Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4](S(C)=O)[N:3]=1.[NH3:27]>>[NH2:27][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=1
Reactant: N
Reactant: Cc1nc(-c2nccnc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Product: Cc1nc(N)cc(-c2nccnc2Nc2cccc3[nH]ncc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
The mixture from Step 3 was treated with ammonia (30% in water) in a sealed tube. The mixture was stirred at 100° C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% THF/CH2Cl2 to give N-(3-(6-amino-2-methylpyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (7 mg, 39% yield) as a yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 13.17 (s, 1H); 12.95 (s, 1H); 8.37 (d, J=2.05 Hz, 1H); 8.25 (s, 1H); 8.18 (d, J=2.05 Hz, 1H); 8.10 (d, J=7.75 Hz, 1H); 7.45 (s, 1H); 7.33 (t, J=8.11 Hz, 1H); 7.19 (d, J=7.31 Hz, 1H); 2.65 (s, 3H). m/z (ESI, +ve ion) 319 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:32]3=[O:42])=[O:30])=[C:23]([F:43])[CH:22]=2)[CH:17]=[CH:16][N:15]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Cl:27][C:26]1[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:19]=2)=[CH:22][C:23]([F:43])=[C:24]([NH:28][C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:32]2=[O:42])=[O:30])[CH:25]=1
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.7 %

Procedure:
A RT solution of cyanoacetic acid (0.500 g, 5.88 mmol) in DCM (20 mL) and DMF (0.1 mL) was treated drop-wise with oxalyl chloride (1.1 mL, 12.52 mmol), stirred at RT for 2.5 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), added drop-wise to a 0° C. solution of N-(4-((2-aminopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.210 g, 0.467 mmol) in pyridine (10 mL), stirred for 0.5 h, then concentrated to dryness. The residue was dissolved in DCM, washed with satd. NaHCO3 and the aqueous layer extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc). The material was further purified via silica gel chromatography (MeOH/DCM) to afford N-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (120 mg, 49%). MS (ESI) m/z: (M+H+): 516.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:3][CH:2]=1.C(O)(=O)C>[Pt].CCOC(C)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccncc2)C1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(OCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g) was mixed with acetic acid (25 ml) and EtOAc (25 ml), and 10% platinum/carbon was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(piperidin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22]>Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:21]([NH2:22])=[NH:20])=[C:10]([O:15][C:16]([F:19])([F:17])[F:18])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#CN
Reactant: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(NC(=N)N)c(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (275 mg, 1 mmol) in HCl 6N (1 mL), cyanamide (336 mg, 8.0 mmol) was added and the reaction was stirred at 60° C. for 1 h. The mixture was cooled down to room temperature, diluted with water (3 mL), extracted with DCM (10 mL). NaOH 2N was added to pH>11. The aqueous phase was extracted with Et2O (3×10 mL), dried over sodium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (240 mg, 76% yield) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A 4 g. sample of ethyl 4-(14-methylpentadecyl)aminobenzoate is hydrolized with 2.0 g. of 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water, and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected and dried in vacuo to yield the title compound as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1cccnc1OC1CCNCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3OC3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 3-bromo-2-(piperidin-4-yloxy)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H20FN5O, 365.17; m/z found, 366.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=1.5, 2H), 8.20 (dd, J=4.9, 1.9, 1H), 7.89 (dd, J=7.4, 1.9, 1H), 7.68-7.51 (m, 3H), 7.14 (dd, J=7.4, 4.9, 1H), 6.90 (s, 2H), 5.36 (s, 1H), 3.06 (d, J=11.3, 4H), 2.13 (s, 2H), 1.86 (s, 2H).
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[S:31])[CH2:21][CH2:20]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CO>[N:25]1([CH:22]2[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]2)[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=[S:31]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCCC2=S)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COc1ccccc1
Solvent: ClCCl
Product: S=C1CCCCN1C1CCNCC1
Reaction time: 0.5 h

Procedure:
Anisole (2.5 mL) was added to a solution of 2-thioxo-[1,4′]bipiperidinyl-1′-carboxylic acid benzyl ester (2.4 g) in methylene chloride (40 mL) at 0° C. followed by the addition of trifluorosulfonic acid (3.4 mL). After 30 minutes, solid potassium carbonate was added, then sodium sulfate and methanol. The solids were removed by filtration and the filtrate was concentrated. The residue was dissolved in methanol and neutralized by passage through a column of Amberlyst A-21 (slightly basic) resin. The filtrate was collected and concentrated and purified by chromatography, with methylene chloride:methanol (gradient 95:5, 90:10) as eluent. The title compound was obtained as a white solid (0.93 g). MS: m/z=199 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]3[C:9]=2[C:17](=[O:19])[N:23]([CH:24]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]2=[O:26])[C:11]3=[O:13])=[CH:20][CH:21]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 48.5 %

