Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:13]>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:18]2[CH:17]=[CH:16][S:15][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:20])=[O:21])=[O:24])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Reaction time: 2 h

Procedure:
To 1.23 g of 2-amino-4,6-dimethyl pyrimidine in 30 ml of anhydrous acetonitrile was added with stirring 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point, whereupon all of the insoluble material dissolved and the mixture was allowed to cool. After stirring for two hours the mixture was filtered to remove the desired product which had precipitated as a white solid. After washing with anhydrous ethyl ether the product melted at 191°-193° with decomposition and showed absorption peaks by nuclear magnetic resonance at 3.8 ppm for the methoxy group, 2.44 ppm for the two methyl groups on the pyrimidine ring, a peak at 7.0 consistent for the hydrogen in the pyrimidine ring and a peak at 7.42 for the hydrogens on the thiophene ring. The infrared absorption spectrum showed absorption peaks at 1720 and 1700 cm-1 consistent for the two carbonyl groups present in the desired product.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH:17]([CH3:19])[CH3:18])[CH:6]=1)=[O:4].[OH-:22].[Na+]>>[CH:17]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:22])=[CH:6]1)([CH3:19])[CH3:18]
Reactant: [OH-]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-nitro-1H-indol-3-yl)-ethanone (525 mg, 1.75 mmol) in a 20% aqueous sodium hydroxide solution (10 mL) was heated at 1110° C. for 2 h. At this time, the reaction was cooled to 25° C., partitioned between water (75 mL) and ethyl acetate (75 mL), and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (436 mg, 99%) as a yellow solid: mp 242-243° C.; EI-HRMS m/e calcd for C12H12N2O4 (M+) 248.0797, found 248.0796.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[N:8]=[C:11](/[N:13]([CH3:15])[CH3:14])\[CH3:12])=[CH:6][CH:7]=1
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1ccc(Cl)nn1
Solvent: Cc1ccccc1
Product: C/C(=N\c1ccc(Cl)nn1)N(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
In a 2 L round bottom flask combine 3-chloro-6-pyridazinamine (43.2 g, 333.5 mmol), toluene (500 mL), and N,N-dimethylacetamide dimethyl acetal (67.8 mL, 1.25 equiv.). Attach a reflux condenser then heat to reflux for 2 h. Let cool to RT. Concentrate in vacuo. Triturate the crude material with hexanes and filter to isolate the title compound (60.4 g, 91%) as a light tan solid. MS=199.0 (M+1).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:9].[CH2:10]=O>C1C=CC=CC=1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:10][Cl:9])=[CH:3][CH:2]=1
Reactant: C=O
Reactant: Cl
Reactant: COc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(CCl)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution comprising 108.1 grams of anisole in 450 ml of benzene was cooled to 2° C. and then saturated with gaseous hydrogen chloride for a period of 3 hours at a maximum temperature of 5° C. Then 38.6 grams of paraformaldehyde was added thereto at 20° C. and, following the addition, the reaction mixture was heated to 45° C. and maintained thereat for 1 hour and again cooled to 20° C. Following, gaseous hydrogen chloride was introduced for an additional 5 hours. Next, the aqueous layer was separated and the benzene solution washed with a saturated solution of calcium chloride in eight 150 ml portions and dried over magnesium sulfate. The residue was distilled in vacuum to yield 102.7 grams (65.7%) of 4-methoxybenzyl chloride, b.p. 108°-110° C./12 Torr.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:28]([CH:31]([CH3:33])C)=[C:29]=[O:30]>C(N(CC)CC)C>[C:29]([N:28]1[CH2:31][CH2:33][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[C:2]([F:27])([F:26])[F:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:30])[CH2:9][CH2:8][CH3:17]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1C(F)(F)F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 8.68 (d, 1H), 8.25 (m, 2H), 8.11 (d, 1H), 7.85 (m, 4H), 7.76 (m, 3H), 4.06 (m, 1H), 4.01 (m, 1H), 3.62 (d, 1H), 2.94 (t, 1H), 2.59 (t, 2H), 1.48 (m, 2H), 1.41 (m, 2H), 1.19 (m, 2H), 0.82 (t, 3H); LC/MS m/z 546 (M−H)−, 548 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][CH:6]=2)[N:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1nc(-c2ccccc2)cs1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Temperature: 25 °C

