Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:10](=NC#N)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1.CN(C=[O:42])C>>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:9]2[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[C:10]2=[O:42])=[CH:32][CH:33]=1
Reactant: N#CN=C1NCC(c2ccccc2)N1c1ccncc1
Reactant: CN(C)C=O
Reactant: BrCCCCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1N(CCCCCCOc2ccc(Br)cc2)CC(c2ccccc2)N1c1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [5-phenyl-1-(4-pyridyl)tetrahydro-1H-2-imidazolyliden] aminomethane-nitrile (0.1 g, 0.38 mmol) in 6 mL of DMF at 0° C. was added sodium hydride (75% dispersion in mineral oil, 24 mg) in one portion. The mixture was stirred at room temperature for 20 min and then 1-[(6-bromohexyl)oxy]-4-bromobenzene (192 mg, 0.57 mmol) dissolved in DMF (4 mL) was added dropwise. The resulting mixture was stirred and heated at 80° C. for 16 hours. The reaction was quenched with water and aqueous solution was extracted with ether (3×20 mL). The organic layers were combined, washed with NaCl(sat.), dried over MgSO4, and concentrated under reduced pressure to give the crude residue, which was subjected to purification by chromatography elution with ethyl acetate and methanol (20:1) to afford the product (i.e., Compound 15) as a white solid (90 mg, 45%).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][CH:15]=[O:16]>O.C(O)(C)(C)C.CC(=CC)C>[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][C:15]([OH:6])=[O:16]
Reactant: O=P([O-])(O)O
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 l of 2-methyl-2-butene. After 2½ hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxyl)-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:8][C:7]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 0.17 h

Procedure:
To a mixture of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.179 g, 0.41 mmol) in tetrahydrofuran (2 ml) was added triethylamine (0.058 ml, 0.41 mmol). The suspension was stirred for 10 minutes. The ammonium salts were removed by filtration. The filtrate was concentrated in vacuo. The residue was redissolved in tetrahydrofuran (3 ml) followed by consecutive addition of N,N-dimethylglycine (0.056 g, 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol Stirring for 18 h at 50° C. was followed by partitioning between water (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.057 g, 28%) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13]Cl.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:16]
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCBr
Reactant: CCNCC
Product: CCN(CC)CCCOc1ccc(C#N)cc1
Yield: 100 %

Procedure:
According to a similar manner as that in Reference Example 36 except that 4-cyanophenol, 1-bromo-3-chloropropane, and diethylamine were used, 4-[3-(diethylamino)propoxy]benzonitrile (100%) was obtained as a crude product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Into a 10 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (60 mg, 0.13 mmol, 1.00 equiv) in methanol (10 mL), cyclopropane-carbaldehyde (50 mg, 0.71 mmol, 5.61 equiv), and piperidine (70 mg, 0.82 mmol, 6.46 equiv). The resulting solution was stirred for 30 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.015 g (23%) of the title compound as an off-white solid. LC-MSO: (ES, m/z): 524 [M+H]+. H-NMR (CD3OD, ppm) 8.270 (1H, s), 7.711 (2H, d), 7.316˜7.242 (4H, m), 7.149 (2H, d), 6.450 (1H, d), 4.872 (1H, s), 4.192 (1H, s), 3.966 (2H, d), 3.556-3.488 (1H, m), 2.392˜2.363 (1H, m), 2.253˜2.209 (2H, m), 1.951 (1H, s); 1.306-1.181 (3H, m); 0.918-0.793 (2H, m)
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.C1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:3])[CH2:5]1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(N1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C

Procedure:
A solution of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 3 g (0.022 mole) of potassium carbonate and while stirring, 1.9 g (0.022 mole) of piperidine was added dropwise. The mixture was then treated with 10 g of ice and stirred for 2 hr. The tetrahydrofuran was decanted then concentrated on a rotary evaporator to yield an amber oil, 6.9 g. The oil was dissolved in benzene, washed with dilute acid then water, dried over magnesium sulfate and concentrated in vacuo. This oil crystallized when cooled to -70° C. and was recrystallized from hexane with charcoal treatment at 0° C. yielding pale tan crystals, 4.5 g (68.5%), m.p. 50°-52° C.
Reaction SMILES: Cl.[CH2:2]([CH:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7]1)[CH2:3][CH2:4][CH3:5].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.O.ClCCl>C1(C)C=CC=CC=1>[CH2:2]([C:6]1[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC1NC(=O)C2(CCCC2)N1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
A preferred embodiment of the process comprises reacting a 2-butyl-1,3-diazaspiro[4.4]nonan-4-one hydrochloride and 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile in a water-immiscible organic solvent such as dichloromethane or toluene, in the presence of methyl-tributylammonium chloride and aqueous sodium or potassium hydroxide, separating the organic phase of dichloromethane or toluene, washing the separated organic phase with water, optionally drying the organic phase over a desiccant, filtering the organic phase, evaporating the organic phase to an oily residue and finally crystallizing the oily residue from an organic solvent, such as methyl tert butyl ether to give 4'-[[2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3yl]methyl][1,1'-biphenyl]-2-carbonitrile. This compound is an intermediate in the synthesis of the compound 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one known by the trademark (Irbesartan) and can be easily converted to Irbesartan and its salts according to the process described in U.S. Pat. No. 5,270,317. The compound Irbesartan antagonizes the action of angiotensin II.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6]Cl.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].[F:16][C:17]([F:22])([F:21])[C:18]([O-:20])=[O:19].[Na+]>>[F:9][C:10]([F:15])([F:14])[C:11]([O:13][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][O:20][C:18](=[O:19])[C:17]([F:22])([F:21])[F:16])=[O:12]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(CCCl)CCCl
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Product: O=C(CCOC(=O)C(F)(F)F)CCOC(=O)C(F)(F)F
Temperature: 75 °C

