Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:7]=[C:6]2[NH:14][CH:15]=[CH:16][C:5]=12.[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:14]1[C:6]2=[CH:7][N:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[CH:16]=[CH:15]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COCc1c(C(=O)OC)ncc2[nH]ccc12
Product: COCc1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1F

Procedure:
The title compound was prepared by alkylation of methyl 4-methoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate [prepared according to X. Doisy et al., Bioorg. Med. Chem. 1999, 7, 921-932) with 2,4-difluorobenzyl bromide in a manner similar to step 1 of example 2. 1H NMR (CDCl3) δ ppm. 8.70 (s, 1H), 7.31 (d, 1H, J=4.0 Hz), 6.71-6.98 (m, 4H), 5.36 (s, 2H), 5.12 (s, 2H), 3.92 (s, 3H), 3.38 (s, 3H). LCMS (API-ES, M+H+): 347.1
Reaction SMILES: [H][H].C(OCC)(=O)C.CCCCCC.[C:15]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:43]([OH:45])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])([OH:17])=[O:16].CO>C(O)C.[Pd].C(O)(=O)C.C1(C)C=CC=CC=1>[C:15]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[C:24]([NH:26][C@@H:27]([C:35]([NH:37][C@@H:38]([C:43]([OH:45])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])([OH:17])=[O:16]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1C(=O)O)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCC[C@H]1C(=O)O)C(=O)O

Procedure:
An argon flushed solution of this phenylmethyl ester product (0.71 g., 1.2 mmole) in 95% ethanol (30 ml.) is treated with 10% palladium on carbon catalyst (70 mg.). The mixture is hydrogenated under a positive pressure of hydrogen, with thorough stirring, overnight at room temperature. After filtering the mixture through Celite, the filtrate is concentrated in vacuo to give 0.41 g. of a light brown solid. An analytical sample is prepared by recrystallization of 0.33 g. from ethyl acetate/hexane to yield 0.243 g. of white solid (trans)(R,R)-N-[N-[N-[(2-carboxycyclohexyl)carbonyl]-L-phenylalanyl]-L-leucine; m.p. 183.5°-185°. [α]D =39.8° (C =1.0, methanol). TLC (silica gel; toluene:acetic acid, 9:2) Rf =0.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cccc(Cl)n1
Product: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,6-dichloropyridine. The title compound was obtained as a yellow solid (Yield=60%). MS ISP (m/e): 315.1 & 317.1 (100 & 37) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): 8 (ppm)=7.63 (s, 1H), 7.48 (t, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 6.95-6.80 (m, 2H), 6.82 (d, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[Cu]I.O.CN(C)C(=O)C>[C:16]1([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@@H]1CCCN1c1ccccc1
Temperature: 90 °C

Procedure:
Step D (1): To a sealed tube flushed with nitrogen was added L-proline (3.684 g, 32.0 mmol), potassium carbonate (6.634 g, 48.0 mmol), copper (I) iodide (609 mg, 3.2 mmol), iodobenzene (3.58 mL, 32.0 mmol) and N,N-dimethylacetamide. The mixture was heated at 90° C. for 48 hours, then cooled to room temperature. Water was added, and the pH adjusted to <3 with concentrated HCl. The aqueous phase was extracted 4 times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (0 to 100% EtOAc/hexane gradient) afforded N-phenylproline which was used directly in the next step. LC-MS (M+H)+=192. LC-MS RT (column 1)=2.230/4.00. 1H NMR (500 MHz, CDCl3): δ 10.574 (br s, 1H), 7.29-7.25 (m, 2H), 6.785 (t, J=7.5 Hz, 1H), 6.613 (d, J=8.0 Hz, 2H), 4.25 (dd, J=2.4, 8.8 Hz, 1H), 3.60 (dt, J=2.8, 8.3 Hz, 1H), 3.36 (m, 1H), 2.38-2.01 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cl

