Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CN(C)C=O.CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 8 ml of warm dimethylformamide and 12 ml of methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30°C and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazide is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is recrystallised from ethanol, melting point = 200°-201°C. In a thin layer chromatogram on silica gel RF43C = 0.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[C:15]([N+:27]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:56](OC2C=CC=CC=2)=[N:57][C:58]#[N:59])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)/[C:56](=[N:57]/[C:58]#[N:59])/[NH:27][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CCN(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1CCN(n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(4-methyl-piperazin-1-yl)-amine (0.008 mol, 3.96 g) in tetrahydrofuran (150 mL). Add triethylamine (0.018 mol, 1.84 g) and 10% platinum on carbon (1.3 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, and add pyridine (150 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.17 g). Stir at room temperature for 16 h and then heat to 70° C. for 8 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 60% acetone in hexanes as eluent to obtain the title compound (1.8 g, 43%) as an off-white solid. LC-MS m/z 499.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:14])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Oc1cnc(Cl)c2ccccc12
Solvent: CC#N
Product: COc1cnc(Cl)c2ccccc12
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M++1).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([OH:23])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:3][C:2]#[CH:1])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: C#CCBr
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 15 h

Procedure:
1.73 g (14.6 mmol) of propargyl bromide were added dropwise to a mixture of 3.00 g (9.74 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine, 4.0 g (29 mmol) of potassium carbonate and 100 ml of anhydrous dimethylformamide. The mixture was stirred at 20°-25° C. for about 15 hours and then poured into 400 ml of water. The solution was kept cold for a few hours, and the resulting crystals were then separated off, washed with water and dried under reduced pressure. Yield: 3.1 g (92%) of colorless crystals of melting point 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([S:36]([CH2:39][CH2:40]Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][N:10]([CH2:40][CH2:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:42])([F:28])[F:43])[CH:31]=3)(=[O:37])=[O:38])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: O=S(=O)(CCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1cccc(C(F)(F)F)c1
Yield: 19.2 %

