Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=[C:20](SC)[N:19]=3)=[CH:13][C:12]=2[F:31])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]>C(O)C.[Ni].O>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:13][C:12]=2[F:31])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cncnc1Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-2-(methylthio)pyrimidine-5-carboxylate (260 mg, 0.58 mmol) in ethanol (5 mL) was added Raney nickel in water (Raney®2400, approx. 3 g). The mixture was heated to 70° C. and was allowed to stir overnight. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the desired product (91 mg, 39%) as a solid. MS(ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: OC(Cc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 2-bromobenzaldehyde (18.50 g) in dry ether (20 ml) was added dropwise to a stirred solution of benzylmagnesium chloride [prepared from benzyl chloride (12.64 g) and magnesium (2.68 g)] in dry ether (120 ml), a thick precipitate forming during the addition. The mixture was stirred for 1 hour at room temperature then poured into water, acidified with 2M hydrochloric acid, and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using dichloromethane and petrol (1:1) as eluant to give 1-(2-bromophenyl)-2-phenylethan-1-ol (10.95 g, 40%) as a white solid, melting point 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].N1C=CN=C[C:33]=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:33][CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Nc1cnccn1
Product: CCO[C@H]1CCc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.14, 1.20, 1.29, 1.95, 2.31, 2.45, 2.73, 2.82, 3.12, 3.48, 3.74, 3.99, 5.42, 5.75, 7.12-7.21, 7.36, 7.51; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1617.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[C:14](Cl)(=[O:16])[CH3:15].Cl>CCOC(C)=O>[Br:5][C:6]1[C:7]([F:13])=[CH:8][C:9]([F:12])=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)c(F)cc1F
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A mixture of AlCl3 (1040 g, 7878.7 mmol) in 1-bromo-2,4-difluorobenzene ([CAS 348-57-2], 600 g, 3108.9 mmol) was stirred for 10 min at 60° C. Acetyl chloride [CAS 75-36-5], 366 g, 4662.4 mmol) was added dropwise in the reaction mixture for 4 h at 60° C. The mixture was stirred an additional 6 h at 95° C. The reaction mixture was cooled to −10° C. Ice (2450 g) was added for 1.5 h. HCl (12 N, 1500 mL) was added and the mixture was stirred for 1 h. EtOAc (9000 mL) was added and the organic layer was washed with water, dried over Na2SO4 and filtered. After concentration, the residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc, 50/1) to yield I-18 (300 g, 41%).
Reaction SMILES: CO[C:3](=[O:14])[CH:4]=[C:5]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:3]([OH:14])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:4]=[C:5]1[CH2:6][CH:7]2[N:12]([CH3:13])[CH:10]([CH2:9][CH2:8]2)[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C=C1CC2CCC(C1)N2C
Reactant: Cl[Mg]Cc1ccccc1
Product: CN1C2CCC1CC(=CC(O)(Cc1ccccc1)Cc1ccccc1)C2

Procedure:
The title compound was prepared from (8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-acetic acid methyl ester and benzylmagnesium chloride by following the experimental procedures in Example 1 (31% yield): LCMS (ES) m/z 348 (M+H)+; 1H-NMR(CDCl3) δ 0.90 (m, 1H), 1.25 (m, 1H), 1.61 (m, 1H), 1.81 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 2.70 (m, 1H), 2.87 (m, 1H), 2.97 (m, 2H), 3.08 (m, 1H), 3.42 (s, 2H), 5.24 (s, 1H), 7.26 (m, 10H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([OH:15])(=O)[C@H:11]([CH3:13])[OH:12].Cl.[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1>CN(C)C=O>[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][N:40]([C:10](=[O:15])[C@@H:11]([OH:12])[CH3:13])[CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)[C@H](C)O)CC1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
DIPEA (0.120 g, 0.92 mmol) and L-lactic acid (0.083 g, 0.92 mmol) were added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.10 g, 0.184 mmol) in dimethylformamide at room temperature. O-(1H-Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.295 g, 0.92 mmol) was added and the reaction mixture was stirred for 30 minutes, concentrated and purified by preparative LCMS (standard acidic system) to give the title product (0.044 g, 43.4%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 1.29 (d, 3H), 1.91 (m, 2H), 2.06 (m, 2H), 2.20 (m, 3H), 3.34 (m, 4H), 3.65 (s, 2H), 3.94 (s, 3H), 4.45 (m, 1H), 4.83 (m, 1H), 7.19 (s, 1H), 7.29 (m, 3H), 7.49-7.57 (m, 2H), 8.34 (s, 1H), 8.42 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 545.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of ethyl {4-[(butyl{6-[4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)methyl]-2-methylphenoxy}acetate (150 mg, 0.3 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×50 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a bright yellow solid (115 mg).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([NH2:36])[N:38]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc(N)n1

