Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:36])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[F:36][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexane carboxylate (150 mg) was dissolved in a mixed solvent of methanol (750 μL) and tetrahydrofuran (750 μL), and a 1 M aqueous sodium hydroxide solution (899 mL) was added thereto, followed by stirring at room temperature for 2 hours. After the completion of the reaction, 1 M hydrochloric acid was added thereto under ice-cooling until the reaction solution became weakly acidic, followed by stirring at 0° C. for 1 hour. The resulting solid was collected by filtration and washed with hexane to obtain trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexanecarboxylic acid (74 mg) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: CC(=O)N1CCC(NCc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(4-aminopiperidin-1-yl)ethanone via General Procedure E to give 19.6 mg of 286 following reverse phase purification. MS (Q1) 504.3 (M)+
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:18]2([O:20][CH2:19]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:18]([CH2:19][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:20])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CO2)C1
Reactant: NCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNCc2ccccc2)C1
Yield: 100 %

Procedure:
Benzyl amine (1.7 mL, 1.1 eq) was added to a solution of rac-1-oxa-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (commercial, 2.80 g, 14.05 mmol) in MeOH (25 mL) and the mixture was heated at reflux for 2 h. The resulting solution was concentrated under reduced pressure and the residue was purified by CC (DCM-MeOH—NH4OH 1000:50:4) to afford the title compound as colourless oil (4.29 g, 100%).
Reaction SMILES: C(OC(N1CCC([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=2)CC1)=O)(C)(C)C.[C:28](O)([C:30](F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N+:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][N:16]2[CH2:30][CH2:28][CH2:23][CH2:24][CH2:15]2)=[N:16][CH:17]=1)([O-:27])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(ON2CCCCC2)c2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cold solution of 4-(4-nitro-isoquinoline-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (9.68 g, 25.9 mmol, 0° C.) in DCM (100 mL) add TFA (80 mL). Stir at 22° C. for 2 hours, then remove solvent under reduced pressure. Dissolve residue in DCM and treat with 1 N sodium hydroxide to pH˜14. Isolate the aqueous phase and extract twice with DCM. Combine the organic phases and dry with anhydrous sodium sulfate. Removal of the solvent gives (4-nitro-isoquinoline-1-yloxy)-piperidine (7.06 g, 99% yield, ES+ (m/z) 274.3 [M+H]).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-(1-Benzyl-piperidin-4-yl)-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure F by the reaction of 4-[4-(4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59) with trifluoroacetic acid in dichloromethane followed by reaction with benzyl bromide (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.93-1.99 (m, 2H), 2.20-2.22 (m, 4H), 2.93-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.55 (s, 2H), 4.75-4.81 (m, 1H), 7.26-7.35 (m, 5H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=464.
Reaction SMILES: [CH:1]1([C:4](=C)[CH2:5][C:6]2([C:19]([O:21]CC)=O)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(C1CC2(CCNCC2)C(=O)[N:28]1[C:38]1[CH2:39][O:40][C:41](=[O:43])[CH:42]=1)C>>[CH:1]1([CH:4]2[CH2:5][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:19](=[O:21])[N:28]2[C:38]2[CH2:39][O:40][C:41](=[O:43])[CH:42]=2)[CH2:2][CH2:3]1
Reactant: CCC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Reactant: C=C(CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1)C1CC1
Product: O=C1C=C(N2C(=O)C3(CCNCC3)CC2C2CC2)CO1

