Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[NH:12][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)=O)[CH2:3][CH2:2]1>C(O)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:13]2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(F)cc1NC1CC1)c1cncc(F)c1
Solvent: CC(=O)O
Product: Fc1cncc(-c2nc3ccc(F)cc3n2C2CC2)c1
Temperature: 25 °C

Procedure:
A solution of the title compound from Step A (0.038 g, 0.131 mmol) in acetic acid (0.66 mL) was heated at 100° C. for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (30-50% ethyl acetate in hexanes) provided the title compound: LCMS m/z 272.16 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1 H), 8.60 (d, J=2.7 Hz, 1 H), 8.03 (m, 1 H), 7.73 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.6, 2.4 Hz, 1 H), 7.10-7.06 (m, 1 H), 3.59-3.55 (m, 1 H), 1.25-1.22 (m, 2 H), 0.83-0.80 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:14]
Reactant: CCI
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(F)cc1C(C)=O

Procedure:
5′-Fluoro-2′-hydroxyacetophenone (9.38 g, 61 mmole), iodoethane (7.3 ml, 91 mmole) and K2CO3 (12.6 g, 91 mmole) in acetone (100 ml) was stirred at 60° C. overnight. The mixture was filtered, evaporated, dissolved in hexane/ethyl acetate, washed with 2M NaOH (2×20 ml) and water, dried (MgSO4) and evaporated to give 2′-ethoxy-5′-fluoroacetophenone. A solution of mCPBA )19.3 g, 112 mmole) in CH2Cl2 (500 ml) was dried with MgSO4. 2′-Ethoxy-5′-fluoro-acetophenone (10.2 g, 56 mmole) was added and the mixture was stirred for 3 days. More mCPBA (5 g, 29 mmole) and MgSO4 was added and stirring was continued for 2 days. The mixture was filtered, diluted with ethyl acetate, washed with 2 M NaOH (2×70 ml), NH4Cl (sat, 50 ml), dried (MgSO4) and evaporated. The residue (10.45 g,) was dissolved in ethanol (100 ml). KOH (8.9 g, 160 mmole) was dissolved in water (50 ml). The solutions were combined and stirred for 1 h. The mixture was washed with diethyl ether/hexane 2×(50+25 ml), acidified with HCl (konc), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated. The residue (8.22 g) was dissolved in CH2Cl2 (100 ml). Triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and the solution was refluxed for 2 hrs. More triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and refluxing was continued overnight. The solution was evaporated, CH2Cl (200 ml) was added and the solution was washed with water, 2M NaOH and NH4Cl. Drying (MgSO4) and evaporation provided 4.0 g of 1-ethoxy-4-fluoro-2-methoxymethoxybenzene. This compound was reacted in a manner analogous to Example 39 to give (+,−)-N-(cis-2-(3-ethoxy-6-fluoro-2-methoxymethoxyphenyl)-cyclopropyl)-N′-(5-chloropyrid-2-yl)-urea. Finally deprotection with 2 M HCl in dioxane gave the titled compound. 1NMR (250 MHz, DMSO-D6) δ 1.04-1.14 (m, 1H), 1.41-1.56 (m+t, 4H), 1.96-2.06 (m, 1H), 3.05-3.15 (m, 1H), 4.06-4.19 (m, 2H), 6.64 (t, 1H), 6.94 (dd, 1H), 7.19 (d, 1H), 7.82 (dd, 1H), 8.10 (d, 1H), 8.61 (br.s, 1H), 9.08 (br.s, 1H), 9.57 (br.s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+]>ClCCCl>[CH3:19][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Cl)cc1
Yield: 94 %

Procedure:
4-Chlorophenylacetic acid (100 g, 0.59 mol) was dissolved in 1,2-dichloroethane (165 ml) and methanol (96 ml, 2.4 moles) and to the solution was added concentrated sulfuric acid (2.75 ml), followed by refluxing for 6 hours. The mixture was cooled and aqueous NaHCO3 was added, followed by stirring. The resulting organic layer was separated, dried over anhydrous sodium sulfate, collected by filtration and concentrated to dryness to obtain methyl-(4-chlorophenyl)-acetate (102 g, yield 94%).
Reaction SMILES: [CH3:1][C:2](=[CH2:37])[C:3]#[C:4][C@@H:5]([N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH2:18][C@H:17]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:37][C:2](=[CH2:1])[C:3]#[C:4][C@@H:5]([N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C@H:17]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1
Reactant: C=C(C)C#C[C@H](c1ccc(C(F)(F)F)nc1)N1CC[C@@H](CC(=O)OC)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C#C[C@H](c1ccc(C(F)(F)F)nc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Yield: 70.7 %