Procedure:
The title compound was prepared by reacting 2-chloro-phenol, with ethyl 2-bromoacetate and K2CO3 in DMF. Yield, 97%, colourless oil; 1H NMR (CDCl3): 1.29 (3H, t, J=6.3, CH2CH3), 4.29 (2H, q, J=6.3, CH2CH3), 4.72 (2H, s, OCH2), 6.76 (1H, d, J=8.2, H-6), 6.95 (1H, m, H-4), 720 (1H, m, H-5), 7.40 (1H, dd, J=8.2, H-3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29]C[C@@H:27](O)[CH2:26]1>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:29]1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: O[C@@H]1CCN(CCCc2cccs2)C1
Product: O=C(O[C@@H]1CCN(CCCc2cccs2)C1)C(O)(c1cccs1)c1cccs1
Yield: 49.1 %

Procedure:
Prepared as described in Intermediate I-1 from 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester and (3R)-1-(3-thien-2-ylpropyl)pyrrolidin-3-ol (Intermediate I-17). The yield was 0.83 g (49.1%) of the title product as an oil. A portion of this product was solidified by formation of the oxalate salt.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([CH3:25])[N:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[S:31][C:30]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:29][N:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:18]1[N:19]=[C:20]([CH3:25])[N:21]=[C:22]([N:33]([CH2:32][C:30]2[S:31][C:27]([CH3:26])=[N:28][N:29]=2)[C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Reactant: Cc1ccc(C2C(COc3cc(Cl)nc(C)n3)C2OC(C)(C)C)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2C(COc3cc(N(Cc4nnc(C)s4)C(=O)OC(C)(C)C)nc(C)n3)C2OC(C)(C)C)nc1
Temperature: 80 °C
Yield: 48.9 %

Procedure:
The mixture of 12-6 (160 mg, 0.4421 mmol), tert-butyl (5-methyl-1,3,4-thiadiazol-2-yl)methylcarbamate (122 mg, 0.53 mmol), BINAP (31 mg, 0.049 mmol) and cesium carbonate (173 mg, 0.53 mmol) in toluene (2 mL) was stirred for 5 min before Pd(OAc)2 (10 mg, 0.044 mmol) was added. The mixture was degassed with nitrogen for 5 min, then it was heated to 80° C. for overnight. The solvent was removed under reduced pressure and the residue was purified by Pre-TLC (PE/EA=1/1). The product was obtained as a white solid (120 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.17 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 5.52 (s, 2H), 4.52-4.18 (m, 2H), 3.64 (dd, J=6.8, 3.6 Hz, 1H), 2.73 (s, 1H), 2.69 (s, 3H), 2.52 (s, 3H), 2.30 (s, 3H), 2.27 (m, 1H), 2.04 (m, 1H), 1.50 (s, 9H), 1.07 (s, 9H); LRMS (ES) calculated M+H for C28H39N6O4S: 555.7. Found: 555.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:22])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@@H:32]([CH3:43])[CH2:31]2)[CH:24]=1.O[Li].O.CC(O)=O>CO.O>[CH3:42][C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:25]2[CH:24]=[C:23]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH2:8][N:9]([CH3:22])[C:10]([C:12]4[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=4)[C:18]([OH:20])=[O:19])=[O:11])[CH:4]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:31][C@@H:32]1[CH3:43])=[O:37])([CH3:40])[CH3:41]
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Agent: [Li]O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(C)C(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-4-[(2′-fluoro-5′-{[methyl({3-[(methyloxy)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (0.215 g, 0.365 mmol) in MeOH/H2O (1.0/0.5 mL) was added LiOH.H2O (0.077 g, 1.83 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then it was acidified with HOAc. This mixture was extracted with DCM which was dried over Na2SO4, filtered, concentrated and purified using a Gilson HPLC to afford the title compound 0.0639 g (30%). LC-MS m/z 576 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:9]=1.Cl.[CH2:21]([NH:23][CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22].[I-].[K+].C(OCC)C>CN(C)C=O>[CH2:21]([N:23]([CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:9]=1)[CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH3:22]
Reactant: CCNC/C=C/C#CC(C)(C)C
Reactant: O=C(CCCBr)COc1cccc(-c2ccsc2)c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(C/C=C/C#CC(C)(C)C)CCCC(=O)COc1cccc(-c2ccsc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
50 mg of 5-bromo-1-[3-(3-thienyl)phenoxy]-2-pentanone was dissolved in 1.8 ml of dimethylformamide, and 125 mg of a (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 29 mg of potassium iodide were added. The mixture was stirred at 40° C. for 1 hour, and then ethyl ether and ice water were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane→chloroform] to give 20 mg (yield 27%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](O)=[O:5])[CH3:2].C(Cl)([Cl:13])=O>ClC1C=CC=CC=1>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([Cl:13])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCCCC(CC)C(=O)O
Solvent: Clc1ccccc1
Product: CCCCC(CC)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
87 g (0.6 mol) of 2-ethylhexanoic acid and 890 g of monochlorobenzene are introduced into the reactor and 607 g (6.14 mol) of phosgene are then added over about 30 minutes, while maintaining the temperature of the reaction medium at a maximum of 25° C. The set pressure is adjusted to 10.5 bar relative and the reaction medium is heated. The reaction is complete after one hour 30 minutes. The levels of residual acid and anhydride are zero and the level of 2-ethylhexanoyl chloride obtained is greater than 99.8 mol %.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.N1(C(=O)C)CCNCC1.[CH3:62][C:63]([OH:67])([C:65]#[CH:66])[CH3:64]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:66]#[C:65][C:63]([OH:67])([CH3:64])[CH3:62])=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(Br)cc2-3)CC1
Reactant: C#CC(C)(C)O
Agent: CC(=O)N1CCNCC1
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: CC(=O)N1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(C#CC(C)(C)O)cc2-3)CC1
Yield: 42 %