Procedure:
The title compound was prepared from 1-tert-butyl 4-ethyl 4-(2-cyclopropylallyl)piperidine-1,4-dicarboxylate in four steps in an analogous fashion as described for 3-ethyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-43).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]2[S:23][C:22]([CH:24]=O)=[CH:21][C:19]=2[N:20]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:18]2[S:23][C:22]([CH2:24][N:10]3[CH2:9][CH2:8][C:7]([OH:13])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)=[CH:21][C:19]=2[N:20]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccccn2)CCNCC1
Product: OC1(c2ccccn2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 402. 400 MHz 1H NMR CDCl3 9.16 (s, 2H); 8.47 (d, 1H, J=4.8 Hz); 7.70 (t, 1H, J=7.7 Hz); 7.45 (d, 1H, J=7.9 Hz); 7.26 (s, 1H); 7.19 (t, 1H, J=6.2 Hz); 4.00 (t, 4H, J=4.6 Hz); 3.87 (s, 2H); 3.85 (t, 4H, J=4.7 Hz); 2.875 (d, 2H, J=11.0 Hz); 2.63 (t, 2H, J=11.2 Hz); 2.16 (m, 2H); 1.63 (d, 2H, J=12.6 Hz). LC-MS (m+1)=505.18
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11]Br)[N:8]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:28][C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)[N:8]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CBr)n(-c2c(Cl)cccc2Cl)n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1

Procedure:
Into a 500 mL flask was weighed 19.3 g (53 mmol) of 5-bromomethyl-1-(2,6-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester, 13.7 g (79 mmol) of 4-bromophenol, 10.9 mg (79 mmol) of potassium carbonate, and 100 mL of ACN. The reaction mixture was heated to reflux for 4 h. After cooling, the crude reaction mixture was washed into a separatory funnel with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with DCM-methanol (100:0 to 98:2) to afford 5-(4-bromophenoxymethyl)-1-(2,6-dichlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as an off white solid (25.3 g, 100%); 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 6H), 7.06 (s, 1H), 6.67 (d J=8.8 Hz 2H), 4.88 (s, 2H), 4.43 (q, J=7.07 Hz 2H), 1.41 (t, J=7.07 Hz 3H), MS (ES): 491 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: BrCC=Cc1ccccc1
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g; 1.04 mmol), cinnamyl bromide (1.6 mL; 10.5 mmol) and indium (1.22 g; 10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].C([Li])CCC.COC1C=CC(CNC2C3C(=CC=CC=3)N=C(CN3CCCCC3=O)N=2)=CC=1>C1COCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: COc1ccc(CNc2nc(CN3CCCCC3=O)nc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(CN3CCCC3=O)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol), 2-pyrrolidinone (128 mg, 1.5 mmol) and n-butyllithium (2.5 M in THF, 1.2 mL, 3 mmol) in THF (2 mL) by a procedure similar to the preparation of 1-{4-[(4-methoxyphenyl)methylamino]quinazolin-2-ylmethyl}piperidin-2-one in Example 252 and was isolated as a yellow solid. 1H NMR (CDCl3) δ 7.75-7.73 (m, 1H), 7.55-7.51 (m, 1H), 7.13-7.10 (d, 2H), 6.99-6.97 (m, 2H), 6.93-6.90 (d, 2H), 4.72 (s, 2H), 3.84 (s, 3H), 3.61 (t, 2H), 3.54 (s, 3H), 2.53 (t, 2H), 2.15-2.10 (pentet, 2H); LC-MS (ESI+; 363 ([M+H]+)).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1

Procedure:
The product was made by reducing ethyl 4-nitrocinnamate (110.6 g, 0.5 mol) with 10% palladium on Carbon (4.0 g) in 95% ethanol (2 L) in the presence of ammonium formate (126 g) to afford ethyl 3-(4-aminophenyl)propionate which was sulfonated with methanesulfonyl chloride in CH2Cl2 in the presence of pyridine to produce 102 g (75.2%) of N-[4-(ethoxycarbonylethyl)phenyl]methanesulfonamide.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:10]([CH:12]([NH:17][C:18](=[O:21])C=C)[CH2:13][CH2:14][CH:15]=[CH2:16])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH2:29]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:10]([CH:12]1[NH:17][C:18](=[O:21])[CH:16]=[CH:15][CH2:14][CH2:13]1)[OH:11])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=CCCC(NC(=O)C=C)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=C1C=CCCC([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1

