Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34]
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
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: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Temperature: 90 °C
Yield: 119.1 %

Procedure:
To a solution of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74, Step C (0.200 g, 0.356 mmol), and 2-methoxyphenylboronic acid (0.081 g, 0.533 mmol) in acetonitrile (3 mL) was added a 0.4 M aqueous sodium carbonate solution (3 mL) and the mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.018 mmol) was then added and the reaction mixture heated to 90° C. for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over amnhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (0.23 g). Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from dichloromethane/hexane to afford the title compound (0.181 g, 94%) as a white solid, m.p. 119-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[CH3:27][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:27])[C:8]=2[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (208 g, 0.55 mol) in a mixture of dichloromethane (830 mL) and methanol (410 mL) at 10° C., a solution of (trimethyl-silyl)diazomethane (600 mL, 1.2 mol; 2M) in hexanes was added over a period of 1 hour with the reaction temperature maintained below 15° C. The reaction mixture (unstirred) was allowed to stand at 10° C. overnight, and then at 20° C. for additional 4 hours. The reaction mixture was cooled back to 10° C. and quenched with acetic acid (˜75 mL). The product mixture was concentrated under vacuum and the residue recrystallized from boiling methyl tert-butyl ether and heptane. The solid recrystallized was collected by filtration, washed with a mixture of methyl tert-butyl ether and heptane (1:1, v/v), and air dried to afford the title compound.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: C=CCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCCCCCCC=COS(=O)(=O)c1ccc(C)cc1

Procedure:
10-undecene-1-ol was reacted with 4-methylbenzene sulfonyl chloride to produce 1-methyl 4-undecenyloxy sulfonyl benzene;
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]([NH:27][NH:28][C:29](=[O:31])[CH3:30])=S.C(O)C>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]1[O:31][C:29]([CH3:30])=[N:28][N:27]=1
Reactant: CC(=O)NNC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3C[C@H]2C)OCO4)o1
Yield: 51 %

Procedure:
A stirred mixture of 2.2 g (5.15 mmol) of (R)—N′-(8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-7-carbothioyl)-acetic hydrazide (an intermediate of method B of Example 28), 44 ml of ethanol and 1.72 g (5.39 mmol) of mercury (II) acetate was refluxed for 2 h. The residue obtained on concentration was dissolved in dichloromethane and filtered through a neutral aluminum oxide column. After washing the column the filtrate was concentrated and the residue was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of n-hexane-ethyl acetate (1:2.5) as eluent to yield 1.07 g (51%) of the title compound. Mp.: 202-204° C. after recrystallization from ethanol. [α]: −249° (c=0.22; CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[N:4]=1.CN(C=O)C.[CH:40]#[C:41][CH2:42][CH2:43][CH3:44]>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.C(N(CC)CC)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([C:40]#[C:41][CH2:42][CH2:43][CH3:44])[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[O:15])[N:6]=1
Reactant: C#CCCC
Reactant: COc1cc(OC)nc(Oc2cccc(OS(=O)(=O)C(F)(F)F)c2C(=O)OCC[Si](C)(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Temperature: 0 °C
Yield: 62.8 %

Procedure:
In a 100 ml flask equipped with a thermometer, a cooling tube and a nitrogensintroducing tube, there were charged 2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-trifluoromethylsulfonyloxybenzoate (4.72 g, 9.0 mmol), bis(triphenylphosphine)palladium dichloride (300 mg, 0.4 mmol), DMF (30 ml) and triethylamine (5 ml), and the resultant mixture was stirred at room temperature for 1 hour under nitrogen stream. Thereafter, 1-pentyne (2.0 g, 29.40 mmol) was added to the resultant mixture, and the mixture was reacted at 80°-90° C. for 3 hours. After cooling, the mixture was poured into an ice water, and was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The residue thus obtained was then purified by silica gel column chromatography to obtain 2.50 g (yield: 62.8%) of the aimed product (red-brown transparent viscous liquid).
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[O:16][CH2:15]1.[CH2:23]([CH2:25][NH2:26])[OH:24]>C(O)C>[OH:24][CH2:23][CH2:25][NH:26][CH2:15][CH:14]([OH:16])[CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC(C)CCCCCCCCCOCC1CO1
Reactant: NCCO
Solvent: CCO
Product: CCCCCCC(C)CCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C

