Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([C:17]3[C:21]([Cl:22])=[C:20]([Cl:23])[NH:19][C:18]=3[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]C)[C:12]([Cl:16])=[C:13]([Cl:15])[CH:14]=2)=[O:9])=[C:4]([O:34]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([C:17]3[C:21]([Cl:22])=[C:20]([Cl:23])[NH:19][C:18]=3[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[C:12]([Cl:16])=[C:13]([Cl:15])[CH:14]=2)=[O:9])=[C:4]([OH:34])[CH:3]=1
Reactant: COc1ccccc1C(=O)c1[nH]c(Cl)c(Cl)c1-n1c(C(=O)c2ccc(Cl)cc2OC)cc(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccccc1O)c1[nH]c(Cl)c(Cl)c1-n1c(C(=O)c2ccc(Cl)cc2O)cc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of Compound 5 (33 mg, 0.058 mmol) in anhydrous DCM (1 mL) was slowly added 1.0 M solution of BBr3 in DCM (23 μL, 0.23 mmol, 4 eq.) via a syringe under N2 at −78° C. After being stirred for 0.5 h, the mixture was quenched by addition of MeOH (0.5 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, hexanes: 12% EtOAc) to give Compound 2 (30 mg, 96% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.34 (s, 1H), 10.39 (s, 1H), 9.77 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.43 (dd, J=8.0, 1.7 Hz, 1H), 7.36 (ddd, J=8.8, 7.4, 1.6 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.95-6.90 (m, 1H), 6.87 (dd, J=8.6, 2.0 Hz, 1H), 6.68 (s, 1H), 6.53 (ddd, J=8.0, 7.3, 1.1 Hz, 1H); HRMS (ESI-TOF) [M+H]+ calcd for C22H12Cl5N2O4 542.9234. found 542.9237; HPLC purity 96.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(N2CCNCC2)cc1Cl
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 19.3 g (0.08 mol) of 2-chloro-4,5-difluoronitrobenzene in 100 g of toluene are introduced into a 200 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 18.1 g (0.21 mol) of piperazine are added dropwise to this solution at room temperature and with stirring over the course of one hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed during the reaction is washed three times with 20 ml of water in each case and dried. The solvent is removed to give 18.5 g (0.071 mmol) of 2-chloro-5-fluoro-4-piperazinonitrobenzene. This corresponds to a yield of 95%, based on 2-chloro-4,5-difluoronitrobenzene used.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[N:9]1.[CH3:14]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1ccccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of the above-mentioned 1-(2-methylphenyl)-1,4-dihydrotetrazole-5-one 69.8 g and N,N-dimethylformamide 380 mL was added 55% sodium hydride 18.2 g under ice-cooling. After stirring the resulting mixture for twenty minutes, thereto was added methyl iodide 59.4 g. The mixtures were raised to room temperature and were stirred for two and a half hours. To the reaction mixtures was added water and the mixtures were extracted with methyl tert-butyl ether. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 52.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH2:19](Br)[CH3:20].C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:19]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:20]
Reactant: CCBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 71.6 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Ethyl bromide (0.297 mL, 0.00401 mol), Sodium iodide (0.0029 g, 0.000019 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol;) in N,N-Dimethylformamide (4 mL, 0.05 mol;) was reacted in an analogous manner to example 743-C to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.40 g, 72%). Mp129-131° C.
Reaction SMILES: N[C:2]12[CH:17]([OH:18])[CH2:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N(O)=O.N([O-])=O>>[CH:17]([C:2]12[CH2:16][CH:9]([C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=31)[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NC12c3ccccc3C(CC1O)c1ccccc12
Agent: O=NO
Agent: O=N[O-]
Product: O=CC12CC(c3ccccc31)c1ccccc12

Procedure:
9-Formyl-9,10-dihydro-9,10-methanoanthracene (iii) is prepared from 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (ii) by treatment with nitrous acid or metal nitrite in an acidic medium.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C:10](=[O:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3=O)cc1OCC2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.29 mmol) in dry THF (10 mL) was cooled to −78 C and a solution of lithium tri-sec-butylborohydride in THF (L-Selectride®, 1M, 0.30 mL, 0.30 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h, then aqueous sodium bicarbonate was added dropwise. After warming to room temperature, the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give racemic-cis-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (92 mg, 64%). LCMS RT=3.39, [M+H]+=495.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:15]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[C:5]#[N:15]
Reactant: NO
Reactant: COc1cc(C=O)c(OC)cc1C
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C#N)c(OC)cc1C
Temperature: 105 °C
Reaction time: 2 h

