Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20]Br.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-piperazine (2 g, 9.66 mmol) in DMF (10 mL) was added 3-bromopropionic acid methyl ester (1.6 g, 9.66 mmol) and the mixture was stirred at ambient temperature for 16 h. Water was added to the reaction, followed by adjusting pH to 7 with sat. aqueous NaHCO3. The resulting precipitate was collected by filtration and washed with water to furnish the title compound as a yellow solid (1.8 g, 63.6%): MS (ESI) m/z 294 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J=7.2 Hz, 2H), 2.62 (t, J=4.8 Hz, 4H), 2.77 (t, J=6.8 Hz, 2H), 3.42 (t, J=5.2 Hz, 4H), 3.71 (s, 3H), 6.81-6.83 (m, 2H), 8.11-8.14 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](NC2N=CC(N3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34]([N:37]2[C@@H:42]([CH3:43])[CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:39]([CH3:51])[CH2:38]2)=[CH:33][CH:32]=1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:30][C:31]2[N:36]=[CH:35][C:34]([N:37]3[C@@H:42]([CH3:43])[CH2:41][N:40]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C@H:39]([CH3:51])[CH2:38]3)=[CH:33][CH:32]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: C[C@@H]1CN(c2ccc(N)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: Cn1cc(Br)cc(Br)c1=O
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
Following the procedures as described for compound 101i, reaction of 122b (766 mg, 2.50 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (668 mg, 2.50 mmol) afforded 122c as a yellow solid (978 mg, 79%). LCMS: [M+H]+ 492
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[S:17]([CH3:20])(=[O:19])=[O:18])C.O>O1CCCC1>[CH3:20][S:17]([N:12]1[CH2:13][C@H:14]([OH:16])[CH2:15][C@H:11]1[CH2:10][OH:9])(=[O:19])=[O:18]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1C[C@H](O)C[C@H]1CO
Reaction time: 3 h
Yield: 87 %

Procedure:
To 360 ml of tetrahydrofuran was added 3.98 g (0.105 mol) of lithium aluminum hydride, and the mixture was stirred. To this mixture was slowly added dropwise a solution of 16.6 g (0.07 mol) of (2S,4R)-N-methanesulfonyl-4-hydroxyproline ethyl ester [III] in 200 ml of tetrahydrofuran under agitation and ice-cooling. After stirring the suspension at 0° C. for 3 hours and then at room temperature for 3 hours, 14 ml of water was added dropwise in small portions to the suspension under ice-cooling, and thereafter the mixture was stirred for 30 minutes. Any insoluble matter was removed by filtration and the filtrate was concentrated until dryness under reduced pressure whereby 11.9 g (yield: 87%) of an oily substance was obtained.
Reaction SMILES: [C:1]1([C:7]2([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([NH:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:25]
Reactant: NC1(c2ccccc2)CCCCC1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCl)NC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Dissolve 1-phenyl-cyclohexylamine (Preparation 28) (0.41 g, 2.32 mmol) in dichloromethane (50 mL) and cool to 0° C. Add pyridine (1.18 g, 11.61 mmol) and 4-chloro-butyryl chloride (0.65 g, 4.64 mmol). Stir the reaction mixture for one hour under nitrogen. Add water (50 mL), and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 10-50% of EtOAc/Hexane) to give 0.58 g (89%) of the title compound as a colorless oil.
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])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1([CH2:43]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.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:29](=[O:35])[O:28][CH2:26][CH2:43][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCCC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCC4CCCCC4)c(C)c3C)c2cc1OC
Yield: 88.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-cyclohexyl-1-ethanol (30 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 (65 mg, yield 84%).
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCCCC.[C:15]([O-])(=[O:27])[CH2:16]CCCCCCCCCC.C([Sn+2]CCCC)CCC.CC(CCCCN=C=O)C(N=C=O)(C)C.[N-:53]=[C:54]=[O:55].OCCOC(=O)C=C>C(OCC)(=O)C>[C:1]([OH:14])(=[O:13])[CH:2]=[CH2:3].[NH2:53][C:54]([O:27][CH2:15][CH3:16])=[O:55]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: [N-]=C=O
Agent: C=CC(=O)OCCO
Agent: CC(CCCCN=C=O)C(C)(C)N=C=O
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 72 h