Procedure:
A mixture of 3-(4-chloro-benzyloxy)-phthalic acid (1.9 g, 6.2 mmol), alpha-amino-glutarimide hydrochloride (1.1 g, 6.5 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(4-chloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (1.2 g, 49% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 6.64 min (99.9%); mp, 239-241° C.; 1H NMR (DMSO-d6) δ 2.00-2.07 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.38 (s, 2H, CH2), 7.48-7.86 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.91, 48.75, 69.18, 115.66, 116.65, 120.16, 128.50, 129.02, 132.52, 133.25, 135.22, 137.03, 155.27, 165.30, 166.74, 169.89, 172.75. Anal Calcd For C20H15N2O5Cl: C, 60.24; H, 3.79; N, 7.02; Cl, 8.89. Found: C, 60.41; H, 3.63; N, 7.02; Cl, 8.72.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>>[ClH:34].[ClH:34].[CH3:33][O:32][C:30]([CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:17][CH2:18]2)=[CH:23][CH:24]=1)=[O:31]
Reactant: COC(=O)COc1ccc(N2CCC(NCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N2CCC(NCC3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[(1-tert-butyloxycarbonylpiperidin-4-yl)methylamino]-1-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 1-methylpiperidin-4-amine (58 mg, 0.51 mmol). The title compound was obtained as a solid (95.0 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (1H, m), 8.65 (1H, m), 8.49 (1H, m), 3.60 91H, m), 2.78 (2H, m), 2.18 (3H, s), 1.98 (2H, m), 1.75 (2H, m), 1.53 (2H, m). MS m/z: 447.31, 449.29 [M+H]+.
Reaction SMILES: S[CH2:2]CC(OCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS)=O.[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:33])[CH:31]=[CH2:32].C([Si](OC(C)C)(OC(C)C)OC(C)C)=C.C(O)(=O)C=C.[OH-].[NH4+]>CC(N=NC(C#N)(C)C)(C#N)C>[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:33])[CH:31]=[CH2:32].[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:33])[C:31]([CH3:2])=[CH2:32]
Reactant: O=C(CCS)OCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCCC
Agent: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Product: C=C(C)C(=O)OCCCC
Reaction time: 0.5 h

Procedure:
A heteroarm star polymer was prepared by stage polymerization using pentaerythritol tetrakis(3-mercaptopropionate). A monomer blend of 5 pphm vinyltriisoproxysilane, 5 pphm of butyl acrylate, 40 pphm of butyl methacrylate and 2.5 pphm of pentaerythritol tetrakis(3-menrcaptopropionate) was polymerized for 45 minutes with 0.5 pphm AIBN as catalyst. A second monomer mixture of 5 pphm of butyl acrylate, 5 pphm of vinyltriisopropoxysilane and 40 pphm of acrylic acid was then added to the reaction and the polymerization continued for 2 additional hours. The reaction was cooled and aqueous ammonium hydroxide was added and stirred for 30 minutes. After that, the isopropyl alcohol was removed and water was added to make a stable colloid. The end polymer pH was adjusted to 9.5 using aqueous ammonium hydroxide. The physical properties of the polymer are summarized in Table I.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][CH:7]=1)=[O:5])C.[I-].[Li+]>N1C=CC=CC=1>[O:12]=[C:11]1[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:8][CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinecarboxylic acid ethyl ester (i.e. Step B product (A)) (2.30 g, 7.18 mmol) in pyridine (15 mL) was added lithium iodide (2.46 g, 18.0 mmol). The reaction mixture was heated to reflux with stirring for 24 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (10 mL) followed by 1 N hydrochloric acid until the pH was 7. The solution was filtered though Celite® diatomaceous filter aid. The filtrate was acidified with 1 N hydrochloric acid until the pH was 1, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a white solid (1.40 g).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[C:8]1[C:13](=O)[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C>CO>[NH:2]1[C:13]2[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:8]=2[CH:7]=[N:5]1
Reactant: CN(C)C=C1CC(NC(=O)OC(C)(C)C)CCC1=O
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2[nH]ncc2C1
Yield: 55.3 %

Procedure:
Hydrazine monohydrate (0.11 mL, 2.35 mmol) was added to a solution of tert-butyl {3-[(dimethylamino)methylene]-4-oxocyclohexyl}carbamate obtained in Example (242a) (526 mg, 1.96 mmol) in methanol (10 mL), and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated. The resulting residue was azeotropically distilled with toluene and then purified by silica gel column chromatography (elution solvent: dichloromethane/methanol 20/1) to obtain 257 mg of the title compound as an amorphous compound (55%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C([O:15][C:16](=[O:19])[CH2:17]Br)(C)(C)C.[OH-].[Na+].FC(F)(F)C(O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:17][C:16]([OH:19])=[O:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccccc1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1CCOCC(=O)O