Procedure:
By analogy to steps outlined in J. Med. Chem. 1976, 19(12), 1400-1404. 2,5-dimethoxy-4-methylbenzaldehyde (14.8 g, 82.2 mmol) is dissolved in pyridine (300 mL) and to it is added hydroxylamine hydrochloride (6.8 g, 98.6 mmol). The suspension is heated at 105° C. for 2 h. Acetic anhydride (15.5 mL, 164 mmol) is then added to the reaction and stirring is continued for another 2 h. The solution is evaporated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic fraction is dried (Na2SO4) and evaporated to give a yellow solid which is taken up in hexanes and filtered to give 2,5-dimethoxy-4-methylbenzonitrile as a white solid. (cas # 51267-09-5) MS (ESI) m/z 178.2 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C:5](=[O:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>>[Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C@@H:5]([OH:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A 5-L mini-jar fermenter containing 3 L of medium A was inoculated with Candida magnoliae IFO0705 and incubated at 30° C. with 0.5 vvm aeration and stirring at 500 rpm for 24 hours. After completion of cultivation, 30 g of tert-butyl(5S)-6-chloro-5-hydroxy-3-oxohexanoate (synthesized by the process described in Example 1) and 60 g of glucose were added and the reaction was carried out, with the pH maintained at 6.5 with sodium hydroxide, for 18 hours. After completion of the reaction, the cells were removed centrifugally and the supernatant was extracted twice using 1.5 L of ethyl acetate each. The organic phase was separated and dehydrated over anhydrous sodium sulfate and the solvent was distilled off by heating under reduced pressure to recover 24 g of tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate as a solid. As analyzed by the method described in Example 4, the diastereomer ratio of this product was (3R,5S)/(3S,5S)=100/0. 1H-NMR (CDCl3, 400 MHz/ppm): 1.47 (9H, s), 1.62-1.78 (2H, m), 2.43 (2H, d, J=6.4. Hz), 3.51-3.58 (2H, m), 3.75 (1H, bs), 3.84 (1H, bs), 4.07-4.13 (1H, m), 4.23-4.28 (1H, m)
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C@H:12]([F:17])[C:13](OC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:18]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C@H:12]([F:17])[CH2:13][OH:14])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H](F)CN(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Yield: 92.4 %

Procedure:
Lithium borohydride (17.7 g, 0.81 mol) was suspended in THF (400 mL) under a nitrogen atmosphere and cooled to −15° C. with stirring. Methyl (2S)-3-(dibenzylamino)-2-fluoropropanoate (188.3 g, 0.62 mol) was suspended in THF (400 mL) and added dropwise to the mixture. On completion of addition, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 3 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to 0° C. and cautiously quenched with a saturated aqueous solution of ammonium chloride (300 mL). Additional water (400 mL) was added then the reaction mixture was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N hydrochloric acid and the aqueous phase was washed twice with ether. The aqueous phase was basified (pH=10 approx.) with 80% ammonium hydroxide in brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (2S)-3-(dibenzylamino)-2-fluoro-1-propanol (156.6 g, 92%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, 10H), 4.65-4.78 (m, 0.5H), 4.48-4.58 (m, 0.5H), 3.50-3.82 (m, 6H), 2.70-2.88 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.O.O.O.O.O.O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[OH:6][CH:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:9][CH2:8][CH:7]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC1(C)OCC2OC2CO1
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: O
Product: CC1(C)OCC(O)C(N2CCNCC2)CO1
Yield: 20.4 %

Procedure:
14.4 g (0.1 mol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (J. Org. Chem. 41, 2469 [1976]) are heated under reflux in 100 ml of acetonitrile with 20 g (0.1 mol) of piperazine hexahydrate for 8 hours and the 1,4-bis-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine precipitated [melting point: 235°-237° (from isopropanol)] is filtered off with suction. The mother liquor is concentrated and the residue is purified by chromatography on 200 g of silica gel with methylene chloride/methanol (9:1) as the mobile phase, the main component being eluted towards the end of the chromatography with methylene chloride/methanol (4:1). 4.7 g of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine are obtained as an oil; Rf value=0.05 (on silica gel; methylene chloride/methanol (9:1)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:17][CH:18]([OH:34])[CH:19]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1COCC1.[Br:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](Cl)=[O:54]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:17][CH:18]([OH:34])[CH:19]([NH:29][C:30](=[O:33])[CH2:31][NH:32][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][Br:48])[CH2:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCCCBr
Reactant: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CN)C(=O)OC(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CNC(=O)CCCCBr)C(=O)OC(C)(C)C)c1
Yield: 87.8 %

Procedure:
To a solution of the product from Step 5 (60 mg, 0.12 mmol, 1.00 eq.), triethylamine (33 μL, 0.24 mmol, 2.00 eq.), and anhydrous THF (0.6 mL) is added bromovaleryl chloride (15 μL, 0.11 mmol, 0.95 eq.) under N2 with stirring. The reaction mixture is stirred for 2 hours, then diluted with ethyl acetate, quenched with 1N HCl, and washed with 10% NaHCO3. The organic layer is dried over MgSO4, filtered, and then concentrated in vacuo, yielding product as a white solid (63 mg, 80% crude yield). Calculate mass for C31H43BrFN3O6: 651.23 (mass calculated for Br79 isotope). Mass found for C31H43BrFN3O6: (LCMS) ES+: 676.1 (M+Na), ES− 652.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[C:8]=2[CH:9]=1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1cc2cccc(OC)c2o1
Product: COC(=O)c1cc2c(S(=O)(=O)Cl)ccc(OC)c2o1
Yield: 80 %