Procedure:
Dissolve N-[1-((1R,2S)-2-dibenzylamino-1-hydroxy-3-phenyl-propyl)-pent-4-enyl]-acrylamide (0.5 g, 1.06 mmol) in dichloromethane (50 mL) under nitrogen atmosphere and add Grubb's second generation catalyst (20% mol). Stir the reaction at 50° C. for one day. Concentrate under reduced pressure. Purify on silica gel with hexane/ethyl acetate mixtures to give a mixture of two products. (0, 210 g, 45%) that may be separated using HPLC-MS (19×300 mm, 7 μm, C-18 column; flow rate=20 mL/min; mobile phase gradient 5%-95% over 26 minutes; Solvent A: acetonitrile; Solvent B: 0.1% trifluoroacetic acid in water).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Product: Nc1ccc(-c2cccc(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyridine (example E.82) (0.30 g, 0.727 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.192 g, 0.873 mmol) according to the general procedure VI. Obtained as a light grey solid (0.200 g, 65%). MS (ISP) 426.0 [(M+H)+] and 428 [(M+2+H)+]; mp 172° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:25](=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](Cl)(=[O:54])[CH3:53].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>CCOC(C)=O.CCCCCC>[CH2:1]([O:8][N:9]([C:16](=[O:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:25](=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:52](=[O:54])[CH3:53])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCN(OCc1ccccc1)C(=O)CCCCCCCNOCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N(CCCCCCCC(=O)N(CCCCCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1

Procedure:
Compound [VI] (0.93 g, 1.33 mmol) was treated with acetyl chloride (0.160 g, 2.04 mmol) by the procedure used for (3). Silica gel column chromatography (3:1 EtOAc/hexane) produced 0.95 g (96%) of [VII] as an oil: NMR δ 1.17-1.87 (m, 24H), 2.07 (s, 3H), 2.27-2.47 (m, 6H), 3.47-3.73 (m, 6H), 4.77 (s, 6H), 7.33 (s, 15H). Anal. (C44H60N4O6) C, H, N.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@@H:45]1[C@@H:50]([CH2:51][O:52]C(=O)C2C=CC=CC=2)[O:49][C@H:48]([O:61][C@@H:62]2[C@@H:100]([CH2:101][O:102]C(=O)C3C=CC=CC=3)[O:99][C@@H:65]([O:66][NH:67][C:68](=[O:98])[CH2:69][O:70][CH:71]3[CH2:95][CH2:94][C@@:93]4([CH3:96])[CH:73]([CH2:74][CH2:75][C@@H:76]5[C@@H:92]4[CH2:91][CH2:90][C@@:89]4([CH3:97])[C@H:77]5[CH2:78][CH2:79][C@@H:80]4[C@H:81]([CH3:88])[CH2:82][CH2:83][CH2:84][CH:85]([CH3:87])[CH3:86])[CH2:72]3)[C@H:64]([O:111]C(=O)C3C=CC=CC=3)[C@H:63]2[O:120]C(=O)C2C=CC=CC=2)[C@H:47]([O:129]C(=O)C2C=CC=CC=2)[C@H:46]1[O:138]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.C1COCC1>[C@H:11]1([O:44][C@@H:45]2[C@@H:50]([CH2:51][OH:52])[O:49][C@H:48]([O:61][C@@H:62]3[C@@H:100]([CH2:101][OH:102])[O:99][C@@H:65]([O:66][NH:67][C:68](=[O:98])[CH2:69][O:70][CH:71]4[CH2:95][CH2:94][C@@:93]5([CH3:96])[CH:73]([CH2:74][CH2:75][C@@H:76]6[C@@H:92]5[CH2:91][CH2:90][C@@:89]5([CH3:97])[C@H:77]6[CH2:78][CH2:79][C@@H:80]5[C@H:81]([CH3:88])[CH2:82][CH2:83][CH2:84][CH:85]([CH3:86])[CH3:87])[CH2:72]4)[C@H:64]([OH:111])[C@H:63]3[OH:120])[C@H:47]([OH:129])[C@H:46]2[OH:138])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@H:10]1[OH:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)NO[C@@H]5O[C@H](COC(=O)c6ccccc6)[C@@H](O[C@H]6O[C@H](COC(=O)c7ccccc7)[C@@H](O[C@H]7O[C@H](COC(=O)c8ccccc8)[C@@H](OC(=O)c8ccccc8)[C@H](OC(=O)c8ccccc8)[C@H]7OC(=O)c7ccccc7)[C@H](OC(=O)c7ccccc7)[C@H]6OC(=O)c6ccccc6)[C@H](OC(=O)c6ccccc6)[C@H]5OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)NO[C@@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
Amide 132 (345 mg, 175 μmol) was dissolved in MeOH/THF 1:1 (16 mL). NaOMe (500 μL of a 6M solution) was added and the solution was stirred at room temperature for 24 hrs. The mixture was neutralized with acidic resin and the solution filtered before the solvent was evaporated to yield the white solid product which was triturated with EtOAc and the solvent decanted (×3). The solid was dried under vacuum to yield 124 mg of the white solid product (76%) which was reacted on without further purification or characterisation.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[C:13]1([CH2:12][O:4][C:1](=[O:5])[C:2]#[CH:3])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a stirring mixture of propiolic acid (1.79 mL (2.04 g), 28.65 mmol) and potassium carbonate (4.87 g, 35.2 mmol) in anhydrous DMF (40 mL) was added benzyl bromide (3.78 mL (5.43 g of 99% pure), 31.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting heterogeneous mixture was poured into 40 mL of H2O and was extracted with ethyl ether (3×40 mL). The combined ether extracts were dried (Na2SO4). Filtration and concentration provided 12.16 g of crude product, which upon high vacuum distillation yielded 2-propynoic acid phenylmethyl ester (bp 60° C. 0.5 mm) as a clear oil (3.57 g, 22.3 mmol) in 78% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[O:5][C:6]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:19][CH2:18]2)[CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:42][O:43][CH2:44]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]2[CH2:26][C:27]([CH3:30])([CH3:31])[CH2:28][CH2:29][C:24]=2[CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]3[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:5][C:4]4[CH:39]=[CH:40][CH:41]=[C:2]([O:1][CH2:42][O:43][CH3:44])[CH:3]=4)[CH:16]=3)[CH2:22][CH2:21]2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(OCOC)c1