Procedure:
N-(4-phenyl-thiazol-2-yl)-acetamide was added to chlorosulfonic acid (5 eq) at 0° C. and allowed to warm to room temperature. The mixture was heated at 70° C. for 1 h and carefully poured into ice. The solid was filtered, washed with water and dried under vacuum to give 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride. Characterized by derivatization as N-[4-(4-Isobutylsulfamoyl-phenyl)-thiazol-2-y]-acetamide, 1H NMR (400 MHz, CD3OD) 8.08 (d, 2H), 7.85 (d, 2H), 7.58 (s, 1H), 2.66 (d, 2H), 2.22 (s, 3H), 1.7 (m, 1H), 0.87 (d, 6H). LCMS (m/z): 354.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH2:3]1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[CH2:5][CH2:6][N:7]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18](=[O:20])[CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccccc3C(F)(F)F)C[C@H]2C)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a stirred solution of (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine (500 mg, 2.05 mmol) and 4-acetylbenzenesulfonyl chloride (448.23 mg, 2.05 mmol) in anhydrous dichloromethane (6 mL) was added diisopropylethylamine (0.71 mL, 4.1 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield (R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-phenyl}-ethanone in 74.0% yield (646.7 mg) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 (d, J=6.57 Hz, 3H) 2.67 (s, 3H) 2.75-2.83 (m, 2H) 2.98 (d, J=10.11 Hz, 1H) 3.06 (d, J=10.11 Hz, 1H) 3.33-3.43 (m, 1H) 3.76 (d, J=10.61 Hz, 1H) 4.26 (d, J=6.82 Hz, 1H) 7.23-7.30 (m, 2H) 7.52 (t, J=7.71 Hz, 1H) 7.62 (d, J=8.08 Hz, 1H) 7.89-7.99 (m, 2H) 8.07-8.14 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, t-butyl bromoacetate (1.5 eq) and Cs2CO3 (1.5 eq) with MeCN as the solvent (in a sealed tube): MS (ES) m/z 341 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[C:11]([O:14][CH2:15][CH2:16][O:17]C)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:11][O:14][CH2:15][C:16]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:17]
Reactant: CC1CCC(=O)CC1
Reactant: COCCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
2.5 g of 60% sodium hydride was suspended in 50 ml of benzene and a mixture of 5.6 g of 4methylcyclohexanone and 5.4 g of methoxyethyl acetate was added dropwise thereto under cooling. After stirring at room temperature for two hours, 20 ml of water was added and the pH value of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid. After removing the benzene phase the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined, washed with water, dried and concentrated to give 7.4 g of crude 2-methoxyacetyl4-methylcyclohexanone. This crude product was subjected to the subsequent step.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[N:26]1[NH:27][N:28]=[N:29][C:30]=1[NH2:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[N:26]1[NH:27][N:28]=[N:29][C:30]=1[NH:31][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[NH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: Nc1nn[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1)Nc1nn[nH]n1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), 2H-tetrazol-5-amine (8.00 mg, 0.088 mmol) and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.26 (m, 2 H), 1.43-1.57 (m, 2 H), 1.76-1.92 (m, 5 H), 2.36-2.41 (m, 2 H), 6.96-7.23 (m, 1 H), 7.23-7.46 (m, 2 H), 7.57-7.80 (m, 2 H), 11.99 (s, 1 H), 13.98 (s, 1 H), 15.83 (s, 1 H); MS (ESI) m/z 420 [M+H]+.
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[C:7]([Cl:25])=[CH:8][C:9]([F:24])=[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])[C:4]=2[O:3]1.P(Cl)(Cl)([Cl:28])=O.C(N(CC)CC)C>>[Cl:28][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3[nH]c(=O)oc23)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Cl)oc23)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of 3.8 grams (10 mmole) of 3-(2-oxo-4-chloro-6-fluoro-2,3-dihydrobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione and 7.7 grams (50 mmole) of phosphorus oxychloride is cooled in an ice bath. To this 5.0 grams (49.4 mmole) of triethylamine is added via syringe during a ten minute period. At the conclusion of this period the reaction mixture is heated to reflux where it stirs for four hours. After this period the reaction mixture is cooled to ambient temperature and poured into ice water. The resulting mixture is extracted with portions of diethyl ether. The extracts are combined, washed with an aqueous saturated sodium bicarbonate solution, dried with sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, yielding 3-(2,4-dichloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[Sn](CCCC)(CCCC)CCCC)/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[I:31]I>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[I:31])/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: II
Solvent: ClCCl
Product: C/C(I)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 3 h