Procedure:
A solution of the ester from Step 2 (0.146 g, 0.28 mmol) and LiOH (0.133 g, 5.6 mmol) in THF (3 ml) and water (3 ml) was stirred at rt for 16 hrs. The reaction mixture was acidified to pH6 with 2N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 1-2% MeOH/DCM) to give the acid (0.101 g, 71%). 1H NMR (360 MHz, CD3OD): δ 1.26-1.38 (1H, m), 1.51 (1H, q, J 12.1), 1.77 (1H, m), 1.90-1.98 (2H, m), 2.03 (3H, s), 2.24 (2H, d, J 6.9), 2.43-2.57 (2H, m), 3.74 (1H, dd, J 2.6, 11.4), 4.70 (1H, s), 5.39 (1H, m), 5.46 (1H, s), 7.70-7.72 (4H, m), 7.80 (1H, d, J 8.2), 8.17 (1H, d, J 8.1), 8.82 (1H, s).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[F:13][C:14]([F:49])([F:48])[C:15]1[CH:16]=[C:17]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:18][N:19]([CH:25]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]2[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:26]1=2)[C:20]1[NH:24][N:23]=[N:22][N:21]=1>ClCCl>[CH2:5]([O:4][C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH:25]([N:19]([CH2:18][C:17]2[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=[C:15]([C:14]([F:13])([F:49])[F:48])[CH:16]=2)[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:26]2[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([F:39])([F:38])[F:40])=[CH:32][C:27]1=2)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 14 h
Yield: 20.5 %

Procedure:
Add ethyl chloroformate (0.24 mmol) and pyridine (0.24 mmol) to a dichloromethane (5 mL) solution of (3,5-bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(1H-tetrazol-5-yl)-amine (0.045 g, 0.08 mmol). After stirring 14 h, wash the reaction with 5% HCl (3 mL), water (3 mL) and brine (3 mL). Dry the organic portion over sodium sulfate and filter. Chromatograph the crude product, eluting with ethyl acetate/hexane (20-60%), to provide the title compound (0.01 g, 20%) as an oil: MS (ES+): 611 (M+H).
Reaction SMILES: CC1OC(CO)C(O)C([O:11][CH:12]2[O:17][CH:16]([CH2:18][O:19]C3OCC(O)C(OC)C3O)[CH:15]([OH:30])[CH:14]([O:31]C)[CH:13]2[OH:33])C1O.Cl>O>[O:11]=[CH:12][C@@H:13]([C@H:14]([C@H:15]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:30])[OH:31])[OH:33]
Reactant: COC1C(O)COC(OCC2OC(OC3C(O)C(C)OC(CO)C3O)C(O)C(OC)C2O)C1O
Agent: Cl
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 20 °C
Reaction time: 24 h