Procedure:
A mixture of 17.85 g of 1,5-dichloropentan-3-one, 92 mL of trifluoroacetic acid, and 34.55 g of sodium trifluoroacetate was stirred and heated at 75° C. for 64 hours. The mixture was allowed to cool to room temperature, was poured over crushed ice, and a product of 1,5-bis(trifluoroacetoxy)pentan-3-one was extracted with dichloromethane. After drying with MgSO4, filtering, and removal of the solvent, 24.4 g of crude 1,5-bis(trifluoroacetoxy)pentan-3-one product was obtained. Analysis of the 1,5-bis(trifluoroacetoxy)pentan-3-one showed 1HNMR (CDCl3, TMS ref.): 2.94 (t, 4H), 4.63 (t, 4H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=O.C([OH:34])C>O.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:34])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: CCO
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 21.35 g portion of 5-fluoroisatin was suspended in 175 ml of water in a three-necked 2 liter flask equipped with a reflux condenser and addition funnel. To the suspension was added a solution of 28.5 g of sodium hydroxide in 100 ml of water, then the mixture was heated to 90° C. A solution of 44.08 g of 2-amino-4'-phenylacetophenone, hydrochloride in 550 ml of a 1:1 mixture of ethanol:water was warmed slightly, then 200 ml of tetrahydrofuran was added to effect dissolution. This solution was added dropwise to the hot solution of 5-fluoroisatin over 2.75 hours with vigorous stirring. When addition was complete the solution was stirred at 90° C. for 2 hours, then the organic solvents were removed by distillation at 85° C. The remaining solution was cooled, added to 1 liter of water and the red solids collected, washed with water and saved. The filtrate was acidified to pH 5 with glacial acetic acid and the resulting yellow solid collected, washed with water and saved. The red solids saved above were stirred in a mixture of 3 liters of water and 100 ml of ammoninum hydroxide for 1 hour, then filtered and the filtrate acidified to pH 5 with glacial acetic acid. The resulting yellow solid was collected, washed with water, combined with the yellow solid saved above and dried, giving 26.9 g of the desired product, mp 229°-232° C. (dec.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[NH:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[N:16]([CH2:2][C:3]3[CH:13]=[CH:12][C:6]4[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=4[CH:4]=3)[CH:15]=[N:14][CH:18]=2)[CH:20]=[N:21]1.[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[N:16]=[CH:15][N:14]([CH2:2][C:3]3[CH:13]=[CH:12][C:6]4[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=4[CH:4]=3)[CH:18]=2)[CH:20]=[N:21]1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc(-c4cnn(C)c4)c3)cc2s1
Product: CSc1nc2ccc(Cn3cncc3-c3cnn(C)c3)cc2s1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (209 mg, 0.9 mmol) from Step 4 of Example 36 and 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248 mg, 1.0 mmol) from Step 3 of this Example, in anhydrous DMF (3.0 mL) was added K2CO3 (700 mg, 5 mmol). After stirring for 3 h at 80° C., the reaction mixture was cooled to rt and partitioned between EtOAc (150 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (eluting isocratically with 1% MeOH in CH2Cl2) to afford separately 6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole and 6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole as white solids. The first eluting regioisomer is referred to as regioisomer 1 (55 mg, 16%) and the second eluting regioisomer is referred to as regioisomer 2 (142 mg, 42%). The regiochemistry of the alkylation was examined by 2-dimensional nuclear Overhauser effect (NOE) experiment but was inconclusive. Regioisomer 1: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.08-7.14 (m, 2H), 5.23 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 342 (M+H)+. Regioisomer 2: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 1H), 7.60-7.71 (m, 2H), 7.47-7.56 (m, 2H), 7.22 (dd, J=1.6, 8.4 Hz, 1H), 6.94 (s, 1H), 5.15 (s, 2H), 3.87 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.CO.[NH3:14]>>[I:1][C:2]1[CH:10]=[C:6]([C:7]([O-:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:14]
Reactant: N
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CO
Product: Nc1ccc(I)cc1C(=O)[O-]
Product: [NH4+]
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 200 mL volume glass vessel equipped with a stirrer and a thermometer were placed 10.0 g (38 mmol) of 5-iodoanthranilic acid and 100 mL (780 mmol) of 15 wt. % ammonia methanol solution. The reaction was carried out for 3 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, to obtain 9.0 g (isolated yield: 85%) of ammonium 5-iodoanthranilate as pale red solid.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=3)[C:10](=O)[C:9]=2[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=3)[C:10](=[CH2:1])[C:9]=2[CH:8]=1
Reactant: [Li]CCCC
Reactant: Cc1ccc2c(=O)c3cc(Br)ccc3oc2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2ccc(C)cc2Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2664 mg, 7457 μmol) in THF (19 ml) at 0° C. was added butyllithium (1.6 M in Hexanes, 3995 μl, 6392 μmol) dropwise. After stirring at 0° C. for 30 minutes, a solution of 2-bromo-6-methyl-9H-xanthen-9-one (1540 mg, 5326 μmol) in THF (5 ml) was added dropwise. The solution was allowed to warm to RT and stirred for 1 hour. The reaction mixture was quenched with water and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude product was flashed with the MPLC (100% hexanes to 10% EtOAc in hexanes to 30% EtOAc in hexanes) MS m/z=289.1 [M+H]+. Calc'd for C15H11BrO2: 287.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[C:30](Cl)(=[O:32])[CH3:31].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 56.9 %

