Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:14])=[CH:7][CH:8]=1
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1cccnc1)C(=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1cccnc1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (132 mg, 0.35 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 10% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][CH:16]3[O:20]CC[O:17]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16]([OH:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2CCC1OCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCC1c2ccccc2-c2ccccc21

Procedure:
3-(9-Fluorenyl)propionic acid was prepared from 2-(9-fluorenyl)ethyl-1,3-dioxolane (50.0 g, 187 mmol) which was dissolved in 20 ml of acetone and 450 ml of Jones' reagent (64 g chromic acid and 64 ml of sulfuric acid in 400 ml of water). After the reaction was complete, the acetone was evaporated, the residue taken into ethyl acetate, washed with water, and organic layer extracted with 1N sodium hydroxide which was acidified with 10% HCl to yield a tan precipitate. FTIR 1954, 1913, 1707, 1429, 1316, 1257, 1208, 948, 933, 735 cm-1. 1H NMR (300 MHz, DMSO-dis) δ 1.84 (t, 2H, J=7.5 Hz), 2.21 (m, 2H), 4.03 (t, 2H, J=5.5 Hz), 7.28-7.38 (m, 4H), 7.56 (d, 2H, J=7.0 Hz), 7.84 (d, 2H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14]C1C=C2C(OC(=O)NC2=CC=1)=O>>[F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[N:11]([CH3:14])[C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Product: Cn1c(=O)oc(=O)c2cc(F)ccc21

Procedure:
By substituting 27 g of 5-fluoroisatoic anhydride for the 5-methylisatoic anhydride Preparative Example 13, there is obtained 5-fluoro-N-methylisatoic anhydride; mp 150°-155° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[Cl:28]>>[Cl:28][C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:22]=2)[CH:25]=[C:26]([CH3:27])[C:17]=1[OH:16]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1O
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(O)c(Cl)c3)no2)cc1C
Yield: 24 %

Procedure:
The title compound (11 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-3-chloro-5-methyl-benzamidine (23 mg, 117 μmol) according to Method A; LC-MS: tR=0.60 min; [M+1]+=392.12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]/[CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC/C(=C\C=O)c1cccc(F)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1cccc(F)c1

Procedure:
As described in Example 99, (E)-3-(3-fluorophenyl)-2-octenal (5.43 g was treated with (carbomethoxymethylene)triphenylphosphorane (9 g) in dichloromethane (50 mL) for 4 days at room temperature. The ester was isolated in the usual manner and purified by HPLC (ether-hexane; 1:9) to provide 6.04 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[CH:13]=[C:14]([N+:21]([O-:23])=[O:22])[C:15]([NH2:20])=[N:16][C:17]=1[O:18][CH3:19]>>[Br:11][C:12]1[CH:13]=[C:14]([N+:21]([O-:23])=[O:22])[C:15]([NH:20][CH:8]=[O:10])=[N:16][C:17]=1[O:18][CH3:19]
Reactant: O=CO
Reactant: COc1nc(N)c([N+](=O)[O-])cc1Br
Solvent: CC(=O)OC(C)=O
Product: COc1nc(NC=O)c([N+](=O)[O-])cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of acetic anhydride (15.9 mL, 168.7 mmol) and formic acid (6.4 mL, 168.7 mmol) was heated at 60° C. for 3 h. After cooling to rt, 5-bromo-6-methoxy-3-nitropyridin-2-amine (2.1 g, 8.4 mmol) from Step 1 of this Example was added in portions. The resulting mixture was heated at 60° C. for 1 h, then at 70° C. for 1 h. LCMS analysis showed that the reaction was complete. The volume was condensed under reduced pressure, and the precipitated solid was collected by filtration to give N-(5-bromo-6-methoxy-3-nitropyridin-2-yl)formamide as a light yellow solid (2.2 g, 94%). LCMS (ESI) m/z 276, 278 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3ccccc3n2)CC1
Yield: 66 %

Procedure:
A mixture of 2-chloro-4-(2-fluoro-phenyl)-quinazoline (0.8 g, 3.09 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 4.02 mmol, 1.3 equiv; commercially available) in anhydrous NMP (8 mL) was heated by microwave irradiation to 180° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with heptane/ethyl acetate (10:1) providing 0.86 g (66%) of the title compound. MS (ISP): 423.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[NH:20]1>C(O)C>[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[N:20]1[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccccc1OCC(O)CCl
Reactant: CC1CCCC(C)N1
Solvent: CCO
Product: COCCOc1ccccc1OCC(O)CN1C(C)CCCC1C
Yield: 74.3 %

