Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:7](=[O:25])[N:8]([CH2:21][CH2:22][CH2:23]O)[N:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(Br)([Br:28])=O>O>[Br:28][CH2:23][CH2:22][CH2:21][N:8]1[C:7](=[O:25])[C:6]([Cl:5])=[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]=[N:9]1
Reactant: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCO
Reactant: O=S(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCBr
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To 170 ml of chloroform were added 9.9 g of 4-chloro-5-(4'-chlorobenzyloxy)-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.03 mol) and slowly added 9.4 g of thionyl bromide (0.045 mol) under stirring for about 2 hours at -5° to 5° C. After reaction, the resulting solution was added little by little with water and the chloroform layer was separated. The layer was washed with water and then with aqueous solution of 5% sodium hydrogen carbonate, and further washed with saturated saline and dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The solid product thus obtained was recrystallized from a mixed solvent of n-hexane-benzene to give 5.2 g of 2-(3'-bromopropyl)-4-chloro-5-(4'-chlorobenzyloxy)-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]1([NH:9][CH2:10][CH2:11]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:15]>>[Cl-:15].[CH:1]1([NH2+:9][CH2:10][CH2:11][Cl:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNC1CCCCCCC1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]C1CCCCCCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:18]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[C:2]1=[O:1])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: Cn1cnc2c(O)nc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2ncn(C)c2c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
3.0 g (0.015 mole) of 4-hydroxy-1-methyl-1H-imidazo[4,5-c]quinoline was suspended in 50 ml of dimethylformamide, and 0.80 g (0.020 mole) of 60% sodium hydride was added with ice cooling, followed by stirring at 50° C. for 30 minutes. Then, the mixture was again ice-cooled and 2.6 ml (0.023 mole) of n-butyl iodide was added dropwise, followed by stirring at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residues, followed by extraction with chloroform. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform/methonal=17/1), followed by recrystallization from isopropanol-isopropyl ether, to afford 2.5 g of Compound 1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[CH:14]([NH:16][NH2:17])=O>C(O)CCC>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:14]=[N:16][N:17]=2)[N:4]=1
Reactant: Clc1ccc(-c2ccccn2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: c1ccc(-c2ccc3nncn3n2)nc1

Procedure:
A mixture of 1.0 g. of 3-chloro-6-(2-pyridyl)pyridazine and 0.6 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is heated at the reflux temperature for 18 hours. The volatiles are removed in vacuo and the residue is partitioned between dilute aqueous sodium hydroxide and methylene chloride. The organic layer is dried over sodium sulfate and filtered. The filtrate is evaporated and the residue is crystallized from methylene chloride-hexane to afford 1.0 g. of the desired product as off-white to yellow crystals, m.p. 191°-192° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)[CH3:17]
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NCc1ccc(CN(C)C)cc1
Yield: 136.1 %

Procedure:
N-(4-Chloromethylphenylmethyl)acetamide (20.0 g) and dimethylamine hydrochloride (9.1 g) were dissolved in acetonitrile (190 ml), and potassium carbonate (28 g) was added. The mixture was refluxed under heating overnight. An insoluble solid was filtered off and the solvent was evaporated to give the objective N-(4-dimethylaminomethylphenylmethyl)acetamide (28.4 g) as an oil.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:8][C:9]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=1[CH:11]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:8][C:9]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=1[CH:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([NH2:7])=[O:6]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)CC(N)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of acetoacetamide (5.05 g, 50 mmol), 2,4-di-chlorobenzaldehyde (9.20 g, 52 mmole), piperidine (170 mg, 2 mmol) and acetic acid (120 mg, 2 mmol) in isopropanol (50 mL) was stirred at room temperature for 14 h. The precipitation was collected and rinsed with an additional isopropanol (20 mL). After drying in vacuo, 2-(2,4-dichlorobenzylidene)-3-oxobutanamide was obtained as a white solid (6.3g, 49%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[CH2:38][NH2:39].C(N(CC)C(C)C)(C)C.CS(C)=O>O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([NH:39][CH2:38][C:37]6[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:35]([O:34][CH3:33])[CH:36]=6)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CNc2nccc(-c3ccc4c(c3)ncn4-c3ccnc(N[C@@H](C)c4ccccc4)n3)n2)cc(OC)c1OC
Temperature: 100 °C