Procedure:
To 10.0 g (18.6 mmol) 1-(4-chloro-phenyl)-3-((Z)-3-tributylstannanyl-but-2-enyloxy)-1H-pyrazole in 100 ml methylene chloride have been added 4.7 g (18.6 mmol) iodine at ambient temperature with stirring which was continued for 3 h. After removal of the solvents in vacuo the crude product was dissolved in 200 ml MTBE. 100 ml 20% aqueous potassium fluoride solution have been added and the mixture was stirred for 2 h at ambient temperature. The aqueous layer was separated and extracted with 20 ml methyl-tert.-butyl ether twice. The combined organic phases have been washed twice with 20 ml of water each, dried with sodium sulfate, and the solvents were removed in vacuo. The crude product (7.2 g) has been purified by chromatography on 50 g silica with methyl-tert.-butylether/hexane (1:20). Yield 5.9 g, melting point 75-77° C.
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[OH-].[K+]>CN(C=O)C.CO>[Cl:2][C:1]([Cl:4])([Cl:3])[CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH3:5])[CH:8]=1)[OH:11]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1.8 mL (22.5 mmol) of chloroform in 10 mL DMF was added 1.4 g (10 mmol) of 3-methoxybenzaldehyde. The reaction mixture was chilled to 0° C. and a solution of 0.40 g (7 mmol) of potassium hydroxide in 1.8 mL of methanol was added. The reaction mixture was stirred for 3 h at 0° C., then quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH:14][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCC(C#N)c1ncc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 3 h

