Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121.0 g (0.45 mole) of cis-9-octadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5-(cis-9-octadecen-1-yloxy)-2-furoic acid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18]C>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CC#CC(C)(C)C
Reactant: CCCC(=O)Nc1cccc(F)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et3N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)2Cl2 (500 mg) successively at room temperature under N2. The mixture was heated at 80° C. overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL×3). The organic layers were washed with sat. NaCl, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.6, 1 H), 7.95 (s, 1 H), 7.21 (m, 1 H), 6.77 (t, J=7.6 Hz, 1 H), 2.39 (t, J=7.6 Hz, 2 H), 1.82-1.75 (m, 2H), 1.40 (s, 9 H), 1.12 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Temperature: 90 °C

Procedure:
To a solution of (methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate), 5-(4-morpholinylcarbonyl) (25 mg, 0.05 mmol) in MeOH//THF (1:1, 1.6 mL) was added 1 M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 90° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (1 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carboxylic acid, 5-(4-morpholinylcarbonyl) (21 mg, 0.05 mmol, 85%) as a light yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.4, 1.5 Hz, 1H), 7.60-7.47 (m, 3H), 7.29 (dd, J=7.0, 1.5 Hz, 1H), 4.84 (br s, 2H), 3.98-3.55 (m, 4H), 3.23-3.05 (m, 2H), 2.88-2.69 (m, 5H), 2.12-1.63 (m, 6H), 1.51-1.06 (m, 4H). LCMS: m/e 472 (M−H)−, ret time 1.39 min, column A, 3 minute gradient.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.O[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:35])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added CICO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1 M HCl, saturated Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38. found: [M+H]+=372.3.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8]>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
N,N-Dimethylethylendiamine (14.25 g, 61.0 mmol) was added dropwise into a solution of commercially available 3-nitrobenzoyl chloride (25.0 g, 134 mmol) in dry THF (150 mL) at 0° C. and stirred for 45 min. The reaction mixture was evaporated to under reduce pressure to dryness and residue was recrystallized from EtOH to give N-(2-dimethylaminoethyl)-3-nitrobenzamide; 31.0 g (97%); mp 89-90° C.; 1H NMR (CDCl3) δ 2.29 (6H, s, 2×Me), 2.57 (2H, t, J=5.8 Hz, CH2), 3.57 (2H, q, J=5.6 and 5.8 Hz, CH2), 7.37 (1H, brs, exchangeable, NH), 7.63 (H, d, J=7.9 Hz, ArH) 8.19 (1H, m, ArH), 8.33 (1H, m, ArH), 8.66 (1H, s, ArH). Anal. Calcd. for (C13H21N3O3): C, 58.41, H, 7.92, N, 15.72. Found: C, 58.23, H, 7.69, N, 15.90.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(NCC)C>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCO
Reactant: COC(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COC(=O)c1ccccc1C#CCO
Reaction time: 18 h

Procedure:
Step 1--A mixture of methyl o-iodobenzoate (9.17 g), propargyl alcohol (3.06 ml) and diethyl amine (90 ml) is treated with bis(triphenylphosphine)palladium chloride (1.23 g) and copper iodide (333 mg) and the reaction is stirred at 20-25° under nitrogen for 18 hrs. The reaction is then filtered through a filter agent and concentrated. The resulting residue is partitioned between water and dichloromethane. The combined organic phases are washed once with saline, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by silica gel chromatography gives methyl o-(1-hydroxy-2-propyn-3-yl)benzoate (CXIX).
Reaction SMILES: O=S(Cl)Cl.[I:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]([NH2:10])=O.O>CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: CCCOc1ccc(I)c(C(N)=O)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)c(C#N)c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
1.67 mL (22.9 mmol) SOCl2 are added to 1.40 g (4.59 mmol) 2-iodo-5-propoxy-benzamide (XXIX.1) in 40 mL DMF. The mixture is stirred at 115° C. for 1 h. After that time, water is added and the mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13].CC1CCCCN1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: O=S(=O)(O)Cl
Agent: CC1CCCCN1
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is prepared by reacting o-bromobenzoic acid with chlorosulfonic acid by the method of Example 1. This is reacted with 2-methylpiperidine by the procedure of Example 6. Recrystallization from acetone-hexane yields the product, m.p. 148°-150° C.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](O)=O.O[CH:17]([CH2:22][CH2:23][CH2:24]COC1C=CC=CC=1)[CH2:18][C:19]([OH:21])=[O:20].OC(CCCCCCOC1C=CC=CC=1)CC(O)=O>>[O:9]([CH2:8][CH2:7][CH2:2][CH2:3][CH2:4][CH2:24][CH2:23][CH2:22][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CC(O)CCOc1ccccc1
Reactant: O=C(O)CC(O)CCCCOc1ccccc1
Agent: O=C(O)CC(O)CCCCCCOc1ccccc1
Product: O=C(O)CCCCCCCCCCOc1ccccc1

