Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][C:49]#[C:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58]([C:60]2[CH:61]=[C:62]([S:66]([C:69]3[CH:70]=[C:71]4[C:76](=[C:77]([CH3:79])[CH:78]=3)[N:75]=[CH:74][C:73]([C:80]([NH2:82])=[O:81])=[C:72]4[NH:83][C:84]3[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=3)(=[O:68])=[O:67])[CH:63]=[CH:64][CH:65]=2)=[O:59])=[CH:53][C:52]=1[CH3:92]>>[CH3:91][O:90][C:86]1[CH:85]=[C:84]([NH:83][C:72]2[C:71]3[C:76](=[C:77]([CH3:79])[CH:78]=[C:69]([S:66]([C:62]4[CH:63]=[CH:64][CH:65]=[C:60]([C:58](=[O:59])[NH:57][C:54]5[CH:55]=[CH:56][C:51]([C:50]#[C:49][CH2:48][CH2:47][CH:46]=[O:45])=[C:52]([CH3:92])[CH:53]=5)[CH:61]=4)(=[O:68])=[O:67])[CH:70]=3)[N:75]=[CH:74][C:73]=2[C:80]([NH2:82])=[O:81])[CH:89]=[CH:88][CH:87]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCO)c(C)c5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCC=O)c(C)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 112, using Intermediate 75 as a substrate. ES/MS calcd. for C37H32N4O6S 660.2. Found m/z=661 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.8 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (100 mg, 0.21 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (45 mg, 0.64 mmol, 3.00 equiv), piperidine (9 mg, 0.11 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 24 mg (24%) of the title compound as a white solid, LC-MS (ES, m/z): 524 [M+H]+. H-NMR (CDCl3, ppm): 8.397 (1H, s), 7.628˜7.427 (3H, m), 7.283˜7.231 (1H, m), 7.203˜7.124 (2H, m), 6.9796.866 (2H, m), 6.722 (1H, s), 5.717 (2H, s), 4.973 (1H, s), 4.8˜3.1 (4H, m), 2.581˜2.045 (5H, m), 1.329˜1.228 (2H, m), 0.893 (2H, m).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:38][C@H:37]([CH3:39])[O:36][C@H:35]([CH3:40])[CH2:34]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([OH:29])=O)[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1.C(N(CC)CC)C>CN(C=O)C.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:34][C@H:35]([CH3:40])[O:36][C@H:37]([CH3:39])[CH2:38]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[O:29])[CH:25]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)O)c(F)c2F)C[C@H](C)O1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)N3CCOCC3)c(F)c2F)C[C@H](C)O1
Yield: 78.5 %

Procedure:
2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-oxoacetic acid (Intermediate 118, 150 mg, 0.26 mmol), HATU (121 mg, 0.32 mmol), morpholine (0.025 ml, 0.29 mmol) and triethylamine (0.055 ml, 0.40 mmol) in DMF (5 ml) were stirred at room temperature for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were washed three times with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (130 mg, 0.204 mmol, 77%)
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH:10]1[OH:16])=O>C1(C)C=C(C)C=C(C)C=1>[OH:16][CH:10]1[CH2:11][CH:12]2[CH2:13][CH2:14][CH:9]1[C:7](=[O:6])[NH:15]2
Reactant: COC(=O)C1CCC(N)CC1O
Solvent: Cc1cc(C)cc(C)c1
Solvent: CC(=O)O
Product: O=C1NC2CCC1C(O)C2
Temperature: 25 °C
Yield: 72.6 %

Procedure:
4-Amino-2-hydroxy-cyclohexanecarboxylic acid methyl ester acetic acid salt (6.6 g) was heated to reflux in mesitylene (60 ml) for 3 h. After cooling to rt, solvent was decanted and the crystals were washed with hexane three times to provide 2.9 g of 5-hydroxy-2-aza-bicyclo[2.2.2]octan-3-one (M+: 141).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#N)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:27].[Na+].Cl.[OH2:30]>>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:30])=[O:27])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (12.5 g, 0.0368 moles) (Preparation 15) in a mixture of industrial methylated spirits (80 ml) and deionised water (35 ml) was added sodium hydroxide (1.2 g, 0.13 moles) and the resultant mixture was heated under reflux for 17 hours during which time a clear solution was formed. The mixture was cooled to ambient temperature and was acidified by the addition of 1 M aqueous hydrochloric acid solution (105 ml) to give a suspension. The solid was collected by filtration and was dried under reduced pressure at 50° C. to give the title compound as a colourless solid (13.5 g), m.p. 241-249° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@@H:19]([OH:42])[C@H:20]([N:28]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@@H:19]([OH:42])[C@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](N)Cc2ccccc2)C1