Procedure:
A suspension of EXAMPLE 176B (0.295 g), methoxymethyl chloride (0.117 mL) and cesium carbonate (0.334 g) in N,N-dimethylformamide (3 mL) was stirred at 60° C. for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The water layer was extracted with dichloromethane. The combined organic extracts were washed with water (2×), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromotography (silica gel, 5%-20% ethyl acetate/hexanes) providing the product.
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([CH2:27][OH:28])=[C:13]([C:24]([O-:26])=[O:25])[CH:14]=[C:15]4[C:23]=3[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[CH:16]4)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+]>O>[CH2:29]([O:25][C:24]([C:13]1[CH:14]=[C:15]2[C:23](=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:2][CH2:3][O:4][C:5]=4[CH:10]=3)[C:12]=1[CH2:27][O:28][CH2:11][C:9]1[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:19]1[O:20][CH2:21][O:22][C:18]=1[CH:17]=[CH:16]2)=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C([O-])c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 140 °C
Yield: 102.5 %

Procedure:
A mixture of 3 (78 mg, 0.2 mmol) and benzyl bromide (0.38 mL, 3.2 mmol), and powdered KOH (168 mg) was heated at 140° C. for 3 h, and then cooled to room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The extract was washed with water (3×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH2Cl2 to give 4 (56 mg, 51%) as a colorless liquid. 1H NMR (CDCl3) δ 8.27 (s, 1H, H4), 7.51 (d, 1H, H5, J=8.4 Hz), 7.23-7.44 (m, 10H, 2×OCH2Ph), 7.22 (d, 1H, H6, J=8.4 Hz), 6.82 (d, 1H, H5′, J=7.8 Hz), 6.77 (d, 1H, H2′, J=1.5 Hz), 6.71 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=10.2 Hz, J=1.2 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.8 Hz, J=1.2 Hz), 5.34 (s, 2H, 3-COOCH2Ph), 4.67 (s, 2H, 2-CH2OCH2Ph), 4.32 (s, 2H, 2-CH2OBn); MS (EI) m/z 546 [M]+.