Procedure:
A mixture of 5.2 g of 1-chloro-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, 4.6 g of 2,6-dimethylpiperidine and 50 ml of ethanol is refluxed for 16 hours. The ethanol is removed, and ether is added to the residue. The insoluble matter is filtered off, and the filtrate is extracted with two 80 ml portions of 10% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and the separated oil is extracted twice with ether. The ether layer is dried over anhydrous potassium carbonate, and the ether is removed to give 5.0 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, melting at 92°-94°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:15][C:13]1[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 0.73 mmol) from Example 51, Step A in DMF (3 mL) was added 3,4-difluorobenzyl bromide (0.122 mL, 0.95 mmol) and then cesium carbonate (310 mg, 0.95 mmol). The reaction was stirred at 50° C. for 3 h and was then diluted with water and extracted three times with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude products. The products were separated by preparative TLC (3×1 mm) eluted with 25% ethyl acetate in hexanes to yield faster eluting O-alkylation title product. HPLC/MS: 534 (M+1), 536 (M+3); Rt=5.17 min. 1HNMR (CDCl3): δ 3.981 (s, 3H), 5.489 (s, 2H), 7.04 (br d, J=8.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.2-7.6 (m, 3H), 7.38 (d, J=2.0 Hz, 1H), 8.285 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.B(Br)(Br)Br.[C:25]([O-])(O)=[O:26].[Na+]>ClCCl>[CH3:25][O:26][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:1])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-2-amine (52.8 mg, 0.185 mmol) in dichloromethane (2 mL) was added BBr3 in dichloromethane (1 M, 925 μL) at 0° C. under an argon atmosphere. The reaction was then stirred at 0° C. for 3 h before it was neutralized with NaHCO3 (sat aq). The precipitated product was filtered off, washed with water and DCM and dried. Recrystallization from (MeOH/toluene) gave the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.75 (br s, 1 H) 8.58 (d, 1 H) 7.93 (dd, 1 H) 7.73 (d, 1 H) 7.34 (d, 1 H) 7.19 (t, 1 H) 6.92 (dd, 1 H) 6.56 (d, 1 H) 3.32-3.38 (m, 2 H) 1.16 (t, 3 H); MS m/z (M+H) 272.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[CH3:16][O:20][N:21]([CH3:22])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1)=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nonc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of benzo[c][1,2,5]oxadiazole-5-carboxylic acid (0.49 g, 2.987 mmol) in DCM (50 mL) were added HATU (1.7 g, 4.481 mmol), N-methoxy, N-methylamine (0.44 g, 4.481 mmol) and TEA (914 mg, 8.963 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.49 g, 79%) as a yellow oil.
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:7]=1[O:8][CH2:9][CH2:10][S:11][C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.C(=O)([O-])[OH:39].[Na+]>>[Cl:5][C:6]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:7]=1[O:8][CH2:9][CH2:10][S:11]([C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1)=[O:39]
Reactant: COc1cc2nccc(Oc3ccc(SCCOc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: COc1cc2nccc(Oc3ccc(S(=O)CCOc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Nitric acid (0.5 ml) was added to 4-(4-{[2-(2,4-dichlorophenoxy)ethyl]sulfanyl}phenoxy)-6,7-dimethoxyquinoline (20 mg), and the mixture was stirred at 0° C. for one hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (19 mg, yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12](Cl)=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2cc(C(=O)Cl)oc12
Reactant: Nc1ccccc1
Product: COc1cccc2cc(C(=O)Nc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Step A of Reference Example 58 was repeated using 7-methoxybenzofuran-2-carbonyl chloride and aniline to give Compound IIbg (13.0 g, 68.2%) as a yellowish white solid.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42](O)=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
4.56 g (16.58 mmol) of diphenylphosphoryl azide, 1.50 g (20.55 mmol) of t-butylamine and 2.78 g (27.80 mmol) of triethylamine were successively added, whilst ice-cooling, to a solution of 3.68 g (13.90 mmol) of (4S)-1-benzyloxycarbonyl-4-hydroxy-L-proline in 30 ml of dimethylformamide, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the resulting mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 1.10 g of the title compound as colorless crystals, melting at 129°-130° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH:11][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(Br)cc(Cl)cc1C(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(Br)cc(Cl)cc1C(C)Nc1ncnc2c1ncn2C1CCCCO1
Yield: 98.3 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5 mmol) in ethanol (69 mL), was treated with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) and heated at reflux overnight. The reaction mixture was cooled, poured into sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using acetonitrile in dichloromethane (5%-10%) and then ethyl acetate in hexanes (60%-100%) gave the desired product (3.9 g, 98%). LCMS for C19H22BrClN5O2 (M+H)+: m/z=466.1, 468.1. Found: 466.0, 468.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])S(C(F)(F)F)(=O)=O>CN(C=O)C>[CH:33]([Si:32]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Oc1ccc(-c2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(-c2cc3ccccc3s2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixture of 2-(4-hydroxyphenyl)benzothiophene (2.84 g, 12.6 mmol), triethylamine (2.5 g, 25.2 mmol) and 30 mL dry DMF was cooled in an ice bath and treated with triisopropylsilyl triflate (7.7 g, 25.2 mmol). The reaction was allowed to warm to room temperature, quenched with 100 mL brine then extracted twice with 50 mL EtOAc. The combined extract was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting solid was purified by chromatrography (SiO2, 5% EtOAc in Hexanes) to yield 4.7 g (12.3 mmol, 98%) of a solid.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[C:7]([I:49])=[C:8]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])=[CH:24][CH:23]=2)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:15]([CH2:14][NH:13][C:10]1[C:9]([I:18])=[C:8]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:26][CH:27]=2)=[O:20])[C:7]([I:49])=[C:6]([NH:5][CH2:4][C:1](=[O:3])[CH3:2])[C:11]=1[I:12])(=[O:17])[CH3:16]
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc2)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)O)cc2)c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a solution of 4-[[[3,5-bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepentadecanoic acid, 1.1-dimethylethyl ester XIe of Example 7b (30 mg, 0.3 mmol) in anisole (1 mL), was added trifluoroacetic acid (10 mL) and the mixture stirred at RT overnight (15 h). The solvents were removed in vacuo, and the residue crystallized from ethyl acetate to furnish pure XIIe as a white amorphous solid (205 mg, yield 70%, purity>98%). Additional product (35 mg, purity 96%) was obtained from the mother liquor for a total yield of 81%.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:13][C:10]3[CH:11]=[CH:12][C:7]4[CH2:6][NH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:8]=4[CH:9]=3)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCNCc2ccc(N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)N(C)CCNC3)ncc1Cl
Temperature: 120 °C
Reaction time: 1 h
Yield: 2.2 %