Procedure:
To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.7 gram, 6.60 mmol) and collidine (2 ml) in acetonitrile (25 ml) was slowly added a solution of 2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl chloride (1.5 gram, 5.50 mmol) in acetonitrile (20 ml) and the resulting solution was heated at reflux temperature for 16 hours. After concentration in vacuo the residue was dissolved in ethylacetate and washed with aqueous sodium hydrogencarbonate solution. The resulting ethylacetate layer was successively washed with 1 N hydrochloric acid solution and aqueous sodium hydrogencarbonate solution. Subsequent flash chromatographic purification (petroleum ether/diethyl ether=1/2 (v/v)) gave an oil which was crystallised from diisopropyl ether to afford 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl]-1H-pyrazole (0.52 gram, 19% yield). Melting point: 118-119° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:5]([CH2:8][CH3:9])[C:6]=1Br.[Li]CCCC.CCCCCC.Cl[Si](C)(C)C.[C:36](=O)([O:40]CC)[O:37][CH2:38][CH3:39].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH2:38]([O:37][C:36]([C:2]1[N:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:5]([CH2:8][CH3:9])[CH:6]=1)=[O:40])[CH3:39]
Reactant: CCOC(=O)OCC
Reactant: CCn1c(-c2cccc3ccccc23)nc(Br)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)Cl
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC)c(-c2cccc3ccccc23)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-dibromo-1-ethyl-2-naphthalen-1-yl-1H-imidazole (3.80 g, 10 mmol) in anhydrous THF (60 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 6.88 ml, 11 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, after which chlorotrimethylsilane (1.188 g, 11 mmol, 1.1 eq.) is added. The resulting solution is stirred at −78° C. After 1 hour, n-BuLi in hexane (1.6 M, 6.88 ml, 11 mmol, 1.1 eq.) is added dropwise. The resulting mixture is stirred at −78° C. for 1 hr, followed by the addition of diethyl carbonate (3.54 g, 30 mol, 3.0 eq.). The resulting solution is stirred at −78° C. for 30 min, waned to rt slowly, and stirred for an additional 30 min at rt. Water (30 ml) is added to quench the reaction, and THF is evaporated under reduced pressure. The residue is extracted with EtOAc (30 ml×2). The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated to give the crude product, which is dissolved in THF (30 ml). To this THF solution is added tetrabutylammonium fluoride (1.1 eq.), and the resulting mixture is stirred at it for 2 hr. The solvent is evaporated under reduced pressure, and the residue is diluted with water (30 ml). The mixture is extracted with EtOAc (30 ml×3), washed with water and brine, dried over Na2SO4 and concentrated. Purification through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) affords 1-ethyl-2-naphthalen-1-yl-1H-imidazole-4-carboxylic acid ethyl ester. LCMS 295 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][C:19]([C:27]([F:30])([F:29])[F:28])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1>C(O)C>[C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([C:27]([F:28])([F:30])[F:29])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 95 (1.09 g, 2.43 mmol) in ethanol (8.1 ml) was added a solution of NaOH (2.43 ml, 2N, 4.86 mmol) followed by THF (1.6 ml). After stirring at room temperature for 1 h, the mixture was taken to dryness and crude 96 was used as is for the next step. LRMS (ESI): calc. 420.4; found 421.3 (MH)+.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1ccncc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccncc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 39 mg (45% of theory)
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:40](=[O:41])[CH2:39][N:23]2[CH2:24][CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]2=[O:21])[CH2:11][CH2:10]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (0.27 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.50-7.57 (m, 4H), 7.18-7.36 (m, 14H), 7.11-7.16 (m, 2H), 5.35 (s, 1H), 4.33-4.40 (m, 1H), 4.17 (d, J=16.6 Hz, 1H), 4.10 (d, J=15.7 Hz, 1H), 3.77-3.85 (m, 1H), 3.34 (t, J=6.7 Hz, 2H), 2.93-3.02 (m, 1H), 2.75-2.85 (m, 1H), 2.72 (t, J=6.4 Hz, 2H), 2.53-2.64 (m, 1H), 1.19-1.40 (m, 4H).
Reaction SMILES: C[C:2]([C:5]1[CH:6]=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:8]=[C:9]([C:12](C)(C)C)[C:10]=1[OH:11])(C)C.OC1C(C)=CC(C=O)=CC=1C.CC(C1C=C(C=C(C(C)(C)C)C=1O)C=O)(C)C>>[OH:11][C:10]1[C:5]([CH3:2])=[CH:6][C:7]([CH2:16][N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:8][C:9]=1[CH3:12]
Reactant: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(CN2CCNCC2)cc(C)c1O

Procedure:
This was prepared using the general methodology described for the preparation of 1-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylpiperazine except that 4-hydroxy-3,5-dimethylbenzaldehyde replaced the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde.
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:23][C:24]1(C)[C:28](C)(C)OB(C(C)=C)O1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:23]=[C:24]([C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:28]
Reactant: Ic1cccc2c1oc1ccccc12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cccc2c1oc1ccccc12
Yield: 81.9 %