Procedure:
The subtitle compound (8.91 g) was prepared according to the procedure in example 5 part a using 2-(2-methylphenyl)ethanol (5.0 g), t-butylbromoacetate (5.47 ml), tetrabutylammoniumbromide (0.78 g), toluene (80 ml), 50% aqueous sodium hydroxide (40 ml), trifluoroacetic acid (20 ml) and dichloromethane (20 ml).
Reaction SMILES: S([C:5]1[O:13][C:12]2[CH:11]=[C:10](C)[NH:9][C:8](=[O:15])[C:7]=2[CH:6]=1)(=O)(=O)N.O1C=CC=[C:17]1C(C)=CC(O)=O.O1C=CC=C1C=C(C)C(O)=O>>[CH3:17][C:11]1[C:12]2[O:13][CH:5]=[CH:6][C:7]=2[C:8](=[O:15])[NH:9][CH:10]=1
Reactant: Cc1cc2oc(S(N)(=O)=O)cc2c(=O)[nH]1
Reactant: CC(=CC(=O)O)c1ccco1
Agent: CC(=Cc1ccco1)C(=O)O
Product: Cc1c[nH]c(=O)c2ccoc12

Procedure:
The title compound was prepared according to the procedure described for 2-sulfamoyl-6-methylfuro[3.2-c]pyridin-4-(5H)-one (Example 12 Step A) except 3-(2-furanyl)-3-methylacrylic acid was substituted for 3-(2-furanyl)methacrylic acid. Title compound was obtained in 41% yield, m.p. 239°-241° C., after crystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:29]3[C:30]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc4ccccc34)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 1-naphtaleneboronic acid (56 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.B(O)(O)[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH2:21])[CH2:20]2)[CH:14]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1C1(c2ccc(C)cc2)C=C(N)N=C(N)C1
Yield: 11 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and p-tolylboronic acid provided the title compound (11% yield). 1H NMR (acetone-d6) δ2.26 (s, 3H, CH3), 3.83 (s, 3H, CH3) 5.24 (bs, 2H, NH2), 6.10 (d, 1H, J=1.1 Hz, Ar), 6.26 (t, 1H, J=1.1 Hz, Ar), 7.06 (d, 2H, J=8.5 Hz, Ar), 7.08 (d, 1H, J=8.8 Hz, Ar), 7.29 (d, 1H, J=2.7 Hz, Ar), 7.35 (dd, 1H, J=9.0 Hz, J=3.3 Hz, Ar), 7.53-7.56 (m, 2H, Ar), 7.70 (s, 1H, NH).
Reaction SMILES: [SiH3]O.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:19]12([CH2:26][CH2:27][Si](C)(C)Cl)[CH2:25][CH:22]([CH:23]=[CH:24]1)[CH2:21][CH2:20]2>CO>[CH2:26]([C:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]=[CH:20]2)[CH3:27]
Reactant: C[Si](C)(Cl)CCC12C=CC(CC1)C2
Agent: CN(C)c1ccccn1
Agent: O[SiH3]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC12C=CC(CC1)C2
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Silanol fluid, Rhone Poulenc 48V3500, (0.092 eq OH) was stirred under nitrogen and warmed to 70° C. with triethylamine-dimethylaminopyridine (1.05 eq, 1% DMAP by weight). The product of example 2 (0.0956 eq, 20.5 g) was added. The reaction mixture was stirred at 75° C. for three hours then methanol (50 g) was added slowly. After one hour, volatiles were removed by concentration on a rotary evaporator, the reaction mixture was diluted with hexane and filtered through diatomaceous earth. Removal of solvent on a rotary evaporator at 75° C. (0.1 mm Hg) gave the product: Viscosity 4680 cps, GPC MWwt 30787, MWnumber 23943.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(C)C=CC=CC=1.C(Cl)Cl>CCOCC.C(N(CC)CC)C>[CH2:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)=[O:32])=[CH:29][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
4-Benzyloxyphenol (20.0 g. 100 mmol) was dissolved in 200 mL dry ether and 10 mL triethylamine. 4-Decyloxybenzoyl chloride (30.0 g, 100 mmol) was added dropwise with stirring at room temperature under nitrogen. After 1 day of stirring at room temperature under nitrogen atmosphere, 200 mL toluene and 200 mL methylene chloride were added to the reaction mixture. The reaction mixture was then filtered and the filtrate washed twice with 0.5N HCl, once with water, and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from toluene-ethanol to provide 43.9 g (95% yield) 4-benzyloxyphenyl 4-decyloxybenzoate.
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]([CH3:29])[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:30].[CH3:31][N:32]([CH3:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>C1COCC1>[CH3:42][N:32]([CH3:31])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][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]([CH3:29])[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:30])=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CN(C)CCc1ccc(N)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Dimethylamino-ethyl)-phenylamine (40.9 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a light brown precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 12% (0.016 g, 0.029 mmol) of the title compound.