Procedure:
There was reacted 1.7 g (8.25 mmole) of 2-methoxycarbonyl-7-methoxybenzofuran with chlorosulfonic acid as in Example 1, yielding 2 g of 2-methoxycarbonyl-4-chlorosulfonyl-7-methoxybenzofuran (yield: 80%, MS (m/z): 304 (M+), 269, 238 and 210). The obtained chlorosulfonyl compound was reacted wit glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 88%, MS (m/z): 371 (M+), 340, 298 and 269), which was then hydrolyzed to give 2-carboxy-4-(N-carboxymethylsulfamoyl)-7-methoxybenzofuran (colorless needles, yield: 86%). The physical constants are shown in Table 4.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1I.[O:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1>[Cu]I.CCOC(C)=O>[Br:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[O:35][CH:32]1[CH2:33][CH2:34][O:30][CH2:31]1
Reactant: OC1CCOC1
Reactant: Cc1cccc(I)c1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: Cc1cccc(OC2CCOC2)c1Br
Temperature: 120 °C

Procedure:
A vial was charged with copper(I) iodide (38.5 mg, 0.202 mmol), 1,10-phenanthroline (72.8 mg, 0.404 mmol), cesium carbonate (1.32 g, 4.04 mmol), 2-bromo-1-iodo-3-methylbenzene (600 mg, 2.021 mmol) and tetrahydrofuran-3-ol (1.80 mL, 22.23 mmol). The vial was sealed and the reaction mixture was heated to 120° C. for 24 h. The reaction mixture was cooled to RT, EtOAc was added and the mixture was filtered through a pad of silica gel. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (25% EtOAc/hexanes). 3-(2-Bromo-3-methylphenoxy)tetrahydrofuran was isolated as a light-yellow oil (178 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:16]=23)[CH2:2][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Scheme 1, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with benzimidazole (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield methyl 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.Cl.[C:15]1(Cl)[C:21](=O)C(Cl)=C(Cl)[C:17](=O)[C:16]=1Cl.C(=O)([O-])O.[Na+]>C(O)CCC.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:7]1([CH3:13])[O:8][C:9]2=[CH:10][C:11]3[CH:21]=[CH:15][C:16]([CH3:17])=[N:1][C:2]=3[CH:3]=[C:4]2[CH:5]=[CH:6]1
Reactant: CC1(C)C=Cc2cc(N)ccc2O1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCCCO
Solvent: C1CCOC1
Product: Cc1ccc2cc3c(cc2n1)C=CC(C)(C)O3
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
To 6-amino-2,2-dimethylchromene (1.00 g, 5.71 mmol), 35% hydrochloric acid (1.43 mL, 17.1 mmol), p-chloranil (1.40 g, 5.71 mmol) and n-butanol (1.3 mL) were added at room temperature and the temperature was increased to 120° C. A solution of crotyl aldehyde (0.567 mL, 6.84 mmol) in n-butanol (0.52 mL) was added and the resulting mixture was stirred at 120° C. for 20 minutes. A solution of zinc chloride (0.777 g, 5.71 mmol) in tetrahydrofuran (10 mL) was added, and the resulting mixture was stirred at 120° C. for 20 minutes. Upon the completion of the reaction, sodium hydrogencarbonate aqueous solution was added, and the resulting solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=2/1), and recrystallized with ethyl acetate to obtain the aimed product (yield: 22%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([CH3:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(C)cccc2c1=O
Yield: 91.3 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide (1.71 g, 5.36 mmol) and triphosgene (2.07 g, 6.96 mmol) in THF (20 mL) was heated at reflux for 1 h. The mixture was cooled on an ice-water bath and treated with saturated aqueous NaHCO3. Stirring was continued until gas evolution ceased. The resulting mixture was extracted 3 times with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was triturated with ether to give a white solid, collected by filtration. A second trituration of the concentrated filtrate gave additional solid, collected by filtration. The filtrate from this was concentrated and purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide additional solid. The three solids were combined to provide 3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione as a white solid (1.69 g, 91% yield). Mass spectrum m/z 345, 347 (M+H)+. 1H NMR (400 MHz, chloroform-d): δ 8.07 (d, J=7.9 Hz, 1H), 7.70 (dd, J=7.9, 1.3 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.27-7.17 (m, 3H), 2.41 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>O1CCOCC1.C(O)C.O>[Cl:1][C:2]1[C:3]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(Cl)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1c(Cl)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
A mixture of Example 229D (0.16 g, 0.261 mmol) and 3N sodium hydroxide (0.261 mL, 0.784 mmol) in 1,4-dioxane (1.743 mL), ethanol (1.743 mL) and water (0.7 mL) was heated at 75° C. for 2.5 hours. The mixture was concentrated and the residue was partitioned in ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of from 0-4% methanol in dichloromethane afforded the title compound. MS (ESI+) m/z 458.1 (M+H)+.