Procedure:
Tri(o-toly)phosphine (26 mg, 0.086 mmol), palladium(II) acetate (214 mg, 0.96 mmol), methyl acrylate (90 mg, 1.04 mmol), triethylamine (351 mg, 3.47 mmol) and 2-amino-6-bromopyridine (37) (150 mg, 0.87 mmol) in acetonitrile (3 mL) were heated in a CEM Discover microwave for 1 hour at 90° C. The solvent was removed under a stream of nitrogen gas; 4N HCl was added and the aqueous extracted with TBME (×2). The aqueous layer was then basified to pH 9/10 using K2CO3(aq) and extracted with EtOAc (×5). The organic layer was washed with brine, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography eluting with 50% EtOAc in heptane to give the title compound. Yield: 95 mg, 61%; LC-MS tr 0.76 min; HPLC Purity: 42%; MS (ES+) m/z 179 (M+H)
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:14])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: C#CC[C@H]1CC[C@H](CO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC#N
Solvent: O
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a suspension of Compound 9 (2.45 g, 16 mmol) in 50% acetonitrile/water (35 mL) cooled to 0° C. was added bis-acetoxy-iodobenzene (BAIB) (11.4 g, 35 mmol) and TEMPO (502 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. for 1 hour, then for 90 minutes at room temperature. The solvents were evaporated, and the residue dissolved in 1/1 CH3CN/H2O (100 mL). Once again the solvents were evaporated, and this procedure repeated to remove iodobenzene as its azeotrope. The resulting Compound 11 (2.53 g, 95%) was obtained as a brown sticky solid that was not further purified but carried forward into the next step. 1H-NMR (600 MHz, CD3OD): 1.13 (dq, 2H), 1.45 (dq, 2H), 1.48 (m, 1H), 1.93 (dd, 2H), 2.03 (dd, 2H), 2.12 (dd, 2H), 2.2-2.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CN(C)C=O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]([CH3:30])[N:15]=[C:14]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(Oc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 2,4,6-trimethylphenol (1.03 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 0.30 g), and stirred at ambient temperature for 5 minutes. To the solution was added 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.0 g), and the mixture was stirred at ambient temperature for 18 hours. The solution was poured into water (300 ml), and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenoxy)pyrimidine (1.96 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccc(F)cc1
Yield: 58.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 4-fluorobenzoyl chloride (99 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 103 mg of 4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 58%).
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])C1C=CC=CC=1.ClC(OCC1C=CC=CC=1)=O.S(Cl)(C1C=[CH:34][C:32]([CH3:33])=[CH:31]C=1)(=O)=O.C(Cl)(=O)C1C(=CC=CC=1)C(Cl)=O.C(Cl)(=O)C1C=CC=CC=1>C(N(CC)CC)C>[C:32]([O:10][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:8])([CH3:31])([CH3:33])[CH3:34]
Reactant: C=CCNC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: C=CCNC(=O)OC(C)(C)C