Procedure:
A stirred mixture of (3R)-3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (400 mg, 1 mmol) and acetyl chloride (0.1 mL, 1.4 mmol) in tetrahydrofuran (5 mL) was heated to reflux for 2 h. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 20 mL), brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silica Gel, 1.5:1 ethyl acetate:methylene chloride) to give (3R)-3-[7-(acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (0.25 g, 57% yield); mp, 88-90° C.; 1H NMR (CDCl3) ˜1.43 (t, J=6.9 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.04 (dd, J=5.5, 16 Hz, 1H, CHH), 3.09 (s, 3H, CH3), 3.52 (dd, J=9.5, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.26 (d, J=17 Hz, 1H, CHH), 4.44 (d, J=17 Hz, 1H, CHH), 5.58 (dd, J=5.5, 9.4 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 6.92-7.01 (m, 3H, Ar), 7.41 (t, J=7.8 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 10.37 (s, 1H, NH); 13C NMR (CDCl3) ˜14.65, 24.84, 35.47, 36.16, 37.31, 48.71, 53.54, 55.85, 64.44, 111.35, 112.44, 116.83, 117.40, 117.97, 119.10, 131.72, 132.84, 137.65, 141.53, 148.46, 149.06, 168.98, 169.41, 169.57; Anal Calcd for C24H29N3O5+0.7 H2O: C, 63.76; H, 6.78; N, 9.29; H2O, 2.79. Found: C, 63.89; H, 6.64; N, 9.14; H2O, 2.70.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][CH:16]1[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17]1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:30][C:26]3[CH:25]=[C:24]([C:21]4([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17][CH:16]4[OH:15])[CH:29]=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: COC1(c2cccc(O)c2)CCOCC1O
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Yield: 84 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (3RS,4SR)-3-hydroxy-4-(3-hydroxyphenyl)-4-methoxytetrahydropyran to give (3RS,4SR)-4-{3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran in 84% yield, m.p. 62°-66° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:3][CH2:2]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=5)[CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CC1)C2
Reactant: O=Cc1cccc(F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(CC2CCN(Cc3cccc(F)c3)CC2)cc2c1C(=O)N(CC1CC1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (30 mg, 0.110 mmol) in methanol (2 mL) was slowly added acetic acid (1 mL). After stirring at room temperature for 5 minutes, 3-Fluoro-benzaldehyde (12.8 μL, 0.121 mmol) and sodium cyanoborohydride (8 μL, 0.111 mmol) were added dropwisely. The mixture stirred at room temperature for 2 hours and was neutralized with saturated sodium bicarbonate (10 mL). The aqueous mixture was extracted with dichloromethane and the organics were dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (10-40% ethyl acetate in hexanes) provided the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.70-7.23 (m, 1H), 7.09-7.03 (m, 3H), 6.97-6.92 (m, 2H), 4.41 (s, 2H), 3.48-3.44 (m, 4H), 2.88-2.85 (d, 2H), 2.71 (s, 3M), 2.60-2.57 (d, 2H), 1.93 (t, 2H), 1.64-1.50 (m, 3H), 1.36-1.28 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.34-0.32 (m, 2H)