Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:18])[CH2:7][N:6]1[CH3:19].C(N(CC)CC)C.[CH3:27][C:28]([CH2:34][CH3:35])([CH2:32][CH3:33])[C:29](Cl)=[O:30].O>ClCCl>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:29](=[O:30])[C:28]([CH2:34][CH3:35])([CH3:27])[CH2:32][CH3:33])[CH2:7][N:6]1[CH3:19]
Reactant: CCC(C)(CC)C(=O)Cl
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](N)CN1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(C)(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
A supension of 68 g 2,6-dimethyl-8α-aminoergoline in 1.5 l dichloromethane are pre-cooled to 4° and treated with 78 ml triethylamine. The mixture is treated under stirring dropwise within 25 minutes with 40.5 g 2-methyl-2-ethyl-butyryl chloride. The mixture is stirred for 30 minutes, poured onto 3 l water, the organic phase is dried (Na2SO4) and concentrated. The residue is chromatographed on 800 g silica gel using dichloromethane/methanol (98:2) to yield the title compound, which is crystallised from diethyl ether, m.p. 191°-192°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (35 mg, 45%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C([O-])([O-])=O.[K+].[K+].N#N.I[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][CH2:23][CH2:22][CH2:21][CH2:20][C:19]#[CH:18]
Reactant: COC(=O)[C@H](C)N
Reactant: C#CCCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: C#CCCCCN[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
In a flame-baked, two neck 100 mL round bottom flask, 20 mmol of L-alanine methyl ester hydrochloride (2.8 g), 40 mmol of K2CO3 (5.53 g), and 20 mmol of tetrabutylammonium iodide (TBAI, 7.39 g) were charged under a stream of dry N2 gas. 35 mL of tetrahydrofuran (THF) was slowly added and the mixture was stirred for 15 min at room temperature. 2.6 mL of 6-iodo-hex-1-yne was added dropwise while the mixture was stirred. The reaction mixture was refluxed at ˜70° C. for 15-18 h with TLC check. After consumption of the starting material, the mixture was cooled to room temperature, diluted by diethylether, and filtered. The filtrate was further diluted by diethylether and filtered again. The solvent was removed by rotavap and the crude product was purified by flash chromatography on silica gel (1:2=Hexane/EtOAc, 1% triethylamine) to give N-(5-hexynyl) L-alanine methyl ester (2.044 g, 11.2 mmol) as a yellow oil. Yield: 56%. Rf=0.27 (1:1=Hexane/EtOAc); ESI-MS [M+H]+=184.1 m/z; 1H NMR (300 MHz, CDCl3): δ 3.70 (s, 3H), 3.32 (q, J=7.0 Hz, 1H), 2.53 (m, 2H), 2.18 (m, 2H), 1.92 (t, J=2.6 Hz, 1H), 1.56 (m, 5H), 1.27 (d, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 176.29, 84.21, 68.41, 56.61, 51.74, 47.41, 29.20, 26.01, 19.11, 18.23.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].CSC.B>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCN1CCNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To an ice-cold, stirred solution of methyl 4-butyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (840 mg) in tetrahydrofuran (32 mL) was added borane dimethylsulfide complex (3.2 mL, 2.0 M tetrahydrofuran) and the resulting mixture was refluxed for 24 h. The mixture was cooled to room temperature, quenched with methanol, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided 364 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.27, 7.22, 6.41, 3.84, 3.47-3.45, 3.32-3.23, 1.60-1.58, 1.42-1.37, 0.99-0.94.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].N12CCCN=C1CCCCC2.[F:22][CH:23]([F:42])[O:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32](C2C=CC=CC=2)[C:33](=O)[O-:34])[N:26]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:33]([NH:32][C:27]1[N:26]=[C:25]([O:24][CH:23]([F:42])[F:22])[CH:30]=[C:29]([CH3:31])[N:28]=1)=[O:34])(=[O:9])=[O:8]
Reactant: Cc1cc(OC(F)F)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2ccccn2)n1
Reaction time: 6 h
Yield: 42.3 %

Procedure:
