, 1H), 7.65-7.47 (m, 8H), 7.41 (s, 1H), 7.30 (d, J=10.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 4.05 (s, 6H), 3.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+].CO>O>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]#[C:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(C#CC(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C#CC(C)(C)C)ccc1C(=O)O
Yield: 94.8 %

Procedure:
Ethyl 2-methyl-4-(3,3-dimethylbut-1-ynyl)benzoate (4.8 g, 0.020 mol) and lithium hydroxide (2.8 g, 0.058 mol) were placed in 3:1 mixture of methanol:water (80 mL) and heated at 60° C. for 3.5 h. TLC and LCMS indicated product formation. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid crashed out which was filtered and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (4.1 g, 97%) as a solid. m/z=215.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[C:29]([NH2:30])=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][N:26]=1)=O)C.C([O-])([O-])=O.[K+].[K+]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:23](=[O:22])[C:25]3=[N:26][O:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[C:29]3[N:30]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)onc3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 180 °C

Procedure:
A suspension of N-(4-chloro-phenyl)-4-isopropyl-benzamide (20.0 mg, 0.073 mmol) in thionyl chloride (0.5 mL) is heated at 80° C. for 1.5 h before thionyl chloride is removed in vacuo. The reaction residue is then taken in anhydrous acetonitrile (1.5 mL), followed by the addition of 4-amino-5-phenyl-isoxazole-3-carboxylic acid ethyl ester from step B (18.7 mg, 0.081 mmol) and anhydrous K2CO3 (25.2 mg, 0.182 mmol). The reaction mixture is heated under nitrogen atmosphere at 180° C. in a microwave for 2 h, then cooled down to room temperature. K2CO3 is removed by filtration. The filtrate is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.37 (dd, 2H), 7.53 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H), 7.11 (m, 4H), 2.87 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated for C26H20ClN3O2 (M+H+) 442.1. Found: 442.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21](F)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(F)nc3)cnc12
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(N4CCOCC4)nc3)cnc12
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-3-(6-fluoro-pyridin-3-yl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (64 mg, 0.14 mmol) and morpholine (0.06 mL, 0.70 mmol) in DMSO (1 mL) was heated at 180° C. and stirred for 30 min. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 ml). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to yield the crude 6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(6-morpholin-4-yl-pyridin-3-yl)-imidazo[1,2-a]pyridine-7-carbonitrile intermediate (67.8 mg) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[S:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[S:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)cc1
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromophenol (35.0 g, 145 mmol) in acetic acid (250 ml) was treated with N-iodosuccinimide (32.5 g, 145 mmol) at RT. The reaction mixture was stirred at RT for 18 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with 1% methanol in chloroform to afford the title compound as a brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]=[C:13]([CH3:15])[CH3:14].CCOC(C)=O>[Pd]>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(O)c(C=C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(CC(C)C)c1
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-(2-methylprop-1-enyl)benzoate 66.20B (0.320 g, 1.6 mmol) in EtOAc (2.00 mL, 20 mmol) at 23° C. was added palladium on carbon (0.017 g, 0.16 mmol). The reaction was stirred under an atmosphere of hydrogen (0.0031 g, 1.6 mmol) for 16 hours. The reaction mixture was then filtered and concentrated in vacuo to give a clear oil. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield 66.20C as a colorless oil (0.256 g, 79% yield)
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCCO)CC4)n3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
120 mg (0.34 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine were suspended in 3 ml of DMF with 100 μl (0.68 mmol) of 4-bromobutyl acetate and 56 mg (0.41 mmol) of potassium carbonate and stirred at 60° C. overnight. The reaction mixture was taken up in dichloromethane, washed once each with a concentrated sodium hydrogencarbonate solution and a 1N hydrochloric acid solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The protecting group is cleaved off by means of a 1N NaOH solution in methanol: The reaction mixture was stirred at room temperature and subsequently evaporated. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.