Procedure:
By use of ethanol (4 ml), 10-methylhexadecylglycidyl ether (100 mg, 0.32 mmol) was transferred to a 10 ml dropping funnel, which was fitted to a 20 ml round bottomed flask containing ethanolamine (1 ml) and ethanol (0.2 ml). The content of the flask was stirred at 80° C. in a nitrogen atmosphere. The ethanol solution was added dropwise over 10 minutes. The mixture was stirred for a further 1 hour, and then condensed under reduced pressure. The resulting residue was purified by silica gel flush chromatography. 94 mg of the title compound was obtained as a pale yellow Vaseline-like material (yield: 79%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[O:18]=[C:19]=[C:20]1[C:25](=[C:26]=[O:27])[CH:24]=[CH:23][C:22]([CH2:28][NH2:29])=[CH:21]1>>[O:18]=[C:19]=[C:20]1[C:25](=[C:26]=[O:27])[CH:24]=[CH:23][C:22]([CH2:28][NH:29][C:7]2[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=[C:9]3[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=23)=[CH:21]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NCc1ccc(=C=O)c(=C=O)c1
Product: CCn1ncc2c(NCc3ccc(=C=O)c(=C=O)c3)c(C(=O)O)cnc21
Yield: 80 %

Procedure:
4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and (3,4-dioxomethylenephenyl)methylamine were used to afford the title compound (80%) as a white solid: mp 230° C. (decomposed).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O.Cl.C1(N)CC1>C1COCC1>[CH:13]1([NH:16][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: C=Cn1cnc2c(Cl)ncnc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=Cn1cnc2c(NC3CC3)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[OH-].[Na+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
This preparation is similar to that reported by Krapcho et. al. for Cbz-Mop-OH. (Krapcho et. al. J. Med. Chem. 31:1148-1160 (1988)). To a solution of N-tert-Butoxycarbonyl-(2S,4R)-4-hydroxyproline (Boc-Hyp-OH, 2.00 g, 8.65 mmol) and CH3I (1.90 mL, 30.3 mmol) in acetone (50 mL) was added Ag2O (6.50 g, 28.1 mmol). The vessel was purged with Ar(g) and sealed with a septum, and the resulting suspension was stirred at room temperature for 24 h. The mixture was filtered and evaporated to a residue under reduced pressure. The residue was dried under high vacuum for 1 h, and then resubmitted to the reaction conditions a second time. After filtering and evaporating, the residue was dissolved in H2O (60 mL), a solution of NaOH (0.36 g, 9.08 mmol) in 1 mL H2O was added, and the solution was stirred at room temperature for 24 h (to hydrolyze any methyl ester that might have formed during alkylation). The aqueous mixture was acidified to pH 1 by the addition of 3 N HCl(aq) and extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried over MgSO4(s) and evaporated under reduced pressure, and the product was then isolated by flash chromatography (100:0-95:5 CH2Cl2/MeOH) affording Boc-Mop-OH (0.97 g, 46%) as a tinted residue. 1H NMR (500 MHz, CDCl3, ˜3:2 ratio of 2 rotamers): δ 4.44 (t, J=7.5 Hz, 0.6 H), 4.34 (t, J=7.9 Hz, 0.4 H), 4.01-3.95 (m, 1 H), 3.70-3.65 (m, 0.4 H), 3.60-3.52 (m, 1 H), 3.49 (dd, J=11.7, 4.8 Hz, 0.6 H), 3.33 (overlapping s, 3 H), 2.46-2.36 (m, 1 H), 2.32-2.24 (m, 0.6 H), 2.17-2.07 (m, 0.4 H), 1.49 (s, 5.4 H), 1.43 (s, 3.6 H);
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:32])([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1>C1COCC1>[F:32][C:11]([F:10])([C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]3=[N:24][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:20]3[CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc(C(F)(F)c2ccc(-c3cccnc3N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 362 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.571 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(difluoro(4-methylphenyl)methyl)phenyl)pyridin-2-amine obtained by step C of Example 136 in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo and washed with IPE to give the title compound (197 mg) as an off-white powder. A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)C.CCOCC>C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([CH:25]=[C:1]([Br:5])[Br:2])[CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2×), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 53.458 g crude product as a yellowish solid. Flash chromatography (PC) on 250 g silica gel (0-15% EtOAc in hexanes) gave 21.595 g title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04-4.12 (m, 2H), 2.75-2.83 (m, 2H), 2.42-2.50 (m, 1H), 1.69-1.75 (m, 2H), 1.47 (s, 9H), 1.29-1.37 (m, 2H).
Reaction SMILES: C(Cl)(=[O:3])C.[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:28]=[C:27]([NH:29][C:30]5[CH:35]=CC=CC=5)[CH:26]=[C:25]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[N:6]1>C(Cl)Cl>[N:5]1([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:28]=[C:27]([NH:29][C:30](=[O:3])[CH3:35])[CH:26]=[C:25]([N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: c1ccc(Nc2cc(-c3ccnc(Nc4ccc(-n5ccnn5)cc4)n3)cc(N3CCOCC3)c2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccnc(Nc3ccc(-n4ccnn4)cc3)n2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (0.02 mL, 0.28 mmol) in CH2Cl2 (1 mL) was added to N-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-(3-morpholino-5-(phenylamino)phenyl)pyrimidin-2-amine (0.11 g, 0.28 mmol) in CH2Cl2 (3 mL) drop wise at 0° C. The reaction was warmed to room temperature, stirred for 30 min, concentrated, and purified by chromatography on silica gel (ethyl acetate/hexanes) to afford N-(3-(2-(4-(1H-1,2,3-triazol-1-yl)phenylamino)pyrimidin-4-yl)-5-morpholinophenyl)acetamide. MS (ESI) 457 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:29][CH:30]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
5-Cyano-2-benzofurancarboxylic acid (300 mg, 1.60 mmol) and t-butyl 4-aminophenoxyacetate (395 mg, 1.76 mmol) were dissolved in N,N-dimethylformamide (40 ml), and 1-hydroxy-1H-benzotriazole (238 mg, 1.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (342 mg, 1.76 mmol) were added. The mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give 512 mg of t-butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate as a pale-yellow solid (82%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:35][N:36]([CH3:56])[CH2:37][CH2:38][O:39][CH:40]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([CH:40]([O:39][CH2:38][CH2:37][N:36]([CH3:35])[CH3:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:49][CH:48]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)Cl)cc1
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, 4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine (122 mg, 0.33 mmol) was dissolved in dichloromethane and triethylamine (0.093 mL, 0.67 mmol). The solution was cooled in an ice-water bath and 4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (106 mg, 0.33 mmol) was dissolved/slurried in dichloromethane and added dropwise. The ice bath was removed and the reaction was stirred for an additional 16 hours. The reaction was quenched with 10% aqueous sodium carbonate. The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water followed by brine, dried (Na2SO4), decanted and evaporated to yield a yellow oil. Purification by flash column chromatography (silica gel, 92:8 dichloromethane/methanol gradient to 95:5 dichloromethane/methanol) provided 101 mg of N-[4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a pale yellow solid. The product was determined to be 97+% pure by HPLC. MS(CI): 648 (M+H).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]1[C:17]2([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:18]([NH:20][C:21](=O)[CH:16]12)=[O:19].[OH-].[Na+].[H-]>C1C=CC=CC=1.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:17]23[CH2:15][CH:16]2[CH2:21][NH:20][C:18]3=[O:19])=[CH:24][CH:25]=1
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C1NCC2CC12c1ccc(Cl)cc1