Procedure:
212 g (approx. 0.2 mol) Tego-Diol BD-1000, 70 g ethyl acetate and 0.1 g dibutyltin dilaurate are introduced into a 2 l 3-neck flask equipped with thermometer, reflux cooler, mechanical stirrer and drying tube, and 126 g (0.6 mol) trimethyl-hexamethylene diisocyanate added in measured doses, accompanied by cooling, over a period of 30 minutes. The reaction mixture is stirred for 20 hours at room temperature until the isocyanate content has fallen to 7.7%. 91 g hydroxyethylacrylate is added accompanied by cooling. After 72 hours at room temperature, an isocyanate value of 0 is recorded, at which the reaction is ended. The ethyl acetate can be distilled off in fine vacuum.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[C:10]#N)([F:4])[CH3:3].[OH2:18].Cl>C(Cl)Cl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[CH:10]=[O:18])([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C#N)c1
Reactant: O
Agent: Cl
Solvent: ClCCl
Product: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a stirred solution of Compound 24 (1.31 g, 5.22 mmol) in dry CH2Cl2(20 ml) was added a solution of diisobutylaluminum hydride(DIBAL) (6.20 ml, 6.26 mmol, 1.01M in toluene solution) with ice-cooling. The reaction mixture was stirred at 0° C. for 3 h. To the mixture was added H2O(6 ml), followed by 6M HCl aq. (20 ml) and stirred at room temperature for 1.5 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (50:1-30:1) to give Compound 25 (1.17 g, 88%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:8])[C:4]([CH2:6][OH:7])=[CH2:5]>C(O)(=O)C=C>[OH:7][CH2:6][C:4](=[CH2:5])[C:3]([O-:8])=[O:2].[C:3]([O-:8])(=[O:2])[CH:4]=[CH2:5]
Reactant: C=C(CO)C(=O)OC
Agent: C=CC(=O)O
Product: C=C(CO)C(=O)[O-]
Product: C=CC(=O)[O-]

Procedure:
A polymer was prepared by copolymerisation of 2-hydroxymethylacrylate methyl ester prepared as described in Example 1 (2 g) and acrylic acid (6.5 g). The polymerisation was carried out by the procedure described in Example 1. The yield was 8.0 g.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[Cu](C#N)[C:12]#[N:13]>CN1CCCC1=O>[I:10][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(I)nc1Br
Solvent: CN1CCCC1=O
Product: COc1ccc(I)nc1C#N
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 30.4 %

Procedure:
To a solution of 2-bromo-6-iodo-3-methoxypyridine (627.4 mg, 1.999 mmol) in N-methylpyrrolidinone (10 mL) was added copper cyanide (202.6 mg, 2.262 mmol). The reaction mixture was stirred at 130° C. for 3.5 hours and then cooled to room temperature. The crude reaction was partitioned between ethyl acetate and water, the organic layer washed with brine, dried with magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (20 to 100% ethyl acetate in heptanes) to yield 157.8 mg (37%) of a mixture of the two regioisomeric products 6-bromo-5-methoxypicolinonitrile and 6-iodo-3-methoxypicolinonitrile. 1H NMR (400 MHz, DMSO) δ: 8.12 (d, J=8.3 Hz, 0.75H), 7.98 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.69 (d, J=8.5 Hz, 0.75H), 3.98 (overlapping s and s, 6H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17]>C(C(C)=O)C.CCCCCCC>[CH2:2]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCC(C)=O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Yield: 97.3 %

Procedure:
6.15 mL (54 mmol) of iodobutane and then 14.9 g (108 mmol) of potassium carbonate are added to 10 g (36 mmol) of methyl 3-hydroxy-4-iodobenzoate in 100 mL of methyl ethyl ketone. The reaction mixture is heated at reflux for 1 hour 30 minutes. The reaction medium is filtered off and the filtrate is evaporated to dryness. The solid obtained is taken up in heptane, filtered and dried. 11.7 g (97%) of methyl 3-butoxy-4-iodobenzoate are obtained in the form of off-white crystals.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Br:26]N1C(=O)CCC1=O>ClCCl>[Br:26][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Solvent: ClCCl
Product: CCn1cc(Br)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Yield: 6.5 %