To a solution of 0.52 g of 2-pyridinylsulfonamide and 0.55 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of absolute dioxan is added 1 g of N-(4-difluoromethoxy-6-methylpyrimidin-2-yl)-phenylcarbamate. The reaction mixture is stirred for 6 hours at 20°-25° C., then taken up in water and acidified with 2N hydrochloric acid. The precipitate is isolated, washed with water and recrystallised from a mixture of acetone/ether, affording 0.5 g (42.4%) of N-(2-pyridinylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 1.1) with a melting point of 150°-151° C.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].O>C1C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:13]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:14]#[N:15]
Reactant: CN(C)CCCl
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN(C)CCC(C#N)c1cccc2ccccc12
Temperature: 80 °C
Yield: 57.3 %

Procedure:
6.9 g of sodium amide are added in small portions to 29.4 g of naphth-1-ylacetonitrile in 250 ml of anhydrous benzene and the mixture is heated at 80° C. for 2 hours. It is cooled to +40° C., 19 g of 2-chlorodimethylaminoethane are added dropwise and the mixture is then heated again at 80° C. for 4 hours. It is cooled and 200 ml of water are added. After decantation, the organic phase is extracted with a 10% solution of hydrochloric acid. The aqueous phase is washed with ether, neutralized with a 10% solution of sodium hydroxide and extracted with ether and the extract is then washed with water and dried over sodium sulfate. 24 g of the expected product are obtained after evaporation of the solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1>O.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>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(Cl)nc1
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: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Yield: 97.8 %

Procedure:
3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 mL), [Bu4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (yield 97%, 49.9 g). 1H NMR (400 MHz, DMSO-d6) □ ppm 7.29 (td, J=8.46, 2.42 Hz, 1H) 7.50-7.56 (m, 1H) 7.93 (dd, J=10.47, 2.15 Hz, 1H) 7.97 (d, J=7.79 Hz, 1H) 8.11 (d, J=8.06 Hz, 1H) 8.30 (dd, J=8.32, 2.15 Hz, 1H) 9.11 (d, J=1.88 Hz, 1H), 13.48 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)[CH2:26]C)C.CS(Cl)(=O)=O.Cl.CNC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:25]([CH3:26])[CH3:23])[CH:17]=3)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc2cc(CO)ccc2c1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2cc(C(=O)Nc3ccc(Br)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
The N-(4-bromophenyl)-6-(hydroxymethyl)-2-naphthamide (349 mg, 0.980 mmol) obtained in Reference Example 4 and triethylamine (0.164 ml, 1.18 mmol) were dissolved in N,N-dimethylformamide (5 ml), methanesulfonyl chloride (0.091 ml, 18 mmol) was added thereto under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction solution were added dimethylamine hydrochloride (160 mg, 96 mmol) and potassium carbonate (406 mg, 2.94 mmol), and the mixture was stirred at 60° C. for 16 hours. To the reaction solution were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added diisopropyl ether, followed by crystallization to obtain the titled compound (135 mg) as a white powder.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([CH2:33][F:34])=[CH2:32])[CH:28]=[C:27]([Cl:35])[C:26]=1[Cl:36].Cl>CN(C=O)C.CC(=O)OCC.O>[F:34][CH2:33][C:31]1([C:29]2[CH:28]=[C:27]([Cl:35])[C:26]([Cl:36])=[C:25]([Cl:24])[CH:30]=2)[O:13][N:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=3[CH:10]=2)[CH2:32]1
Reactant: C=C(CF)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(CF)(c4cc(Cl)c(Cl)c(Cl)c4)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (225.5 mg, 1.1 mmol) in DMF (10 mL) at rt was added NCS (177 mg, 1.32 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3-fluoroprop-1-en-2-yl)benzene (260 mg, 1.1 mmol) and TEA (122.2 mg, 1.21 mmol) in DMF (20 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at this temperature for 1 h and then at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2 and then poured into water followed by extraction with EA (100 ml×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (2:1) to give the final title compound (200 mg, yield 41%) as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1 H), 7.77 (s, 2H), 7.69-7.68 (m, 3H), 4.91 (s, 1H), 4.75 (s, 1H), 3.80 (s, 2H), 1.45 (s,6H). MS: m/z=443 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[Li]CCCC.[CH2:15]1[O:17][CH2:16]1.O>C1COCC1.CCOCC>[OH:17][CH2:16][CH2:15][C:5]1[C:4]([O:8][CH3:9])=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: COc1cccc(Cl)n1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1nc(Cl)ccc1CCO