Procedure:
1-Methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (271 mg, 1.53 mmol) and 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (425 mg, 1.28 mmol) were combined in 2-Methoxyethanol (10 mL) and 4.00 M of Hydrogen chloride in 1,4-Dioxane (1.0 mL) was added. The reaction was warmed to 120° C. for 6 h, then the reaction was cooled to room temperature for 1 h before Macroporous carbonate resin (3.16 mmol/g loading; 2.2 g, 6.95 mmol) was added and stirred at r.t. for 1 h, filtered then conc. in vacuo to give an oil. The material was chromatographed on an ISCO column (40 g, 0-15% (5% NH4OH:MeOH):DCM, celite dry load). Product eluted impure with 15% polar solvent, so it was purified by RP-HPLC (5-25% acetonitrile:water). Clean material concentrated followed by formation of the free base with Macroporous carbonate resin to afford 3-Chloro-2-[5-chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (13 mg, 2%) as an orange film. LCMS (m/e) 472 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.04 (s, 1H), 6.91 (m, 3H), 6.07 (s, 1H), 3.88 (s, 2H), 3.48 (s, 2H), 3.06 (m, 2H), 2.94 (m, 2H), 2.72 (d, 3H, J=4.6 Hz), 2.68 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:29](=[O:30])[CH2:28][C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)COC)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)COC)cn1

Procedure:
2-Amino-pentanoic acid [1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: H1NMR (400 MHz, CDCl3) 0.85 (t, 3H, J=7), 1.3 (m, 2H), 1.54 (s, 6H), 1.65 (m, 1H), 1.80 (m, 1H), 3.29 (s, 3H), 3.43 (s, 2H), 3.53 (s, 3H), 4.76, (m, 1H), 6.56 (m, 1H), 6.71 (m, 1H), 6.81 (m, 2H), 7.44 (s, 1H), 7.65 (s, 1H); MS m/z 423.3 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8])=O.[C:13]([C:15]1[CH:20]=CC(O)=[CH:17][CH:16]=1)#[N:14]>>[CH3:9][C:6]([O:5][C:3]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:2]=1)([CH3:10])[C:7]#[CH:8]
Reactant: C#CC(C)(C)OC(=O)C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1

Procedure:
The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0° C., was added to the 4-cyanophenol solution over a 40 minute period while keeping the temperature at ~0° C. The resulting mixture was stirred at ~0° C. (ice bath). After stirring for 5 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between water (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (3×50 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a very pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (8.04 g).