Procedure:
In a 50 mL pear flask was added (R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (13, 125 mg, 0.368 mmol) in dichloromethane (3.7 ml). At 0° C., 1-bromopyrrolidine-2,5-dione (66 mg, 0.37 mmol) was added to the mixture, and the mixture was kept in the refrigerator over the weekend. After concentration in vacuo, the crude product was purified by preparatory HPLC (TFA mode, 15-65% ACN/water). Combined fractions were neutralized by NaHCO3, concentrated and extracted into EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The residue was then re-suspended in ACN and water, and then freeze dried to give the desired product (R)-N-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (20, 10 mg, 7%) as a light orange powder. 1H NMR (DMSO-d6) δ 10.62 (s, 1 H), 8.50 (s, 1 H), 8.36 (s, 1 H), 7.97-8.05 (m, 2 H), 7.70 (s, 1 H), 7.54-7.61 (m, 2 H), 5.00 (s, 1 H), 4.71 (t, J=5.8 Hz, 1 H), 4.21 (d, J=7.1 Hz, 2 H), 3.46 (dd, J=5.8, 2.3 Hz, 2H), 1.42 (s, 4 H), 1.39 (t, J=7.2 Hz, 3 H); ESI-MS: m/z 418 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:6]=2[N:7]=1.B(O)(O)[C:25]1[CH:33]=[N:32][C:28]2[NH:29][CH:30]=[CH:31][C:27]=2[CH:26]=1>>[CH3:17][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([C:25]3[CH:26]=[C:27]4[CH:31]=[CH:30][NH:29][C:28]4=[N:32][CH:33]=3)[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]=2[CH:10]=1
Reactant: OB(O)c1cnc2[nH]ccc2c1
Reactant: CN(Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1)S(C)(=O)=O
Product: CN(Cc1cc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc2s1)S(C)(=O)=O
Yield: 6 %

Procedure:
(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl-n-methyl-N-(methylsulfonyl)methaneamine and 1H-pyrrolo[2,3-b]pyridin-5-yl-5-boronic acid were reacted following General Procedure A to produce 417 in 6.0% yield MS (Q1) 459.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].C(I)[C:20]([CH3:23])(C)[CH3:21]>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[N:10]([CH2:13][CH:21]3[CH2:23][CH2:20]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)CI
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Temperature: 90 °C

Procedure:
5-Chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3, 2.97 g, 16.2 mmol) and cesium carbonate (15.8 g, 48.6 mmol) were added to a round bottom flask and suspended in NMP (25 mL) under nitrogen. Neopentyl iodide (6.4 g, 32.4 mmol) was added to the suspension and then refluxed at 90° C. overnight. The reaction was then cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine(×5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using normal phase chromatography(0-60% ethyl acetate/hexanes), and the desired fractions were collected to produce 5-chloro-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4) as a tan solid. HRMS (M+H)+: observed=253.7341, calculated=253.7340.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.C(N(CC)CC)C.[C:19](Cl)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl.C(N(CC)CC)C>CCC(Cl)Cl>[C:19]([N:8]1[C:7](=[O:11])[CH:2]2[CH2:3][CH:4]=[CH:5][CH2:6][CH:1]2[C:9]1=[O:10])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C1NC(=O)C2CC=CCC12
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCC(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N1C(=O)C2CC=CCC2C1=O
Reaction time: 0.17 h

Procedure:
A solution of 4-cyclohexene-1,2-dicarboximide (151g) and triethylamine (300 mls) in dichloropropane (900 mls) was maintained at a temperature of 50° C during the addition thereto over a period of 10 minutes, with constant stirring, of a solution of stearoyl chloride (302.5g) in a dichloropropane (300 mls). The mixture was stirred at 50° C for a further period of 10 minutes during which time triethylamine hydrochloride precipitated out, and was then filtered hot. The filtered precipitate was then washed with small portions of hot dichloropropane and the washings were combined with the filtrate. The solvent from the combined washings and filtrate was then evaporated off in a rotary evaporator to yield solid N-stearoyl-4-cyclohexene-1,2-dicarboximide, which was recrystallised from 60° - 80° petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30]N(C)C=O.Cl.Cl[C:37]1[C:46](C)=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([O:22][CH2:30][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)=[CH:15][CH:14]=3
Reactant: Cc1cc2ccccc2nc1Cl
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3ccc4ccccc4n3)ccc12