Temperature: 25 °C

Procedure:
To a solution of 1.0 g (7.0 mmol) of 2-chloro-6-methoxypyridine in 20 ml of dry THF cooled to -78° C. was added 10.9 ml (1.6M in hexanes, 17.4 mmol) n-BuLi under an atmosphere of nitrogen. The temperature of the mixture was allowed to raise to -40° C. before an addition of 4 ml ethylene oxide in 6 ml ether. The mixture was warmed to room temperature, 50 ml water was added and the aqueous layer was separated and extracted with 2×100 ml EtOAc. The organic extracts were combined, washed once with water, dried with Na2SO4, and concentrated in vacuo. The crude material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.22 g of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.[CH:41]1([NH:44][C:45](=[O:53])[C:46]2[CH:51]=[CH:50][CH:49]=[C:48](I)[CH:47]=2)[CH2:43][CH2:42]1.O>C(O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH:41]1([NH:44][C:45](=[O:53])[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:47]=2)[CH2:42][CH2:43]1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: O=C(NC1CC1)c1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1CC1)c1cccc(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 6-bromo-1-morpholinophthalazine (95 mg, 323 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (24 mg, 32 μmol), potassium acetate (95 mg, 969 μmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (90 mg, 355 μmol) was added 1,4-dioxane (3.23 mL) before it was heated to 80° C. for 2.5 h. This reaction mixture was added to a mixture of N-cyclopropyl-3-iodobenzamide (111 mg, 388 μmol) and tetrakis(triphenylphosphine) palladium (37 mg, 32 μmol) in ethanol (3.23 mL) and potassium carbonate −1.5 M in water (861 μl, 1292 μmol) and stirred for 2 h at 80° C. The mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 375 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:15](=[O:16])[NH:14][CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36]I>C1COCC1.O>[CH2:1]([C@@H:8]1[C:15](=[O:16])[N:14]([CH3:36])[CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:22])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@@H]1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@H](Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 8 (50 mg, 0.11 mmol) in THF (3 mL) at −10° C. was slowly added NaH (5.2 mg, 0.12 mmol). The mixture was warmed to rt and stirred for 1 h. To it was added CH3I (50 mg, 0.33 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O (10 mL) and extracted with EA (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give 9 (50 mg, 96% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 9.14-9.11 (m, 1H), 8.24-8.19 (m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.59-7.54 (m, 1H), 7.44-7.36 (m, 3H), 7.22-7.13 (m, 5H), 7.08-7.04 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 5.80-5.76 (m, 1H), 5.43-5.30 (m, 2H), 4.20 (d, J=16.8 Hz, 1H), 3.46-3.30 (m, 2H), 3.06-3.00 (m, 1H), 2.75 (s, 3H); MS (ESI+) m/z: 472 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 83 %

Procedure:
2,4-Dihydroxybenzoic acid was reacted with sodium hydride and benzyl bromide in dimethylformamide (DMF) to give a compound protected with benzyl groups at hydroxyl and carboxylic acids moieties in a 91% yield. The benzyl group was removed from the carboxylic acid moiety by refluxing it with 2 N sodium hydroxide in dioxane, followed by acidifying the mixture, to give 2,4-dibenzyloxybenzoic acid in 83% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH3:45])=[O:43])=[C:40]([F:46])[C:39]([F:47])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH3:45])=[O:43])=[C:40]([F:46])[C:39]([F:47])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)[nH]c3nccc2-3)ccc(F)c1F