Procedure:
4-Iododibenzo[b,d]furan (25 g, 85.0 mmol) and potassium phosphate (58.7 g, 255 mmol) were dissolved in 500 mL of toluene and 50 mL of water. The reaction was purged with nitrogen for 20 minutes and then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.98 mL, 85 mmol), Pd2(dba)3 (1.55 g, 1.7 mmol) and S-Phos (2.79 g, 6.8 mmol) were added. The reaction was refluxed for 18 hours. After cooling the reaction to room temperature, 100 mL of water was added, the organic and aqueous layers were separated, and the aqueous layer was extracted twice with 100 mL of ethyl acetate. The organic layers were passed through a plug of silica gel, eluting with DCM. After evaporation of the solvent, the crude product was subjected to column chromatography (SiO2, 3% ethyl acetate in hexane to 5% ethyl acetate in hexane, v/v) to yield 14.5 g (82%) of pure product.
Reaction SMILES: C[Mg]Cl.[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[CH:13](OCC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.O.C(O)(=O)C>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: C#CCCCCCCCl
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(C#CCCCCCCCl)OCC
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer was placed a solution of methyl magnesium chloride (89.7 g: 1.2 mol) in tetrahydrofuran (370.0 g), and stirred at a solution temperature of from 45 to 50° C. The 8-chloro-1-octyne (144.6 g: 1.0 mol) was dropwise added thereto at a reaction mixture temperature of from 50 to 60° C. over one hour, and then stirred at from 60 to 65° C. for 5 hours. A solution of triethyl orthoformate (177.8 g: 1.2 mol) in toluene (120.0 g) was then dropwise added thereto at a reaction mixture of from 80 to 85° C. over 30 minutes, and stirred at from 90 to 95° C. for 6 hours. After completion of the reaction was confirmed by gas chromatography, acetic acid (57.0 g), ammonium chloride (35.0 g) and water (400.0 g) were added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% sodium hydroxide solution (170.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 9-chloro-1,1-diethoxy-2-nonyne [bp: 138-142° C./0.13 KPa, 185.8 g, 0.75 mol]. [Yield: 75.3%]
Reaction SMILES: [CH2:1](/[C:3](=[CH:11]\[CH3:12])/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>CO>[CH2:11](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:12]
Reactant: C/C=C(/C=C/C(=O)OCC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C(/C=C/C(=O)O)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Ethyl (E,E)-4-ethyl-2,4-hexadienoate (134 g) was dissolved in methanol (200 ml) and 1N aqueous sodium hydroxide (880 ml) was added to the solution. The resulting mixture was stirred at room temperature for 20 hours under nitrogen atmosphere. After removal of methanol, the residual aqueous solution was washed with ether. The aqueous layer was acidified with conc. hydrochloric acid and then extracted with three portions of ethyl acetate (500 ml33 3). The combined extracts were washed with brine, dried over magnesium sulfate and then evaporated to dryness to give a white powder which was crystallized from ether to give (E,E)-4-ethyl-2,4-hexadienoic acid (108 g).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:26])([CH3:24])[CH3:25])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 58.1 %

Procedure:
A mixture of 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (290 mg, 0.84 mmol) and 10% palladium on activated carbon (120 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-propan-2-ol (170 mg, 58%): LC/MS m/e calcd for C23H28N2O [M+H]+ 349.49, observed 349.4; 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (d, J=4.5 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.38-7.43 (m, J=8.3 Hz, 2H), 7.23-7.28 (m, J=8.1 Hz, 2H), 7.00 (dd, J=7.7, 4.9 Hz, 1H), 6.29 (s, 1H), 4.13 (t, J=7.8 Hz, 1H), 2.02-2.21 (m, 2H), 1.56-1.84 (m, 5H), 1.39-1.51 (m, 8H), 1.12-1.27 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([CH3:24])[CH2:12]2)(=[O:10])=[O:9])=[C:4]([CH3:25])[CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[C:26]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@H:13]([CH3:24])[CH2:12]2)(=[O:9])=[O:10])=[C:4]([CH3:25])[CH:3]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Ar was bubbled through a solution of 1,1-dimethylethyl (2R)-4-[(4-bromo-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 18) (4.34 g, 10.0 mmol) in dry DMF (40 ml) for 30 min, then Zn(CN)2 (0.647 g, 5.51 mmol), Pd2(dba)3 (0.275 g, 0.300 mmol) and DPPF (0.333 g, 0.601 mmol) were added and the resulting brown solution stirred at 120° C. under Ar for 1 h. The mixture was cooled to room temperature, concentrated under vacuum and the residue partitioned between DCM (100 ml) and water (100 ml). The aqueous layer was extracted with DCM (2×50 ml), then the combined organic layers passed through a hydrophobic frit. Concentration gave a brown residue that was purified by flash chromatography (silica; Flash 40M; linear gradient (8-66%) EtOAc in isohexane) to give the title compound as a viscous pale yellow oil (3.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24]([O:40][CH3:41])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:28]([C:26]1[CH:25]=[C:24]([O:40][CH3:41])[N:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:27]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(OC)n3)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 0.633 g (2.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.700 mg (2.28 mmol) (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone and 954 mg (6.90 mmol) potassium carbonate in 5.0 mL NMP was stirred for 8 h at 130° C. After cooling the reaction mixture to RT the precipitate formed was filtered off and purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac. The residue obtained was digested in DMF and the product remaining as a solid was suction filtered and dried i. vac. The mother liquor was again purified by preparative HPLC, the fractions containing product were combined and evaporated down i. vac. The residue was triturated with ethanol, the solid product was suction filtered and dried i. vac.