Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:30])[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:31].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:30])[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:31]
Reactant: Cn1c(=O)oc2cc(C(=O)CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)oc2cc(C(O)CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc21
Temperature: 25 °C

Procedure:
0.01 mole of 3-methyl-6-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-1-oxopropyl}benzoxazolinone is dissolved in 200 cm3 of methanol in a 250-cm3 flask equipped with a magnetic stirrer. 0.02 mole of sodium borohydride is added very slowly and with stirring. Stirring is maintained for 4 hours at room temperature. The reaction medium is evaporated on a water bath under vacuum. The residue is taken up with water and extracted several times with chloroform. The extracts are filtered and evaporated to dryness on a water bath under vacuum. The product is recrystallized in ethanol.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH3:33])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:32]([O:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:34][CH2:35][CH3:36])[C:21]([CH2:20][C:6]1[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17])=[CH:30]2)[CH3:33]
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OCC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (140 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.60 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided after evaporation 33 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 41 as a yellow solid (31.4 mg, 10% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](I)[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[N:31][CH:32]=1)#[CH:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:11][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[C:26]#[C:25][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[N:31][CH:32]=1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Into a reaction flask were added tert-butyl (4-cyano-2-iodophenyl)carbamate (1.4 g, 4.1 mmol), copper(I) iodide (31 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL, 4.5 mmol). The mixture was stirred under N2 bubbling for 5 minutes and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) (prepared according to Example 17, Step B) was then added. The reaction mixture was stirred at 65° C. for 2 hours. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product (0.94 g, 52%). LCMS for C24H27N4O4 (M+H)+: m/z=435.2.
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O.CN1CCOCC1>C1COCC1.C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]2[NH:31][C:11](=[O:12])[CH:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:33]=2[CH:34]=1
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)OCc1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (0.446 g, 1.965 mmol) in 5 mL of dry THF was cooled to 0° C. and then treated with oxalyl chloride (0.171 mL, 1.34 mmol). The mixture was stirred for 30 min at 0° C. A mixture of Intermediate 7A (0.235 g, 1.034 mmol) and NMM (0.237 mL, 2.59 mmol) in DCM (3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 2 h and then filtered. The filtrate was treated with 2M methanolic ammonia (10 mL) and stirred at room temperature for 12 hrs. The mixture was then evaporated to dryness and the residue was treated with AcOH (5 mL) and stirred for 2 hrs at room temperature. The reaction mixture was then concentrated and purified by flash column chromatography to provide Intermediate 7B as a white solid: 70 mg (16.29%). HPLC: RT=1.908 min (ACN/H2O with TFA, UPLC R BEH C18, 1.7 μm, 2.1×50 mm, gradient=4 min, Flow=1.8 mL/min; Mobile Phase A: 0.1% TFA in water; Mobile Phase B: Acetonitrile; wavelength=220 nm); MS(ES): m/z=416 [M+H]+; 1H NMR (CDCl3) δ 8.681 (brs, 1H), 7.565-7.583 (d, J=7.2 Hz, 1H), 7.30-7.50 (m, 7H), 7.097 (brs, 2H), 6.80 (brs, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.34 (d, J=7.2 Hz, 1H), 5.17 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12](CC#N)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[OH-:18].[K+].[CH2:20]([OH:22])[CH3:21]>>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:21][C:20]([OH:18])=[O:22])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCc1ccc2c(c1)Nc1nccnc1S2
Agent: [K+]
Product: O=C(O)Cc1ccc2c(c1)Nc1nccnc1S2

Procedure:
4.7 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetonitrile was dissolved in 100 ml of ethanol. After adding 2.8 g of potassium hydroxide, the resulting mixture was heated under reflux for 16 hours. After distilling off the ethanol, water was added and the mixture was made weakly acidic with dilute hydrochloric acid followed by the extraction with ethyl acetate and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 3.85 g of the title compound was obtained as yellow crystals.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[CH:23]1([NH:28][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCC1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