Temperature: 120 °C
Yield: 80.3 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (143 mg, 0.203 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluoro-N-methylbenzamide (90 mg, 0.163 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19-2.31 (m, 6 H), 2.77 (br. s., 3H), 3.04-3.23 (m, 4 H), 3.74-3.84 (m, 3 H), 4.17 (d, J=6.59 Hz, 2 H), 6.23-6.37 (m, 1 H), 6.86-7.02 (m, 2 H), 7.29-7.45 (m, 1 H), 7.50 (d, J=3.85 Hz, 1 H), 8.02-8.15 (m, 1 H), 8.65 (d, J=3.11 Hz, 2 H), 9.64 (d, J=3.94 Hz, 1 H), 11.23 (d, J=1.46 Hz, 1H). (ESIMS (M+H)+=551)
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:26]([O-])([O-])=O.[K+].[K+].CI.Cl>C(OCC)(=O)C.CC(C)=O>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:12]([O:14][CH3:26])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCCC(CCCCCCCCC=C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCCCCCCCCCC(CCCCCCCCC=C)C(=O)OC
Yield: 97.5 %

Procedure:
2-(Dec-9-enyl)-tridec-12-enoic acid (63 mg, 0.18 mmol, Example 67) was added to a 100 mL three-neck round-bottom flask fitted with a reflux condenser (cooled with ice cold water) followed by 15 mL of reagent-grade acetone. The resulting solution was vigorously stirred and 0.062 g K2CO3 (0.45 mmol, 2.5 eq.) was added in one portion and the mixture was stirred for 5 minutes at room temperature. An excess of methyl iodide (˜2.0 mL) was then added and the mixture was refluxed under argon for 24 hours, after which TLC analysis (5:95 ethyl acetate:hexanes) indicated complete reaction. The mixture was acidified to pH 5 with 3N aqueous HCl and extracted with CH2Cl2. This solution was dried over MgSO4 and a small amount of Na2S2O3 (to destroy iodine). The solvent was then evaporated to afford methyl 2-(dec-9-enyl)-tridec-12-enoate (64 mg, quantitative yield) as a clear oil. 1H NMR (300 MHz, CDCl3): δ 5.80 (m, 2H), 4.93 (m, 4H), 3.65 (s, 1H), 2.35 (m, 1H), 2.03 (q, 4H), 1.58 (m, 2H) 1.42, 1.35, and 1.27 (m, 28H) ppm. 13C NMR (75 MHz, CDCl3): δ 177.04, 139.17, 139.15, 114.08, 114.06, 51.23, 45.68, 33.78 (2 C, unresolved), 32.48, 29.51, 29.50, 29.48 (2 C, unresolved), 29.42 (2 C, unresolved), 29.37 (2 C, unresolved), 29.09, 29.06, 28.90, 28.88, 27.44 (2 C, unresolved) ppm. Analysis calculated for C24H44O2: C, 79.06; H, 12.16. Found: C, 78.83; H, 12.16. HRMS-FAB: Theoretical: 365.3420; Found: 365.3399 [M]+. A copolymer of methyl 2-(dec-9-enyl)-tridec-12-enoate and 1,9-decadiene, prepared similarly to polymer 21, would have the following features: The end groups R2 and R3 would be H. For this polymer, e and f would be derived from methyl 2-(dec-9-enyl)-tridec-12-enoate and would equal 9 and 10, respectively; d would derive from 1,9-decadiene and would equal 8. The run length distribution would therefore be: rHH=(9+0)+8z; rHT=(9+10)+8z; and rTT=(10+10)+8z; therefore rtotal=(18+8z), (19+8z), (20+8z).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:19]3[CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[C:10]([CH3:42])[CH:9]=1)=[O:7])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:26]([O:25][C:23]([C:20]1[NH:21][C:22]2[C:18]([C:19]=1[CH2:28][CH2:29][CH2:30][O:31][C:32]1[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[CH3:42])=[O:24])[CH3:27]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC(C)(C)C)cc3C)cccc2c1CCCOc1cccc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)O)cc3C)cccc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 98C in dichoromethane (5 mL) and TFA (5 mL) was stirred at room temperature overnight and concentrated. The concentrate was partitioned between water (50 mL) and ethyl acetate (200 mL), and the organic phase was washed with brine and dried (Na2SO4), filtered and concentrated. 1H NMR (300 MHz, DMSO-d6) δ 12.88 (m, 1H), 11.00 (s, 1H), 8.22 (m, 1H), 7.85 (m, 3H), 7.86 (m, 1H), 7.73 (d, 1H), 7.32-7.55 (m, 5H), 7.08 (m, 2H), 6.92 (d, 1H), 4.25 (m, 4H), 3.36 (t, 2H), 2.24 (t, 2H), 2.10 (s, 3H), 1.26 (t, 3H).