Procedure:
Dissolve 2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-4-(3-methyl-butyl)-piperazine-1-carboxylic acid tert-butyl ester in methanol (3 mL) and add 10% palladium on carbon (29 mg). Stir under 1 atmosphere of hydrogen gas for 24 h and filter through a filtering agent, wash with methanol and concentrate to give the title compound which is used without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:15][CH2:16][CH2:17][N:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]1([CH3:27])[CH3:26]>O1CCCC1>[ClH:12].[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][CH2:16][CH2:17][N:18]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)CCCC(C)(C)N1CCN
Solvent: C1CCOC1
Product: CC1(C)CCCC(C)(C)N1CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.72 g (11.1 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride in 50 ml of tetrahydrofuran cooled to 0° C. under an N2 atmosphere add dropwise 2.04 g (11.1 mmole) of N-(2-aminoethyl)-2,2,6,6-tetramethylpiperidine. After the addition is complete, allow the reaction to stir at ambient temperature overnight. Monitor the progress of the reaction by thin layer chromatography on silica gel (acetonitrile: ammonium hydroxide; 9:1). When the reaction is complete, remove the solvent in vacuo. Dissolve the resulting oil in 50 ml of water. Add 50% sodium hydroxide until pH=14. Wash aqueous with 3×50 ml of diethyl ether. To aqueous layer add concentrated hydrochloric acid until pH=9. Extract with 3×50 ml of methylene chloride. Combine extracts and dry over sodium sulfate. Remove solvent in vacuo. Dissolve resulting oil in methanol and bubble hydrogen chloride gas through the solution until pH 1 is reached. Remove the solvent in vacuo. Recrystallize the solid in methanol/ethyl acetate to provide the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:27])[CH2:20][CH:21]2[C:24]([Cl:26])=[O:25])=[CH:17][CH:16]=1>C(N(CC)CC)C>[ClH:26].[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:27])[CH2:20][CH:21]2[C:24]([N:8]2[CH2:9][CH2:10][S:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:25])=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C(C(=O)Cl)CC2=O
Reactant: C1CCN(CC2CSCCN2)C1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C(=O)N1CCSCC1CN1CCCC1)CC2=O
Product: Cl
Yield: 42.1 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.97 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.39 ml of triethylamine and 1.23 g of 6-methoxy-3-oxoindan-1-carbonyl chloride, to afford 0.9 g of the title compound, melting at 225°-233° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1=[O:21].Cl.N.CS(C)=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:26])[CH:6]2[CH2:12][CH2:13][N:14]1[C:15](=[O:21])[CH2:16][CH2:17][CH2:18][C:19]1=[O:20]
Reactant: COc1ccc2[nH]cc(CCN3C(=O)CCCC3=O)c2c1
Reactant: CS(C)=O
Agent: Cl
Agent: N
Product: COc1ccc2c(c1)C(CCN1C(=O)CCCC1=O)C(=O)N2

Procedure:
145 mg of N-[2-(5-methoxyindol-3-yl)ethyl]glutarimide are dissolved in DMSO (30 μl) in a round-bottomed flask and concentrated HCl (72 μl) is added with stirring. The mixture is stirred overnight at room temperature. The crude product is neutralized with NH3 and then extracted with EtOAc. After separation on a silica plate, N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]glutarimide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1C(=O)N([I:20])C(=O)C1>S(O)(C(F)(F)F)(=O)=O>[Br:1][C:2]1[C:11]([I:20])=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc2ccc(Br)cc2cn1
Agent: O=S(=O)(O)C(F)(F)F
Product: Clc1cc2ccc(Br)c(I)c2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 7-Bromo-3-chloroisoquinoline (1.5 g, 6.19 mmol) was added NIS (1.4 g, 6.9 mmol). The flask was placed in an ice bath and treated with TfOH (40 mL) and stirred at RT overnight. The reaction mixture was carefully poured into ice, and the aqueous layer was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (Hexanes:DCM→1:1) to provide the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=O)[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C([O-])(C)C.[K+]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=[CH2:18])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1Cc2ccc(OCc3ccccc3)cc21
Temperature: 0 °C

