Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:4][C:3]=1[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:5]1[S:4][C:3]2[CH2:12][CH2:13][CH2:14][O:15][C:2]=2[CH:6]=1
Reactant: OCCCc1sc(C2OCCO2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: c1c(C2OCCO2)sc2c1OCCC2
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
3-[3-Bromo-5-(1,3-dioxolan-2-yl)-2-thienyl]-1-propanol (1.86 g, 6.3 mmol) was dissolved in dry toluene (150 ml), caesium carbonate (3.58 g, 1.5 equiv.) added, and the mixture evacuated and purged with Argon. The evacuation/purge procedure was repeated twice more. In a separate flask, were placed rac-2-di-tert-butylphosphino-1,1′-binaphthyl (Strem chemicals, 257 mg) and palladium(II) acetate (148 mg) in toluene (50 ml). The flask was evacuated and purged with argon and the procedure repeated twice more. After 10 min, the resultant yellow solution of catalyst was added to the flask containing the thiophene via syringe and the flask once more evacuated and purged with argon. The reaction mixture was heated to 100° C. under an argon atmosphere for 3 days. The reaction mixture was cooled, filtered through Kieselguhr and evaporated to low volume. The residue was chromatographed on silica gel eluting with 0-50% ethyl acetate in hexane, to afford the desired compound as a white solid (0.48 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(C(=O)Nc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 47 %

Procedure:
The product of Example 26A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 26A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (22 mg, 47%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3 H) 6.81-6.89 (m, 2 H) 6.89-7.01 (m, 1 H) 7.22-7.38 (m, 4 H) 7.49-7.64 (m, 1 H) 7.67-7.89 (m, 2 H) 7.92-8.03 (m, 1 H) 8.04-8.17 (m, 1 H) 8.58 (s, 1 H) 8.70-8.91 (m, 1 H) 9.96 (s, 1 H) 10.20 (s, 1 H) 10.31 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)c1
Temperature: 100 °C

Procedure:
A reaction mixture of ethyl 3-chloro-4-(trifluoromethylsulfonyloxy)benzoate (3.00 g, 9.02 mmol), 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (1.84 g, 10.8 mmol), (t-4)-tetrakis(triphenylphosphine)palladium (0.521 g, 0.451 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (20 mL), was purged with N2 three times and then heated at 100° C. for 4 hours. The reaction was cooled to room temperature, and EtOAc (130 mL) was added. The mixture was then washed with brine (30×4 mL). The organic layer was dried over MgSO4. The residue was purified by CombiFlash® silica gel column (eluent with hexane/EtOAc; 85/15) to give B.6. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, 1H), 7.90 (d, 1H), 7.33 (dd, 1H), 6.96-7.02 (m, 1H), 6.82-6.85 (m, 1H), 6.74 (d, 1H), 4.33 (q, 2H), 4.31 (s, 3H), 1.34 (t, 3H). MS ESI (pos.) m/e: 309.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)Cc1ccc(F)cc1F
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Product: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
587 mg (2 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 555 mg (3 mmol) 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up as described for Example 1a). Yield: 220 mg (23%); mass spectroscopy [M+H]+=479.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12].N#N.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
4.4 ml (31.4 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 6.0 g (15.7 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 10.6 g (30.0 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine in 50 ml of dimethylformamide, and the resulting mixture was stirred for 3 days. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with methylene chloride. The diluted solution was washed with a 5% w/v aqueous solution of citric acid, with a 1N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride, in that order, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography, using a 1:30 by volume mixture of methanol and methylene chloride as the eluent, to give 7.6 g of the title compound as a colorless powder, melting at 126°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]Br.C1N2CN3CN(C2)CN1C3.Cl.C(O)(=[O:24])C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:24]
Reactant: CC(=O)O
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cc(Br)cc(C=O)c1
Temperature: 25 °C