Procedure:
N-benzyloxycarbonyl allyl amine was made in the same manner by utilizing benzyl chloroformate and triethylamine at 0° C. Cbz chloride, tosyl chloride, phthaloyl chloride and benzoyl chloride can similarly be used to obtain the corresponding allyl amine.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=[O:37])/C/2=C\C1NC=CC=1)#C.IC1C=C(O)C=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[OH:37][C:7]1[CH:6]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Oc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccc(O)c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner to analogous to the preparation of (Z)-I,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) was coupled with 3-iodophenol (110 mg, 0.50 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst in 1 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 100 mg, 71%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:58]([NH2:76])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][Cl:23])[C:6]1[CH:5]=[CH:4][C:3]2[N:2]([CH3:1])[C:10]([CH2:11][CH2:12][CH2:13][C:14]([NH:76][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[O:16])=[N:9][C:8]=2[CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 2 °C
Yield: 33.1 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, 60 mL pressure equalizing dropping funnel and nitrogen in/outlet was charged with 10.0 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of N,N-dimethylformamide (DMF). To this stirred yellow solution was added 4.41 mL (3.27 g, 25.3 mmol) of N,N-diisopropylethylamine (DIPEA). An exotherm to 27.1° C. was noted and the solution became a darker yellow. The reaction was cooled to 2.0° C. where a suspension of 6.2 mL (4.59 g, 35.5 mmol) of DIPEA, 7.65 g (25.6 mmol) of octadecyl amine in 0 mL of DMF was added via pipette. Once addition was complete the reaction became very thick and difficult to stir. It was warmed to room temperature and the magnetic stir bar was replaced with an overhead stirrer. The batch was stirred at RT overnight after which time an in process analysis indicated the reaction was complete. The batch was quenched onto 300 mL of DI water and extracted with dichloromethane (2×150 mL). The organic phases were combined, washed with 10% sodium hydrogen phosphate (1×300 mL), 8% aqueous sodium bicarbonate (1×300 mL) and brine (1×300 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (2 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (1 L) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 5.11 g (8.38 mmol, 33%) of the desired product as a white solid with an HPLC purity of 90.9A %. The major impurity was shown to be the C-16 amide which results from an impurity in the starting amine 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, b, 1H), 7.33 (d, J=8.84 Hz, 1H), 6.91 (d, J=2.22 Hz, 1H), 6.80 (dd, J=2.36, 8.84 Hz), 3.71 (s, 8H), 3.70 (s, 3H), 3.01 (q, J=6.8, 12.68, 2H), 2.79 (t, J=7.44 Hz, 2H), 2.18 (t, J=7.36 Hz, 2H), 1.97 (m, 2H), 1.36 (m, 2H), 1.28 (s, b, 30H), 0.85 (t, J=6.32 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])([CH3:6])([CH3:5])[CH3:4].[Li]CCCC.CCCCCC.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:29][CH2:12][C:10](=[O:11])[CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:13])[CH:31]=[CH:32][CH:33]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1cccc(Cl)c1
Yield: 86.6 %

Procedure:
Sodium hydride (5.43 g, 0.11 mol, 50% as an oil suspension) is placed in a 500 ml 3-neck flask (equipped with a thermometer, an addition funnel, and a rubber septum) under nitrogen and washed 2×100 ml hexanes to remove the oil. Then 230 ml dry THF (tetrahydrofuran) is introduced and the sodium hydride suspension is cooled to 4° and magnetically stirred. t-butylacetoacetate (16.5 ml, 0.1 mol) is added with a rate which is controlled so that the gas evolution is not too vigorous and the temperature is maintained at less than 10°. Stirring is continued until gas evolution ceases (1 hr). Then 62 ml of 1.7 M BuLi in hexane (0.105 mol) is added via syringe at a rate such that the temperature does not rise above 10°. The initial orange color becomes red during addition, but turns into pink after addition is complete. A fine solid also separates from solution. The resulting mixture is stirred for an additional 15 min. before 15.0 ml m-chlorobenzyl chloride (20.0 g, 0.125 mol) in 20 ml dry THF is added dropwise at a rate such that the temperature is maintained between 9° and 12°. When addition is complete, the cooling bath is removed and the reaction is stirred for an additional 1 hr. The reaction mixture is then poured into a 2 l Erlenmeyer flask and 300 ml diethyl ether is added followed by the addition of 130 ml cold 3 N aqueous HCl with stirring. The mixture is stirred for 15 min, and the layers are separated, and the acid layer is washed twice with 150 ml diethyl ether. The combined organic layers are then washed twice with 200 ml of water, 2×100 ml of aqueous 1% Citric acid (pH 4.5), and finally with 100 ml saturated aqueous brine. The organic layer is dried with anhydrous sodium sulfate and the solvent removed to give 24.5 g of t-butyl 5-(m-chlorophenyl)-3-oxo-pentanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCCCOc1cccc(-c2ccccc2)c1
Product: COC(=O)c1cc(OCCCOc2cccc(-c3ccccc3)c2)cc(OCCCOc2cccc(-c3ccccc3)c2)c1

Procedure:
Using this procedure, the reaction of 3,5-dihydroxybenzoic acid methyl ester with 3-(3-bromopropoxy)-1,1-biphenyl gave 3,5-bis[3-(1,1'-biphenyl-3-yloxy)propoxy]benzoic acid methyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (32.5, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 27% (34 g, 0.065 mmol) of the title compound.