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-(2-chloropyrimidin-4-yl)benzimidazol-1-yl]pyrimidine (EXAMPLE 424) (80 mg), 3,4,5-trimethoxybenzylamine hydrochloride (219 mg), and N,N-diisopropylethylamine (0.16 mL) were dissolved DMSO (4 mL) and the resulting solution was heated to 100° C. for 15 hours. Upon cooling the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×25). The combined organic extracts were dried (MgSO4) and evaporated.
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH3:13].O.[ClH:17]>>[ClH:17].[CH2:12]([C:11]1[CH:10]=[C:9]([CH3:8])[N:5]=[C:3]([OH:4])[N+:2]=1[O-:1])[CH3:13]
Reactant: NC(=O)NO
Reactant: CCC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1cc(C)nc(O)[n+]1[O-]
Temperature: -15 °C
Reaction time: 2 h

Procedure:
0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCl, 20 ml of methanol were added and 0.10 mol (11.41 g) 2,4-hexanedione were added dropwise under cooling by approximately −15° C. Further 30 ml of water and 10 ml of methanol were added. The two-phase reaction mixture was allowed to warm up slowly to room temperature and was stirred at room temperature for further 2 h, then evaporated until dryness. The residue was suspended with 50 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.88 g crude product were obtained which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off and the product was subsequently recrystallized from the filtrate at −18° C. 3.0 g product were obtained which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:21])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Product: O=C(Cl)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 20 °C

Procedure:
47 g of 3-p-chloro benzoyl-benzoic acid were added to 470 cc of thionyl chloride and the mixture was refluxed for 3 hours and then cooled to 20° C. The mixture was concentrated to dryness by distillation under reduced pressure to obtain a residue of 3-p-chlorobenzoyl-benzoic acid chloride which as far as is known is not described in the literature. 54.8 gm of the said acid chloride were added to 500 cc of methylene chloride and after cooling to 5° C., 1.5 liters of a solution of 15.2 g per liter of diazomethane in methylene chloride was added thereto over 20 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:47]2[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 68.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (104 mg, 0.189 mmol) was dissolved in acetonitrile (5.2 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (98 mg, 0.756 mmol), acetic acid (0.216 mL, 3.78 mmol) and sodium triacetoxyborohydride (160 mg, 0.756 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (86.5 mg, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH:16](N)=[NH:17]>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[N:11]=[CH:16][NH:17][C:7]2=[O:9]
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: N=CN
Agent: Cl
Product: O=c1[nH]cnc2cc([N+](=O)[O-])c(Cl)cc12
Temperature: 205 °C
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
A mixture of 5-chloro-4-nitroanthranilic acid (8.7 g, 0.040 mol) and formamidine hydrochloride (4.9 g, 60 mmol) were ground to a fine, intimate powder using a mortar and pestle. The mixture was transferred into a 250 mL round bottomed flask and immersed in an oil bath maintained at 205° C. After 40 min, LCMS analysis of the reaction mixture showed mass corresponding to the product. The reaction mixture was cooled and the crude product was crushed into pieces and washed several times with saturated NaHCO3 (300 mL) and water (200 mL). The solid was air dried and triturated with a minimum amount of MeOH (20 mL) to obtain 6-chloro-7-nitroquinazoline-4-one (7.6 g, 83%) as a tan powder.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:18]1([C:17]#[C:16][CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC#Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OC1(CC#Cc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
To a solution of Compound 256b (179 mg, 0.57 mmol) in CHCl3 (3 mL) was added trifluoroacetic acid (0.219 mL, 2.84 mmol) and the reaction mixture was then stirred at 25° C. for 24 h until the complete conversion of the reagent was observed by LC-MS. Afterwards, to the reaction mixture was added water, followed by aq. 2 N NaOH to give alkaline pH. Separation of the organic layer and extraction of the aqueous layer with CH2Cl2, washing the combined organic layers with brine and drying over Na2SO4 afforded the title compound (122 mg).
Reaction SMILES: C(C1C=CC(C(NC2C(C)=C(C3N=C(NC4C=CC(C(N(C(C)C)C)C(O)=O)=CC=4)C(=O)N(C)C=3)C=CC=2)=O)=CC=1)(C)(C)C.[CH2:45]([N:47]1[CH2:52][CH2:51][N:50]([CH:53]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71](=[O:72])[N:70]([CH3:73])[CH:69]=[C:68]([C:74]4[CH:79]=[CH:78][CH:77]=[C:76]([NH:80][C:81]([C:83]5[S:87][C:86]6[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:85]=6[CH:84]=5)=[O:82])[C:75]=4[CH3:93])[N:67]=3)=[CH:61][CH:60]=2)[C:54]([O:56]CC)=[O:55])[CH2:49][CH2:48]1)[CH3:46]>>[CH2:45]([N:47]1[CH2:52][CH2:51][N:50]([CH:53]([C:59]2[CH:60]=[CH:61][C:62]([NH:65][C:66]3[C:71](=[O:72])[N:70]([CH3:73])[CH:69]=[C:68]([C:74]4[CH:79]=[CH:78][CH:77]=[C:76]([NH:80][C:81]([C:83]5[S:87][C:86]6[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:85]=6[CH:84]=5)=[O:82])[C:75]=4[CH3:93])[N:67]=3)=[CH:63][CH:64]=2)[C:54]([OH:56])=[O:55])[CH2:49][CH2:48]1)[CH3:46]
Reactant: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4cc5c(s4)CCCCC5)c3C)cn(C)c2=O)cc1)N1CCN(CC)CC1
Agent: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Product: CCN1CCN(C(C(=O)O)c2ccc(Nc3nc(-c4cccc(NC(=O)c5cc6c(s5)CCCCC6)c4C)cn(C)c3=O)cc2)CC1
Yield: 97 %