Procedure:
500 kg of galactoarabinan (e.g. FiberAid®) are dissolved or suspended in 4,000-5,000 l of water. The pH is adjusted using approximately 50-60 l hydrochloric acid (30% by weight) to a value in the range from 1.0-1.5. The temperature is adjusted to 100° C. The hydrolysis is carried out for 24 hours (hydrolysis control by means of HPLC). Once the hydrolysis is complete cooling takes place to 50-60° C., with filtration (for example by means of a chamber filter press, for example with the Hyflo filter aid) and neutralization, with the solution or the suspension being passed over an alkaline ion exchanger and then again over an acid ion exchanger and then again over an alkaline ion exchanger. The ion exchangers are rinsed with approximately 2,000 l town water. Then the solution or suspension is concentrated by distillation (to approximately 1,500 l) and made to crystallize. The raw ingredient is centrifuged. 500 l 90% by weight of ethanol (remainder: water) are added to the raw product and agitated for one hour at a temperature of approximately 20° C. Through filtration (for example in a chamber filter press) the flushing liquor is separated from the solid matter. This process is carried out twice. The D-galactose raw product is dissolved for recrystallization (100° C., water, saturated solution), active charcoal is added and then filtration performed, for example via the Hyflo filter aid. From the filtrate the D-galactose can be crystallized again and then centrifuged. If necessary, for further purification, recrystallization can be performed again (saturated solution crystallization). Next, the D-galactose obtained in this way is dried (for example by circulating air or vacuum drying cabinet) and ground to the desired particle size.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=O)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1]
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccccc1I
Solvent: CO
Product: COC(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2-Iodophenylacetic acid (1.45 g) was added to a mixture of methanol (100 mL) and acetyl chloride (5 mL). After stirring at room temperature for 3 hours, the solvent was removed and the residue was dried under vacuum giving the desired 2-iodophenylacetic acid methyl ester. Yield=100%
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC2C=CC=CC=2)[C@H:11]([C:26]([CH3:28])=[CH2:27])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@H:11]([CH:26]([CH3:28])[CH3:27])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-(prop-1-en-2-yl)cyclohexylcarbamate (4.8 g) in MeOH (40 mL) was charged with 10% Pd/C, Degussa (600 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 4 h and then filtered and concentrated to provide (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexanamine (2.9 g). MS (ES+)=272.3 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7](S(C)=O)[N:6]=1.O>CC(O)C>[I:13][C:12]1[CH:11]=[C:8]2[C:9]([NH2:10])=[N:3][NH:2][C:7]2=[N:6][C:5]=1[NH2:4]
Reactant: CS(=O)c1nc(N)c(I)cc1C#N
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Nc1nc2[nH]nc(N)c2cc1I
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
275 μl (2 eq) of hydrazine monohydrate is added to a solution of 872 mg (2.84 mmol) of 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in 11 ml of 2-propanol. The reaction medium is stirred at 80° C. for 3 hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and evaporated. The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield 523 mg (67%) of 5-iodo-1H-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:19]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), cyclopentane carboxylic acid (46 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 m g, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated to obtain 40 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)cyclopentanecarboxamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 0.5 ml). 1H NMR (DMSO) 9.98-10.09 (bs, 1H), 7.93 (t, 1H), 7.37 (d, 1H), 7.20 (s, 1H), 7.0 (d, 1H), 4.59-4.63 (m, 1H), 4.2-4.3 (m, 1H), 4.07-4.15 (m, 2H), 3.73-3.84 (m, 2H), 3.07-3.15 (m, 2H), 2.99 (s, 3H), 2.59-2.68 (m, 2H), 2.4-2.48 (m, 1H), 2.38 (s, 3H), 1.4-1.84 (m, 8H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[C@H:10]([CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[C@H:10]([CH2:16][O:17][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCN(Cc2ccccc2)C[C@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1CN(Cc2ccccc2)CCN1C=O
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a 0° C. solution of alcohol 22 (0.502 g, 2.14 mmol) in dry DMF (20 mL) was added NaH (95%, 0.154 g, 6.43 mmol) in one portion. After stirring 5 min, iodomethane (0.319 g, 2.25 mmol) was added (drop-wise) and the mixture stirred for 20 min at 0° C. then at ambient temperature for 1.5 h. The excess NaH was destroyed by the careful addition of water and the solution was diluted with 40 mL each of water and saturated NaHCO3. The aqueous mixture was extracted with ether (2×40 mL) and ethyl acetate (2×40 mL). The combined extracts were washed with brine (50 mL), dried (K2CO3) and concentrated to give a brown oil that was purified by column chromatography (silica gel, MeOH:CHCl3, gradient 1:199 to 1:49) to afford 23 as a pale colored oil (0.360 g, 69% yield). 1H NMR (400 MHz, CDCl3): δ 2.00-2.12 (m, 1.3H), 2.18 (dd, J=3.7, 11.7 Hz, 0.7H), 2.80-2.92 (m, 2H), 2.93-3.02 (m, 1H), 3.29-3.38 (m, 3H), 3.41-3.76 (m, 5H), 4.16 (bd, 0.7H), 4.60 (m, 0.3H), 7.25-7.35 (m, 5H), 8.04 (s, 0.7H), 8.07 (s, 0.3H); 13C NMR (100 MHz, CDCl3): δ 36.7, 42.7, 47.0, 52.3, 53.2, 53.7, 54.1, 58.8, 59.0, 62.5, 62.6, 69.5, 70.6, 127.2, 128.3, 128.7, 137.7, 161.3, 161.9. HRMS Calcd. for [C14H20N2O2+H+] 249.1603. Found 249.1598. [α]D25-37.6 (c 0.036, CHCl3).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:5]=2[CH2:4][CH2:3]1.C1(C)C=CC=CC=1>O.[Zn]>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCc1ccc2c(c1)CCO2
Reaction time: 8 h