Procedure:
189 g of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]butanenitrile (0.758 mol), 331 g (1.51 mol) of diterbutyl carbonate, 198 g (0.834 mol) of nickel chloride (II)-hexahydrate are stirred in 2 L of methanol at room temperature. 200.6 g (5.31 mol) of sodium borohydride are added portionwise. After 3 hours of stirring, the reaction mixture is filtered over Supercel, 2 L of ethyl acetate are added, followed by 1.5 L of an aqueous solution of sodium bicarbonate.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[C:26]([O:28]CC4C=CC=CC=4)[C:25](Br)=[CH:24][C:23]=3[CH2:37][CH3:38])[C:12]=2[CH2:39][CH2:40][CH3:41])=[CH:8][CH:7]=[CH:6][C:5]=1[F:42].C(=O)([O-])[O-].[Na+:48].[Na+].[F:50][C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[OH2:2].[Na+:48].[Na+:48].[F:42][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[C:26]([OH:28])[C:25]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=4)=[CH:24][C:23]=3[CH2:37][CH3:38])[C:12]=2[CH2:39][CH2:40][CH3:41])[C:4]=1[C:3]([O-:2])=[O:43].[F:42][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[C:26]([OH:28])[C:25]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=4)=[CH:24][C:23]=3[CH2:37][CH3:38])[C:12]=2[CH2:39][CH2:40][CH3:41])[C:4]=1[C:3]([O-:2])=[O:43]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1cccc(F)c1C(=O)OC
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1cccc(F)c1C(=O)[O-]
Product: O
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of 2-fluoro-6-[2-propyl-3-[3-[4-bromo-2-ethyl-5-(phenylmethoxy)phenoxy]propoxy]phenoxy]benzoic acid methyl ester (1.77 g, 2.72 mmol) in benzene (12 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.33 g, 0.30 mmol) and 2.0 M aqueous sodium carbonate (4 mL). To this mixture was added a solution of 4-fluorophenylboronic acid (4.10 g, 8.16 mmol) in ethanol (5 mL). The resulting mixture was refluxed for 4 hours then cooled to room temperature. The mixture was diluted with ethyl acetate and shaken. The organic layer was washed once with water and once with 1N aqueous sodium hydroxide, dried over sodium sulfate, filtered, and concentrated in vacuo to provide an oil. The product was de-benzylated, hydrolysed, salified, and purified to provide 403 mg (25%) of the desired title product as a fluffy white solid: NMR (DMSO-d6) 9.83 (bs, 1H), 7.50 (m, 2H), 6.96-7.16 (m, 4H), 6.96 (s, 1H), 6.74 (t, J=8.4 Hz, 2H), 6.57 (s, 1H), 6.40 (d, J=8.3 Hz, 1H), 6.35 (d, J=8.3 Hz, 1H), 4.16 (t, J=5.7 Hz, 2H), 4.05 (t, J=5.5 Hz, 2H), 2.40-2.58 (m, 4H), 2.18 (quintet, J=4.1 Hz, 2H), 1.41 (hextet, J=7.4 Hz, 2H), 1.07 (t, J=7.5 Hz, 3H), 0.80 (t, J=7.3 Hz, 3H); MS-FAB m/e 586 (p+1, 35), 585 (p, 100), 562 (33), 313 (30). IR (CHCl3, cm−1) 3300 (b), 2967, 1616, 1455, 1398, 1115.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[Cl:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[OH-].[Na+].C(O)C>O>[ClH:13].[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[CH:10][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCc1ccc(O)cc1
Reactant: COc1ccc(CCNCC(O)CCl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOCc1ccc(OCC(O)CNCCc2ccc(OC)c(OC)c2)cc1
Product: Cl

Procedure:
A mixture of 16.4 g. of p-allyloxymethyl-phenol, 27.4 g. of 1-chloro-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-ol [obtainable from epichlorohydrin and 2-(3,4-dimethoxyphenyl)-ethylamine], 8 g. of sodium hydroxide, 400 ml. of ethanol and 20 ml. of water was heated to 100° for 10 hours. The mixture was evaporated to dryness, the residue treated with dilute hydrochloric acid and ethyl acetate and separated and the aqueous phase rendered alkaline with sodium hydroxide solution and worked up in the customary manner to give 1-(p-allyloxymethylphenoxy)-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-ol, hydrochloride, m.p. 126°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[NH2:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(OC)ccc2n1
Yield: 82.6 %

Procedure:
A solution of 1.96 g of 4-chloro-2-ethoxycarbonyl-6-methoxyquinazoline in 70 mL of toluene was combined with 1.58 g of cis-2-tert-butoxycarbonylaminocyclohexylamine and 0.74 g of triethylamine, and heated under reflux for 15 hours. After concentrating, the mixture was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform) to obtain 2.70 g of the desirable compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[CH:11]([NH:13][NH2:14])=[O:12]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:14][NH:13][CH:11]=[O:12])[CH3:2]
Reactant: CC(=O)c1ccncc1Cl
Reactant: NNC=O
Solvent: CCO
Product: CC(=NNC=O)c1ccncc1Cl

Procedure:
A mixture of 6.30 gm (0.0405 mole) of 4-acetyl-3-chloropyridine, 2.46 gm (0.041 mole) of formic acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer to give a solid which was collected in two crops. The product was purified by chromatography [keiselgel 60 (230-400 mesh)] and eluting with 5% methanol/methylene chloride to give 2.56 gm (32%) of white flakes which have a melting point of 175.2° C.