Procedure:
Result indicates that PHA copolymer containing three units of 3-hydroxy-5-phenoxyvaleric acid (3HPxV), 3-hydroxy-7-phenoxyheptanoic acid (3HPxHp) and 3-hydroxy-9-phenoxynonanoic acid (3HPxN) can be produced by the strain H45 with a substrate 11-phenoxyundecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](O)=[O:18].C(N(CC)C(C)C)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:9][C:17](=[O:18])[CH:12]3[CH2:13][O:14][CH2:15][CH2:16][N:11]3[C:6]=2[N:7]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,4-Dichloropyrimidin-5-amine (25 g, 152 mmol) and morpholine-3-carboxylic acid hydrochloride (28.1 g, 168 mmol) were dissolved in DMSO (200 mL) to give a yellow suspension. To the suspension was added N,N-diisopropylethylamine (106 mL, 610 mmol) and the mixture was heated to 100° C. for 18 hours. The mixture was cooled to room temperature and poured into ice. Water was added until the total volume was 1 L. The resulting beige suspension was stirred overnight before the solid was collected on a fritted-glass funnel of medium porosity. The solid was washed with water (3×) and then dried under a stream of nitrogen overnight to afford the title compound as a light yellow solid that was used without further purification (18.6 g, 51%). ESI-MS m/z [M+H]+ calc'd for C9H9ClN4O2, 241.04. found 241.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: CCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (132.5 g, 0.80 mole) was added dropwise to a suspension of 50% NaH (43.2 g, 0.90 mole) in DMF (ie) at 0° C. under N2. The solution was stirred 1 hour at room temperature, cooled in an ice bath, and ethyl bromide (120 ml, 1.6 mole) added. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated in vacuo. A solution of the residue in diethyl ether was washed with dilute NaOH solution and saturated NaCl, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:39→1:9) to give methyl 3-ethoxyphenylacetate (94.9 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (t, J=7 Hz, 3H, ethylCH3), 3.59 (s, 3H, esterCH3), 3.61 (s, 2H, ArCH2), 3.98 (q, J=7 Hz, 2H, ethylCH2), 6.78-6.81 (m, 3H), 7.16-7.24 (m, 1H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Temperature: 0 °C
Yield: 67.2 %

Procedure:
Cyclopentanol (50.0 g, 0.58 mol) and p-toluenesulfonyl chloride (120 g, 0.629 mol) were dissolved in pyridine (200 ml), and the solution was poured into ice-water (about 1 liter), followed by thoroughly stirring. The precipitated solid was filtered and dried to obtain cyclopentyl p-toluenesulfonate as a white solid (94.9 g, 0.390 mol, 68.1% yield).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(Cl)(Cl)Cl>[C:7]1([CH:6]2[S:5][CH2:1][CH2:2][CH2:3][S:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: SCCCS
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
1,3-propanedithiol (11.22 g, 103.7 mmol) was added to a solution of benzaldehyde (10.0 g, 94.2 mmol) in 150 mL of CHCl3. The mixture was stirred at room temperature for 4 h. Concentrated HCl (2 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for additional 2 h. The mixture was washed with H2O and brine. The organic layer was dried over MgSO4 and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:dichloromethane=3:1 (v/v)) to give a colorless solid (15.29 g, 83%). 1H NMR (300 MHz, CDCl3, δ): 7.43-7.48 (m, 2H), 7.25-7.36 (m, 3H), 5.15 (s, 1H), 2.85-3.10 (m, 4H), 2.10-2.20 (m, 1H), 1.84-1.99 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 138.95, 128.59, 128.29, 127.61, 51.48, 32.13, 25.15.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=O)=[CH:6][CH:5]=1.BrC1C2C(=CC=CC=2)C(Br)=CC=1>C(O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=[N:1][OH:2])=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2ccccc12
Agent: Brc1ccc(Br)c2ccccc12
Solvent: CCO
Product: ON=Cc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous solution of hydroxylamine (1.25 mL, 50% in water) was added to a stirred solution of 4-bromo-1-naphthalenecarboxaldehyde (3.7 g, 15.7 mmol, prepared from commercially available 1,4-dibromonaphthalene by the method described in European Journal of Organic Chemistry 2006, 10, 2329-2335) in ethanol (30 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (3.8 g). 1H NMR (Me2S(O)-d6): δ 11.60 (s, 1H), 8.81 (s, 1H), 8.71 (d, 1H), 8.24 (d, 1H), 7.95 (d, 1H), 7.74 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].C(O)(=O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O>[CH:13]1([NH:16][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: C=Cc1ccncc1
Reactant: NC1CC1
Solvent: O
Solvent: CC(=O)O
Product: c1cc(CCNC2CC2)ccn1