Procedure:
1 g 1-(2-Chloro-phenyl)-3,4-dimethyl-7-hydroxy-imidazo(1,5-a)quinoxaline, 2.24 g Caesium carbonate, 50 mL N,N-dimethylformamide, 6 mL water, and 0.86 g 2-Chloro-methylquinoline hydrochloride were stirred for 3 h at 130° C. The reaction mixture was given into 150 mL water, filtered off, washed with water, dried under reduced pressure, and purified with silica gel, dichloromethane/methanol=95/5.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23].CCN(CC)CC.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>C1COCC1.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>[CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: C#CC(C)(C)O
Reactant: Cc1ccc(Cn2c(OS(=O)(=O)C(F)(F)F)cc3ccccc3c2=O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(C#CC(C)(C)O)cc3ccccc3c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of trifluoromethanesulfonic acid 2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydro-isoquinolin-3-yl ester (50 mg, 0.12 mmol) in THF (1.5 mL) was added Et3N (83 μL, 0.59 mmol). The resulting mixture was then degassed by bubbling argon through the solution for twenty minutes. The degassed solution was then treated with 2-methyl-but-3-yn-2-ol (23 μL, 0.24 mmol) followed by tetrakistriphenylphosphine Pd(0) (13 mg, 12 μmol) and Cul (˜2 mg, ˜12 μmol). The resulting suspension was stirred at ambient temperature for 16 hours, then filtered through a short plug of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 50% ethyl acetate/hexane on a silica column. The product peak was collected to afford 2-(2,4-dimethylbenzyl)-3-(3-hydroxy-3-methylbut-1-ynyl)-2H-isoquinolin-1-one (27 mg, 65% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.43 (1H, d, J=8.1 Hz), 7.70-7.64 (1H, m), 7.75-7.49 (2H, m), 7.0 (1H, s), 6.89-6.85 (2H, m), 6.65-6.61 (1H, m), 5.42 (2H, s), 2.40 (3H, s), 2.26 (3H, s), 1.40 (6H, s). ppm.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][N:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]([OH:29])=[N:20]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:29][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]([CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(O)nn1CCNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
Benzyl bromide (0.13 mL, 1.1 mmol) was added to a stirred suspension of ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-hydroxy-1H-pyrazole-5-carboxylate (0.3 g, 1 mmol) and Cs2CO3 (0.65 g, 2 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 16 hours and the solvents were evaporated in vacuo. The crude product was diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 3-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (0.29 g, 73% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([CH3:19])=[CH:12][C:11]=2[CH3:20])[N:6]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:21][C:2]1([F:1])[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:15]=2)[NH2:16])[N:6]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1-c1noc(C2CC2(F)F)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2noc(C3CC3(F)F)n2)cc1N
Temperature: 78 °C

Procedure:
A stirring mixture of 5-(2,2-difluorocyclopropyl)-3-(2,4-dimethyl-5-nitrophenyl)-1,2,4-oxadiazole (149) (190 mg, 0.644 mmol) and tin (II) chloride dihydrate (581 mg, 2.57 mmol) in ethanol (10 mL) was heated at 78° C. for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to basic with a saturated solution of sodium bicarbonate. The resulting solid was filtered through a plug of celite and washed with excess ethanol. The solvent was partially reduced and the crude product was extracted with ethyl acetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography. 1H NMR (400 MHz, d6-DMSO) δ 7.21 (s, 1H), 6.93 (s, 1H), 4.96 (s, 2H), 3.70-3.62 (m, 1H), 2.47-2.41 (m, 1H), 2.37-2.28 (m, 1H), 2.35 (s, 3H), 2.08 (s, 3H). MS m/z 266.10 (M+1)+.