Procedure:
Similar to as described in General Procedure G, 3-((4-acetylpiperazin-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 1-(piperazin-1-yl)ethanone) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (34 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[OH:9].[CH2:24]=O>C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]([CH3:24])[CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[OH:9]
Reactant: COc1ccccc1CNCC(O)c1ccc(OC)c(OC)c1
Reactant: C=O
Solvent: O=CO
Product: COc1ccccc1CN(C)CC(O)c1ccc(OC)c(OC)c1
Yield: 93 %

Procedure:
A mixture of 1.85 g. (0.0058 m) of N-(2-methoxybenzyl)-1-(3,4-dimethoxyphenyl)-2-aminoethanol prepared as in Example 3, 4.8 ml of 90% formic acid and 4.5 ml of 37% formaldehyde was heated in a steam bath for 18 hours. The aqueous portion was evaporated and the residue redissolved in water. After making the solution acid with concentrated hydrochloroic acid, the mixture was heated for 20 minutes, cooled, made basic and extracted with chloroform. The organic extract was washed with water, brine then dried. Evaporation gave 1.8 g (93%) of N-(2-methoxybenzyl)-1-(3,4-dimethoxyphenyl)-N-methyl-2-amino ethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Pb].ClC1C=C2C(=O)OC(=O)C2=CC=1>>[Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: [Pb]
Product: O=C1OC(=O)C2CC(Cl)C=CC12

Procedure:
4-Chlorophthalic anhydride is an expensive starting material which presently must be custom synthesized. Current routes for the synthesis of 4-chlorophthalic anhydride lead to mixtures of isomers, which are difficult to separate, or are prohibitively costly. For example, the Diels-Alder condensation of maleic anhydride with 2-chloro-1,3-butadiene to yield 4-chlorotetrahydrophthalic anhydride, followed by aromatization in the presence bromine requires the subsequent recovery of HBr. Attempted thermal aromatization of 4-chloro-tetrahydrophthalic anhydride results in low yields of 4-chlorophthalic anhydride and tar formation. This and other routes are described in U.S. Pat. Nos. 5,059,697; 5,003,088; 5,322,954; 4,978,760 and 5,233,054.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=3[C:14]#[N:15])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=3[CH2:14][NH2:15])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(Sc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cn1ncc2cc(Sc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of compound (4r), (0.43 g, 1.5 mmol) in MeOH (30 mL) was purged with nitrogen and treated with Pd(OH)2/C catalyst (15% wt, 280 mg, 0.3 mmol) followed by concentrated HCl (0.38 mL, 4.6 mmol). After purging more with nitrogen, a hydrogen-filled balloon was placed on top of the flask. After stirring at room temperature for 18 hours, the LC showed no more starting material. Next, K2CO3 (0.5 g) was added. The catalyst was filtered through a plug of silicagel/celite/sand and washed with CHCl3/Et3N and the solvent was removed under reduced pressure. The resulting pale yellow foam (5r), (0.43 g, 87% isolated yield) was stored under a nitrogen atmosphere. MS (ESI) m/z 287.9 (M+H)+.
Reaction SMILES: CN[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:10])[O:32]2)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNC(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 553.5 %