Procedure:
To a stirred solution of 3.0 ml of sodium bis(2-methoxyethoxy)aluminum hydride is added dropwise a solution of 2.2 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide (U.S. Pat. No. 3,344,026) in 200 ml of benzene, over a 45 minute period, at room temperature, under nitrogen. The mixture is refluxed under nitrogen for one hour. After cooling, 4 ml of 5N sodium hydroxide is added to decompose any excess hydride and the mixture is diluted with 200 ml of water. The benzene phase is separated. The aqueous phase is extracted with ether. The ether and benzene phases are combined, dried over magnesium sulfate and concentrated under reduced pressure to give a white glass which is recrystallized from benzene-hexane to give the product as a white solid, mp 132°-137 ° C. (dec).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)([O-:3])=[O:2].[CH2:12]([N:14](CC)CC)C.ClC(OCC)=O.CN.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:12][NH:14][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2]
Reactant: O=C(O)CCCCO[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CNC(=O)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
To a solution of compound 2 (1.60 g, 1.0 eq) in dry dichloromethane (20.0 mL) cooled to 0° C. was added triethylamine (1.70 mL, 1.2 eq) followed by ethyl chloroformate (1.10 mL, 1.1 eq). The reaction mixture was stirred at 0° C. for 45 minutes and 40% aqueous methyl amine (20.0 mL) was added. The solution was stirred from 0° C. to RT for 18 hours and sodium sulphate was added to dry the reaction mixture. The resulting mixture was filtered off and the filtrate was concentrated under vacuum. The residue was adsorbed on silica gel and purified by flash chromatography [Biotage®, dichloromethane/methanol 100/0→97/3 (15CV*)] affording compound 3 as a colourless liquid (0.84 g, yield=47%).