Procedure:
4-Vinyl pyridine (50 mmol), glacial acetic acid (3 ml), cyclopropylamine (4.28 g, 75 mmol) and water (12.8 ml) were heated at 50° C. for 22 hours. The crude reaction products partitioning, the organic phase was washed with water, brine and dried. Filtered and solvents removed under vacuum. The residue was further distilled under vacuum (Kugelrohr) and the product amine collected. NMR (CDCl3) 8.45 (m, 2H), 7.05 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.07 (m, 1H), 1.37 (m, 2H), 1.25 (m, 2H); m/z 163.17.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCCl.C(Cl)Cl.[Cu]Cl>[O:1]([N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OB(O)c1ccccc1
Agent: Cl[Cu]
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50 mL single neck RB flask wash charged with 2-hydroxy-1H-isoindole-1,3(2H)-dione (1 g, 6.13 mmol), 4 A° molecular sieves (1 g) and copper (I) chloride (0.61 g, 0.06 mmol) in DCE under open atmosphere. To the stirred reaction mixture, was added phenyl boronic acid (1.5 g, 12.2 mmol) followed by pyridine (0.53 g, 6.7 mmol) drop wise. Resulting mixture was stirred at RT for 12 h. The Reaction mixture was diluted with DCM and then filtered through celite pad. The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford off white solid. 1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (q, 2H), 7.73-7.77 (m, 2H), 7.28-7.30 (m, 2H), 7.07-7.11 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].C(=O)(O)[O-].C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:25]1[C:30]([C:31]([CH2:33]Br)=O)=[CH:29][CH:28]=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1>C(O)CCC.C(O)(C)C.C(O)C>[N+:35]([C:27]1[CH:28]=[CH:29][C:30]([C:31]2[N:14]=[C:15]3[N:19]([CH:33]=2)[C:18]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:17]=2[S:16]3)=[CH:25][CH:26]=1)([O-:37])=[O:36]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Temperature: 112.5 °C

Procedure:
Alternatively, the reaction may be carried out in the presence of a base, for example, in the presence of one or more carbonate or bicarbonate salt. For example, sodium bicarbonate is added to a mixture of 2-amino-6-hydroxybenzothiazole and 2-bromo-4-nitroacetophenone in a suitable solvent such as ethanol, isopropanol or n-butanol, and the resulting mixture is stirred at a suitable temperature, for example, to reflux and maintained at reflux (110-115° C.) for 2-3 h or until the reaction is substantially complete.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C(OCC)C.C([Li])CCC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>CCCCCC.O>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:4]#[C:3][CH:2]([OH:5])[CH3:1]
Reactant: C#CC(C)O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(O)C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
A solution of 107.1 parts by weight of 3-butyne-2-ol (I) in 1000 parts by volume of dry ethyl ether is chilled to -50° C. (internal temperature) and 1390 parts by volume of 2.17 M n-butyl lithium in hexane is added over a 2 hour period. The internal temperature is allowed to reach 10° C. during the latter part of the addition to facilitate stirring. The mixture is then cooled again to -30° C. (internal) and 400 parts by volume of chlorotrimethylsilane in 200 parts by volume of ethyl ether is added over a 15 minute period. The mixture is allowed to warm slowly to room temperature overnight. After a brief period of reflux the mixture is again cooled to 25° C. and 100 parts by volume of water is added causing the internal temperature to rise to 37° C. After stirring for 1 hour, more water is added. The organic layer is separated and washed with 5% aqueous hydrochloric acid and water. The solution is dried over sodium sulfate, then concentrated to approximately 400 parts by volume. After adding 500 parts per volume of methanol and 200 parts per volume of 5% hydrochloric acid the solution is stirred at room temperature for one hour then diluted with 1000 parts per volume of water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and concentrated to afford 4-(trimethylsilyl)-3-butyn-2-ol (II) which distills at 49°-50° C./0.25 mm and has the following structural formula ##STR8##
Reaction SMILES: [B:1]#B.[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:4]>C1(C)C=CC=CC=1>[BH3:1].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:4]
Reactant: B#B
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccc1
Product: B

Procedure:
Diborane (1.4 g) was added to a solution of 5-ethyl-2-methylpyridine (12.1 g) in toluene (50 ml) to form a 2M solution of 5-ethyl-2-methylpyridine borane. The temperature of the solution rose 4 degrees during the borane addition. The 11B NMR spectrum showed a quartet at δ=−13.3 ppm (1J(11B1H)=98 Hz). The DSC of the solution had an onset at 212° C. and an energy release of −152 J/g. The solvent was removed under vacuum from 30 ml (27.4 g) of the solution to leave a liquid product (6.4 g, 90% yield). 1H NMR indicated a trace of toluene (<0.5%) remaining.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CN1CCCC1=O.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCC(=O)O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N-methylpyrrolidone and 5 ml of propionic acid is heated to 120° C. The mixture is maintained at this temperature and stirred for 1 hour. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.99 g of raw deferasirox is obtained, i.e. 91% of the theory, with an HPLC content of 92.9% and a melting temperature of 250 to 261° C.