Procedure:
Using the same procedure as described for the preparation of 29, saponification of 45 (1.29 g) gave a 97% yield (1.20 g) of 46 as an off-white solid: mp 168-170° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.25 (s, 1H), 7.96 (d, 2H, J=7.5 Hz), 7.70 (s, 1H), 7.29 (m, 6H), 3.86 (m, 1H), 3.71 (s, 3H), 3.37 (q, 2H, J=7.2 Hz), 2.81 (m, 2H), 2.69 (m, 2H), 2.42 (br s, 8H), 2.19 (s, 3H), 1.83 (br s, 2H), 1.61 (br s, 4H), 0.95 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 655 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:18][CH:17]=1
Reactant: CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 76.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (110 mg, yield 70%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1>CC#N>[Br:8][C:6]1[N:7]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Clc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Solvent: CC#N
Product: Clc1ncc(Br)nc1NCC1CCOCC1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a scintillation vial containing 3,5-dibromo-2-chloropyrazine (1 g, 3.67 mmol) and TEA (1.024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4-yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80° C. in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHCO3, and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (20% EtOAc/Hexane) to yield 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61.1% yield), yield), LCMS (m/z): 308.0 (MH+), retention time=0.94 min, and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89% yield), LCMS (m/z): 308.0 (MET), retention time=0.91 min.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:19]([C:21]3[C:22]([O:40][CH3:41])=[C:23]([CH:29]4[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:16]=[C:17]([Br:18])[C:10]=12>C(Cl)Cl.[OH-].[Na+]>[NH:31]1[CH2:32][CH:29]([C:23]2[C:22]([O:40][CH3:41])=[C:21]([CH:19]([N:15]3[C:11]4=[N:12][CH:13]=[N:14][C:9]([NH2:8])=[C:10]4[C:17]([Br:18])=[N:16]3)[CH3:20])[CH:26]=[C:25]([Cl:27])[C:24]=2[CH3:28])[CH2:30]1
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.2 mL, 16 mmol) was added to a solution of tert-butyl 3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (224 mg, 0.407 mmol) in methylene chloride (2.5 mL) and stirred for 2 h at room temp. The mixture was diluted with dichloromethane and 1 N NaOH was added and stirred rapidly for a few minutes. The layers were separated and the aqueous extracted with dichloromethane. The combined organics were dried (MgSO4), filtered, and concentrated. Drying in vacuo gave 163 mg (91%) of the freebase. LCMS calculated for C18H21BrClN6O (M+H)+: m/z=451.1; Found: 451.0.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][OH:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][O:27][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-benzoyloxypyrrolidine (1.09 g), imidazole (0.46 g) and t-butyldimethylsilyl chloride (0.49 g) were dissolved in 16.5 ml of dry dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC#N>C1COCC1>[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroforinate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1 H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).