Prepared according to Example 127 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 39.8 mg, 0.094 mmol) and cyclopentanamine (0.028 mL, 0.282 mmol) in DMSO (0.8 mL), heating at 100° C. for 50 min. Purification by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) followed by chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-3% MeOH/DCM) furnished 2-(3-(cyclopentylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.8 mg, 0.019 mmol, 20% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br. s.), 7.89 (1H, d, J=7.4 Hz), 7.56 (1H, d, J=7.6 Hz), 7.32 (1H, t, J=7.8 Hz), 7.12 (1H, s), 6.94 (1H, d, J=5.9 Hz), 4.34-4.42 (1H, m), 4.03 (1H, s), 3.43 (2H, t, J=6.9 Hz), 2.87 (2H, t, J=6.8 Hz), 2.55 (3H, s), 2.04-2.17 (2H, m), 1.69-1.83 (4H, m), 1.66 (2H, d, J=7.6 Hz). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:8]1[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([CH2:16]Cl)=[C:10]([CH3:18])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CN(C)C=O>[C:4]([C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([CH2:16][C:1]#[N:2])=[C:12]([CH3:15])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC#N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 41 grams of potassium cyanide dispersed in 300 ml of N,N-dimethylformamide, was slowly added a solution of 97.2 grams of the compound of Example 1, the reaction temperature rising from 25° to 35° C. The reaction mixture was then heated at 70° to 75° for 71/2 hours. Since a sample analyzed after 7 hours reaction time indicated that some unreacted starting 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol remained unreacted, an additional 13.7 grams of potassium cyanide was added and the reaction mixture heated for an additional 2 hours at 60° to 65° C. The reaction mixture was poured on crushed ice, and water added to make the total volume 1.8 liters. The mixture was stirred until the ice melted, the aqueous solid dispersion was filtered by suction, and the filtercake washed well with water. The filtercake was taken up in a toluene-benzene mixture, the resulting solution being successively washed with water, 6N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and treating the clear filtrate with activated charcoal, the solvent was evaporated at reduced pressures. The resulting residue was allowed to crystallize from toluene yielding white crystals melting at 134° to 139°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.C1C=CC=CC=1.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH2:27]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCc1ccccc1
Reactant: NCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.7 Parts 5-aminopentanoic acid and 22.8 parts p-toluenesulfonic acid monohydrate is suspended in 180 parts benzene and 32.4 parts benzyl alcohol is added. A continuous water separator is attached to the flask and the mixture stirred at vigorous reflux temperature for 16 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the residual oil shaken with n-hexane. The supernatant is discarded and the gummy product rubbed with ethyl ether causing crystallization to take place. The solid is separated, by filtration and washed with ethyl ether to afford the desired 5-aminopentanoic acid benzyl ester p-toluenesulfonate.
Reaction SMILES: C(Cl)CCl.[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[C:10]([O:14][C:15]([N:17]([C@@H:22]1[CH2:24][C@H:23]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][C:19](O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>COCCOCCOC>[CH3:6][C:5]1[N:7]=[C:19]([CH2:18][N:17]([C@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(N)=NO
Solvent: ClCCCl
Solvent: COCCOCCOC
Product: Cc1noc(CN(C(=O)OC(C)(C)C)[C@H]2C[C@H]2c2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
EDC (107 μL, 0.585 mmol) and acetoamidoxime (41 mg, 0.532 mmol) was added to a stirred solution of 2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic acid (163 mg, 0.532 mmol) in diglyme (2 mL) under argon atmosphere. The mixture was stirred at 50° C. overnight and then at 110° C. for 14 hours. After removal of solvent under vacuum, the reaction mixture was purified by flash chromatography eluting with hexane/MTBE (80:20 to 0:100) to afford tert-butyl (3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcyclopropyl)carbamate as a colourless oil (35 mg. Yield=20%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@:14]([OH:64])([CH3:63])[C:15](=[O:62])[C@@H:16]([NH:21][C:22](=[O:61])[C@@H:23]([NH:31][C:32](=[O:60])[C@@H:33]([NH:38][C:39](=[O:59])[C@@H:40]([NH:49][C:50](=[O:58])[CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C@:14]([OH:64])([CH3:63])[C:15](=[O:62])[C@H:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:21][C:22](=[O:61])[C@H:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:31][C:32](=[O:60])[C@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:38][C:39](=[O:59])[C@H:40]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:49][C:50](=[O:58])[CH2:51][N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide. MS for C47H65N5O10S m/z: 892 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:27])=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[OH:26][C:22]1[C:21]([CH3:27])=[C:20]([CH:25]=[CH:24][CH:23]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(O)c3C)c2cc1OC