Procedure:
300 g of zinc and 30 g of mercuric chloride are added with stirring to a mixture containing 510 ml of concentrated hydrochloric acid in 240 ml of water, 141 g of 4-(2,3-dihydro-5-benzofuranyl)-4-oxobutanoic acid obtained above and 300 ml of toluene. The reaction medium is brought to reflux for 6 hours. 150 ml of concentrated hydrochloric acid are added and refluxing is continued overnight.
Reaction SMILES: O.[OH-].[Na+].C([O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:25][CH3:26])[C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][C:16]([O:21]C(=O)C)=[CH:15][CH:14]=3)(=O)C.Cl>>[CH2:25]([N:12]1[C:13]2[CH:14]=[CH:15][C:16]([OH:21])=[CH:17][C:18]=2[C:19]2[C:11]1=[CH:10][CH:9]=[C:8]([OH:7])[CH:20]=2)[CH3:26]
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c2ccc(O)cc2c2cc(O)ccc21

Procedure:
To 700 ml of water containing 80 g (2.0 mole) of sodium hydroxide is added 85 g (0.27 mole) of N-ethyl-3,6-carbazolediol diacetate. The reaction mixture is heated for one hour then acidified with 3N hydrochloric acid to give N-ethyl-3,6-carbazolediol which is recrystallized from ethanol-water. M.P. 190°-200°C (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([OH:21])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([O:21][CH2:40][C:41]#[N:42])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:16]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-amide (400 mg, 0.79 mmol), prepared in the previous step, bromoacetonitrile (66 μL, 0.95 mmol) and potassium carbonate (547 mg, 3.96 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a light brown solid. Purification of the solid on a 40 g KP-SIL 60 Δ Biotage column gave 2-butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide (262 mg, 63%) as a white solid, mp 162-164° C.
Reaction SMILES: C(ON=O)CC(C)C.[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1.[I:24]CI.O>C(#N)C>[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([I:24])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Oc2ccccc2F)cc1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: O
Product: Fc1ccccc1Oc1ccc(I)cc1
Temperature: 55 °C
Yield: 91.7 %

Procedure:
Add isoamylnitrite (2.45 g, 2.5 Eq.) to 4-(2-fluoro-phenoxy)-phenylamine (1.70 g, 8.37 mmol) and diiodomethane (7.84 g, 3.5 Eq.) in acetonitrile (10 mL) while stirring at 55° C. under a nitrogen atmosphere. Slowly heat mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the desired material into ethyl acetate. Wash this organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 2.41 g of an oil. Purify the material by silica gel chromatography (Prep. 2000) eluting with hexane/methylene chloride 9:1 to provide 1.60 g of the title compound as a thin oil. Mass spectrum (m/e): 314.0 (M*): (Bruker 300) 1H NMR (CDCl3) δ 7.55-7.60 (2H, d), 7.02-7.20 (4H, m), 6.69-6.72 (2H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](O)=[O:11])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([Cl:22])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(CCC(C)C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(C)(CCC(C)C)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of Example 155C (8.52 g, 0.034 mol) in 200 mL anhydrous dichloromethane was added 2 N oxalyl chloride in dichloromethane (26 mL, 0.052 mol) and drops of dimethylforamide. The solution was stirred for 30 minutes at 0° C. and then room temperature for 2 hours. The solvent was removed under vacuum and the crude product used directly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][N+:11]([O-:13])=[O:12].[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:10][N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(C[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3-bromobenzaldehyde (18.5 g, 100 mmol) in MeOH (100 mL) was added MeNO2 (12.2 g, 200 mmol) at 0° C. followed by addition of KOH (11.2 g, 200 mmol). After 2 hours, MeOH was removed in vacuo and the resulting mixture was partitioned between ethyl acetate and water. Ethyl acetate extracts were dried over MgSO4 and concentrated to give 20 g crude mixture. This crude mixture was dissolved in AcOH (200 mL), to which CrO3 (12.0 g, 120 mmol) was added. Acetic acid was removed under vacuo after 2 hours and water (200 mL) was added and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and then concentrated under vacuo. dichloromethane (20 mL) was added and the titled compound (8.5 g, 35% for 2 steps) was precipitated out and collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 85.3 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pentanoyl chloride (0.48 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (85%) of product as an off-white solid: mp 178-179° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 5.18 (dd, J=5.0 and 12.4 Hz, 1H), 2.99-2.89 (m, 1H), 2.68-2.45 (m, 4H), 2.13-2.09 (m, 1H), 1.69-1.57 (m, 2H), 1.44-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.72, 171.99, 169.73, 167.83, 166.64, 136.64, 136.07, 131.36, 125.96, 118.15, 116.68, 48.97, 36.32, 30.97, 26.88, 22.03, 21.70, 13.64; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.10; H, 5.37; N, 11.58.