Procedure:
To 3-bromo-5-methylbenzyl bromide (Step A above) (5.49 g, 20 mmole) in glacial acetic acid (9.0 mL) and H2O` (9 mL) was added hexamethylenetetramine (4.50 g, 32 mmole) and the reaction was stirred at reflux for 2 hours. Concentrated HCl (7.0 mL) was added and the mixture was refluxed an additional 15 minutes. After cooling to room temperature, the reaction mixture was diluted with H2O (75 mL) and extracted with ether (150 mL). The ether layer was washed with H2O (3×25 mL), 10% NaHCO3 (2×50 mL) and dried over MgSO4. The ether was removed under vacuum and the residue was chromatographed on silica gel eluting with hexane and 10% Et2O/hexane to yield 3-bromo-5-methylbenzaldehyde (2.80 g) as a light yellow oil which solidified upon standing. MS and NMR were consistent with the desired structure.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[C:16]([CH2:17][CH:18]=C)=[CH:15][C:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1)=[O:10]>O.C1COCC1.[Os](=O)(=O)(=O)=O>[CH3:7][O:8][C:9]([C:11]1[C:16]([CH2:17][CH:18]=[O:2])=[CH:15][C:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1)=[O:10]
Reactant: C=CCc1cc(COc2ccccc2)cnc1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ncc(COc2ccccc2)cc1CC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
Sodium metaperiodate (304 mg, 1.42 mmol) was added to a stirred solution of 3-allyl-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (161 mg, 0.57 mmol) and osmium tetraoxide (0.37 mL, 0.028 mmol; 2.5% in tert-butanol) in H2O (3 mL) and THF (6 mL) at 0° C. The mixture was stirred at RT for 2 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-(2-oxo-ethyl)-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (200 mg, 60% purity, 74%) as a black residue which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 500 mg (1.23 mmol) of the compound of Example 5A, 262 mg (1.47 mmol) of 1-benzothien-2-ylboronic acid, 1.34 ml (2.70 mmol, 2M solution in water) of sodium carbonate and 42 mg (0.061 mmol) of bis(triphenylphosphine)palladium(II) chloride in 10 ml of dimethoxyethane are stirred under reflux for 3 hours. The solution is cooled to room temperature and then partitioned between 500 ml of ethyl acetate and water, and the aqueous phase is extracted twice with 200 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered with suction and concentrated. The residue is dissolved in dimethyl sulfoxide and purified by preparative RP-HPLC with acetonitrile and water. 146 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][O:6][C:7]1[C:8]([N+:27]([O-])=O)=[N:9][C:10]([N:13]2[CH2:17][C@@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])=[CH:11][CH:12]=1)C>C(O)(=O)C>[C:22]([O:21][C:19](=[O:20])[NH:18][C@H:16]1[CH2:15][C:14](=[O:26])[N:13]([C:10]2[CH:11]=[CH:12][C:7]3[O:6][CH2:5][C:4](=[O:30])[NH:27][C:8]=3[N:9]=2)[CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)COc1ccc(N2C[C@@H](NC(=O)OC(C)(C)C)CC2=O)nc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
Reduced iron (150 mg, 2.69 mmol) was added to a solution of [(6-{(4S)-4-[(tert-butoxycarbonyl)amino]-2-oxopyrrolidin-1-yl}-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (380 mg, 0.895 mmol) in acetic acid (3.8 ml) and the mixture was stirred at 85° C. for 1.5 hours. After cooling, the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the mixture was stirred for 10 minutes. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 305 mg (98%) of the title compound in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:27][CH:26]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by the method of Preparation is using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14](F)=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.C([N:27](C(C)C)CC)(C)C>CN1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14]([NH2:27])=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN1CCCC1
Product: Nc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Temperature: 135 °C