Procedure:
H7.2 (13.0 g, 58.0 mmol) was dissolved in 300 mL THF. The resulting solution was cooled to 0° C. in an ice-water bath. Methyltriphenylphosphonium bromide (24.8 g, 69.6 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added and some yellow solid appeared. Potassium 2-methylpropan-2-olate (69.6 mL, 69.6 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was then added dropwise over an hour. The reaction was stirred at 0° C. for another hour and then quenched by addition of 200 mL saturated NaHCO3. The THF solvent was evaporated by vacuum and the residue was extracted twice with 200 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated in the presence of silica gel. The residue was purified by column chromatography with 10% EtOAc/hexane to afford H7.3 (4.1 g, 31.8%). MS ESI (pos.) m/e: 223.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][CH3:18])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (255 mg) in anhydrous DMF (1 ml) was added dropwise to a suspension of sodium hydride (40 mg) in anhydrous DMF (1 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Ethyl iodide (0.10 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature overnight. Saturated brine was added thereto and the resulting mixture was extracted with chloroform. Organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/chloroform=1/10) to obtain N-(4-iodophenyl)-N-ethylpyrimidin-2-amine (264 mg). NMR (H1, CDCl3): δ 1.23 (3H, t, J=6.8 Hz), 4.01 (2H, q, J=6.8 Hz), 6.57 (1H, t, J=4.9 Hz), 7.03-7.06 (2H, m), 7.70-7.74 (2H, m), 8.32 (2H, d, J=4.9 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(C(=O)Nc2ccc(-c3ccccc3)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: Cl
Temperature: 25 °C
Yield: 115.4 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.29 g, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol), and phenylboronic acid (81 mg, 0.66 mmol) in toluene (5 mL) was added water (0.55 mL) and a 2 M aqueous sodium carbonate solution (0.55 mL, 1.1 mmol). The mixture was heated to 85–95° C. for 1 h, cooled to room temperature, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was treated with 0.002 N aqueous hydrochloric acid. To the aqueous phase was added dichloromethane followed by saturated aqueous sodium bicarbonate until pH 8–9. The phases were separated and the organic phase was concentrated. The crude product was purified by RPHPLC, eluting with a gradient from 25% through 65% acetonitrile in 0.05% aqueous hydrochloric acid, to give 0.16 g (57%) of a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=O)(C)(C)C.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][N:25]([CH:35]1[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][CH2:36]1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH2:10][CH:9]2[CH2:12][CH2:13][CH2:14][NH:8]2)=[CH:29][CH:28]=1)[CH:35]1[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCC2CCCN2)cc1)Cc1nc2ccccc2[nH]1
Reaction time: 0.67 h

Procedure:
Using General Procedure B: To a stirred solution of N-(tert-butoxycarbonyl)-D-prolinal (0.121 g, 0.61 mmol) in dry CH2Cl2 (9 mL) was added N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.236 g, 0.59 mmol) at room temperature and the mixture stirred for 40 min. To the resultant mixture was added sodium triacetoxyborohydride (0.174 g, 0.82 mmol) and the mixture stirred overnight at room temperature. Purification and separation of the crude material by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 50:1:1) afforded the more polar mono-alkylated (77 mg, 23%) and the less polar dialkylated (70 mg, 21%) products, both as white foams.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[CH:2]1>[Pd].C1COCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[CH:2]1
Reactant: CCOC(=O)C=Cc1cccc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of ethyl 3-(indol-7-yl)acrylate (13.0 g, 60.5 mmol) in 1:1 THF/MeOH (120 mL), was added to a Parr bottle containing 10% Pd/C (0.87 g, 0.83 mmol). The mixture was hydrogenated in a Parr shaker over 3 h. The mixture was filtered over Celite and concentrated to afford the title compound (12.8 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.09 (s, 1H), 7.36 (dd, J=6, 2.4 Hz, 1H), 7.29 (t, J=2.4 Hz, 1H), 6.86–6.90 (m, 2H), 6.40 (dd, J=2.8, 2.0 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.13 (t, J=6.8 Hz, 3H). MS (electrospray, m/z) 218.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=C(OCC)C(F)=C(OCC)C=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([O:48][CH:49]([CH3:51])[CH3:50])[CH:47]=1)[CH:43]=O)([CH3:38])[CH3:37].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:43][C:42]3[CH:41]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:47]=[C:46]([O:48][CH:49]([CH3:51])[CH3:50])[CH:45]=3)[CH2:14][CH2:15]2)=[O:8])[CH:5]=1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50-C to yield the title compound as colorless oil. MS: 499.3 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>CN(C)C=O.CS(C)=O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: Brc1nccs1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: c1cnn(Cc2ccc(OCCOc3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 110 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous dimethylsulfoxide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 488 mg of 2-bromothiazole was added dropwise over 10 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 280 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-thiazolyloxy)ethyl ether (compound 5). Yield, 41%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(CCc4cccc(N(S(C)(=O)=O)S(C)(=O)=O)c4)CC3)cccc2n1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperaziny]ethyl}aniline (370 mg) and triethylamine (178 μL) in DCM (3 mL) was added methanesulfonyl chloride (33 □L). The mixture was stirred for 18 h, then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic layer was -washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH, (20:0)→(20:1)] to give the title compound (342 mg).