Procedure:
A solution of N-methylbenzamide (0.38 g) in 200 mL of anhydrous tetrahydrofuran was cooled to -78° C. and treated with tert-butyl lithium (30 mL, 1.7M). At the end of the addition, the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 1 hour and then cooled back to -78° C. After treatment with a solution of 1-benzyloxycarbonyl-4-piperidone (5.83 g) in 2 mL of tetrahydrofuran, the reaction mixture was stirred at -78° C. for 40 minutes and then quenched with 300 mL of saturated ammonium chloride solution. Extraction with ethyl acetate, washing the organic layer with brine, drying over magnesium sulfate and evaporation afforded the crude product. This material was partially purified by column chromatography; elution with ethyl acetate:hexane (6:4) afforded the named material (5.25 g); MS: 238 (M-99); NMR: 1.6-1.7 (m, 2), 2.0-2.1 (m, 2), 3.4 (br., 2), 4.0-4.1 (br, 2), 5.2(s, 1), 7.2-7.4 (m, 5), 7.5 (m, 1), 7.7 (m, 1), 7.9 (m, 1).
Reaction SMILES: CB(O)O.[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:27]=[C:26]5[N:28]=[C:29]([O:31][C@H:32]6[C@H:36]7[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]7[O:34][CH2:33]6)[NH:30][C:25]5=[CH:24][C:23]=4Cl)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:9]=[N:8][CH:7]=[N:6]1.[C:42](=O)([O-])[O-].[K+].[K+]>[Pd+2].O1CCOCC1>[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:27]=[C:26]5[N:28]=[C:29]([O:31][C@H:32]6[C@H:36]7[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]7[O:34][CH2:33]6)[NH:30][C:25]5=[CH:24][C:23]=4[CH3:42])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccc(-n5cncn5)cc4)cc3)c(Cl)cc2[nH]1
Agent: [Pd+2]
Agent: CB(O)O
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2[nH]c(O[C@@H]3CO[C@H]4[C@@H]3OC[C@H]4O)nc2nc1-c1ccc(-c2ccc(-n3cncn3)cc2)cc1
Temperature: 140 °C

Procedure:
Methyl boronic acid (174 mg, 2.90 mmol), (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (150 mg, 0.290 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (86 mg, 0.116 mmol) were added as solids to a microwave tube, followed by degassed 1,4-dioxane (2 mL) and 2 M aqueous potassium carbonate (1741 uL, 3.48 mmol). The tube was sealed and heated to 140° C. in a microwave for 30 minutes. The organic phase of the reaction was removed and evaporated under reduced pressure. The crude mixture was diluted in DMSO (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 5%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from water/acetonitrile to give the title compound as white solid. LC-MS: calculated for C22H24N6O4 496.19 observed m/e: 497.24 (M+H)+ (Rt 0.79/2.5 min); 1H NMR δ (ppm) ((CD3)2SO):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[C:13]=2[O:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.B(Br)(Br)Br.O>C(OCC)(=O)C.C(OCC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:27][CH:26]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]3)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(Cl)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Dissolve the product of Example 28 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.6 mL, 1.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol). After 1 hour, add water (1.0 mL) and dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with a step gradient of methanol/dichloromethane (0 to 5%) to give 120 mg of the title compound (68%): mass spectrum (ion spray): m/z=552.2 (M+H).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:36]#[N:37])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CN(C)C=O
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
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: [C-]#N
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C#N)ccc43)cc2OC)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (1.00 g, 1.99 mmol) in N,N-dimethylformamide (20 mL) was added zinc(II) cyanide (0.64 g, 3.52 mmol), tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.40 mmol) and potassium carbonate (0.63 g, 4.54 mmol). The mixture was heated to 150° C. After 4 h, the mixture was allowed to cool to room temperature and was concentrated. The residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to give 0.70 g (87%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile as a yellow solid.