Procedure:
A mixture of 2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine, about four equivalents of a primary or secondary amine (R═H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or C1-C20 heteroaryl), and about two eq. diisopropylethylamine in N-methylpyrrolidine (˜0.1M) is heated to about 130-140° C. in a sealed microwave reactor for 10˜40 min, followed by removal of volatiles under high vacuum. The crude mixture is purified by flash chromatography to give intermediate 2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine, which may be Suzuki coupled with a monocyclic heteroaryl, fused bicyclic heterocycle or heteroaryl boronate reagent following General Procedure A.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:48]([O:47][CH2:46][CH2:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:34])[CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:24][CH:25]=4)=[O:18])=[CH:7][C:6]=3[CH:35]=2)=[CH:43][CH:42]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCOCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCOCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
In toluene/ethanol/water (=20/1/1, 14.3 ml) was dissolved 7-bromo-1-(2-ethoxyethyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.17 g) and potassium carbonate (0.18 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate, which was filtered to give a solution. The solvent was removed under reduced pressure, which was recrystallized from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethoxyethyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 90) (15 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=O)[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH:9]=1)(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][S:2]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)c1cc(CC(=O)c2c[nH]c(S(C)(=O)=O)c2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1cc(CCc2c[nH]c(S(C)(=O)=O)c2)cc(C(C)(C)C)c1O

Procedure:
For example, using 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)-1-oxo-ethyl]pyrrole in this generation reaction together with eight molar equivalents of LAH yields 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]pyrrole (a compound according to Formula X wherein: m is 2; n is 0; R is H; and X is SO2CH3 ; and Y and Z are each H). Likewise, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole in this general reaction together with eight molar equivalents of LAH yields 3-(3,5-di-t-butyl-4-hydroxybenzyl)pyrrole (a compound according to Formula X wherein: m is 1; n is 0; R is H; and X, Y and Z are each H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[C:3]1=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:70]1[CH:75]=[C:74]([CH3:76])[C:73]([S:77]([CH3:80])(=[O:79])=[O:78])=[CH:72][C:71]=1[F:81].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:70]4[CH:75]=[C:74]([CH3:76])[C:73]([S:77]([CH3:80])(=[O:79])=[O:78])=[CH:72][C:71]=4[F:81])[C:3]3=[O:22])[CH2:9][CH2:10]2)=[N:19][CH:18]=1)[CH3:21]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](N)C3=O)CC2)nc1
Reactant: Cc1cc(Br)c(F)cc1S(C)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4cc(C)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 90 °C
Yield: 50.2 %

Procedure:
(S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (220 mg, 0.725 mmol) was dissolved in toluene (7 mL) and BINAP (45.2 mg, 0.0725 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (Preparation B; 291 mg, 1.09 mmol) and Cs2CO3 (284 mg, 0.870 mmol) were added. The reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (33.2 mg, 0.0363 mmol) was added and the reaction heated to 90° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was purified over silica gel (90% EtOAc in hexanes) to afford a mixture. The mixture was then purified on reverse phase chromatography (15 to 95% ACN in water) to afford (S)-1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (178 mg, 0.364 mmol, 50.1% yield) as a white solid. Mass spectrum (apci) m/z=490.3 (M+H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:14]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-one (2.0 g, 11.4 mmol) (from Example 123) and benzylamine (1.33 g, 12.5 mmol) were dissolved in 1,2-dichloroethane (35 mL) and acetic acid (1.36 g, 22.6 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium triacetoxyborohydride (3.14 g, 14.8 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3(aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane—30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
562 mg (4 mmol) of 2-(4-fluoro-phenyl) ethyl amine were added to 733 mg (4 mmol) of 4-trifluoromethyl benzaldehyde dissolved in 40 ml methanol. The reaction mixture was stirred at rt over night under nitrogen. 151 mg (4 mmol) of sodium borohydride were added in portions and the reaction mixture was stirred for 2 h at rt. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (60 g silica gel; DCM/methanol 19:1) to yield 1.16 g (98%) of [2-(4-fluoro-phenyl)-ethyl]-(4-trifluoromethyl-benzyl)-amine as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.65 (d, 2H), 7.52 (d, 2H), 7.21 (dd, 2H), 7.06 (dd, 2H), 3.79 (s, 2H), 2.70 (s, 4H).