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-amino-2-methylphenol (0.032 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 1.5 h. After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3. The title compound, which slowly precipitated was filtered off and dried to give 34 mg (55%).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13]>C[O-].C[O-].C[O-].C[O-].[Ti+4]>[C:11](=[O:16])([O:14][C:15]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1)[O:12][C:13]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1.[C:11](=[O:16])([O:14][CH3:15])[O:12][C:13]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: CC(=O)Oc1ccccc1
Agent: [Ti+4]
Agent: C[O-]
Product: COC(=O)Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In the aforesaid apparatus, at 145° C., were charged 74 g of phenyl acetate and, gradually, 90 g of dimethyl carbonate and 1 g of titanium tetramethoxide. Methyl acetate being continuously distilled, after 4 hours there were obtained 80% by mole of diphenyl carbonate and 18% by mole of phenyl methyl carbonate, at selectivity higher than 98% and 97% conversion of methyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:40])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[OH-].[Li+].CN(C)C=O.SCC(O)=O>CCOC(C)=O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([F:40])[CH2:18][NH:19][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NCC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (21.0 mg, 0.030 mmol; see representative procedure 4) was added lithium hydroxide (3.2 mg, 0.134 mmol), dimethylformamide (0.5 ml, 0.06 M) and mercaptoacetic acid (4.2 ul 0.060 mmol). After stirring at rt for 1 h the reaction mixture was diluted with EtOAc and washed sequentially with water, saturated sodium bicarbonate solution, water (3×) and brine. The organic layer was dried over Na2SO4, filtered and condensed. The crude reaction mixture was purified in 30% EtOAc/hexanes (+0.2% TEA), with 13.6 mg isolated. Yield=88%
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:26]=[N-:27]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 3-amino-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (181 mg, 0.487 mmol) was dissolved in trifluoroacetic acid (2.4 mL) and cooled in an ice bath. Solid sodium nitrite (67 mg, 0.97 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (317 mg, 4.87 mmol) was added followed by diethyl ether (2.4 mL). This was stirred in the ice bath for 10 minutes and then partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. The gave methyl 3-azido-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (161 mg) as a yellow solid. MS (ESI) m/z 398.9 (M+H). 1H NMR (CDCl3) δ ppm 7.85 (1H, d, J=2.14 Hz), 7.75 (1H, s), 7.71 (1H, dd, J=8.55, 2.14 Hz), 7.01 (1H, d, J=8.55 Hz), 4.01 (3H, s), 3.96 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])=[O:34])=[CH:28][CH:27]=1
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)Nc1ccc(F)cc1
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.15 mmol) and triethylamine (0.01 mmol) in anhydrous dichloromethane was added 1-fluoro-4-isocyanatobenzene (0.14 mmol) at ambient temperature. The mixture was stirred for 16 h, diluted with of dichloromethane (5.00 mL), washed with 10% HCl solution and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (0.05 g) in 82% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.06-6.91 (m, 3H), 6.67 (s, 1H), 6.52 (t, 1H), 5.94-5.84 (ABq, 2H), 4.74 (d, 1H), 4.61 (d, 1H), 3.91-3.69 (m, 2H), 3.49-3.34 (m, 2H); MS (ES+) m/z 462 (M+1), 484 (M+23).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[S:34]([CH3:33])(=[O:36])=[O:35])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)S(C)(=O)=O
Temperature: 0 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.81 mL, 5.81 mmol) and methanesulfonyl chloride (226 μL, 2.92 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Crystallization of the residue from EtOAc and CH2Cl2 gave 756 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as tan crystals. m.p. 145.0–146.5° C.;
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:10](OC)(OC)([O:12]C)[CH3:11].[CH3:18]O>>[C:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([O:5][CH3:18])=[O:4])(=[O:12])[CH3:11]
Reactant: COC(C)(OC)OC
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCCN1
Product: COC(=O)C1CCCCN1C(C)=O
Yield: 50 %

Procedure:
(S)-pipecolic acid (1.0 g, 7.7 mmol) was treated with trimethyl orthoacetate (15 ml, 171 mmol, 22 eq. 15 vol) and methanol (5 ml, 5 vol). The mixture was stirred and heated for 48 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and filtered through a silica gel plug to yield N-acetylpipecolic acid, methyl ester (730 mg, 50%) which was racemic by GC analysis and had a 1H nmr spectrum which compared favourably with authentic material.