Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][Al](CC)CC)C.O=O>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].C1C=CC([P]([Ni]([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.CCOCC>[C:14]1([P:7](=[O:22])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCO[Al](CC)CC
Agent: [Ni+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Ni]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CCOCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
10 gms. of nickel acetylacetonate and 40.95 gms. of triphenylphosphine are dissolved in 400 ml. of absolute ether and the solution is reduced with 16 ml. of ethoxydiethyl aluminum at 0° C. This results in a red-brown solution from which red-brown crystals precipitate after standing for 30 minutes. Complete precipitation of the crystals is achieved by cooling. The crystals are filtered with suction, washed with ether and dried. There are obtained 32 gms. (80% of the theoretical yield) of red-brown crystals, the elementary analysis of which agrees with the formula Ni(P(C6H5)3)4. The compound is sensitive to air. When allowing oxygen to act on it, triphenylphosphine oxide is formed. The compound is capable of catalyzing the formation of cyclooctadiene from butadiene.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15]CC2C=CC=CC=2)=[C:10]([F:23])[CH:9]=1)=[O:4]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]([F:23])[C:11]([OH:15])=[C:12]([F:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reaction time: 12 h
Yield: 112.9 %

Procedure:
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid methyl ester (21 mg, 0.066 mmol) obtained in Step B was dissolved in THF/MeOH (1 mL/1 mL), and Pd/C (10%, 10 mg) was added thereto. The mixture was stirred under hydroten atmosphere for 12 hours, filtered by using celite, and concentrated under reduced pressure to obtain the title compound (17 mg, 99%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCCOCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)CCCOCc1ccccc1
Yield: 86.9 %

Procedure:
Sodium borohydride (236 mg) was added to a mixed solution of 5-benzyloxy-2-pentanone (1.09 g, 5.67 mmol) in methanol (50 mL) in an ice bath, followed by stirring. After completion of the reaction, water was added to the reaction solution in an ice bath, and methanol was evaporated. The pH was adjusted to 4 with 2 mol/L hydrochloric acid. After extraction with chloroform-water, the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 957 mg of the title compound (yield: 87%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](C(O)=O)[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O>O>[C:12]1([C:11]2[S:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(-c2ccccc2)s1
Agent: O=C=O
Solvent: O
Product: c1ccc(-c2ccsc2-c2ccccc2)cc1

Procedure:
The 4,5-diphenyl-2-thiophenecarboxylic acid (28 g, 0.1 mol) prepared as described above was heated to 220–230° C. until the evolution of carbon dioxide ceased. The residue was diluted in water and extracted with 100 mL of benzene. The organic phase was dried over MgSO4 and evaporated off to give the crystallized product. Yield 22.45 g (95%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C([O:16][CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[C:19](=[O:24])[CH2:20]S(C)=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.O>[OH:4][CH:20]1[O:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[C:19]1=[O:24]
Reactant: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (17.6 g) was added dropwise to a stirred solution of crude product of Step 3 in tetrahydrofuran (220 ml) with water bath cooling to 20° C. After 2 hours the mixture was left to stand for 20 hours. A solution of sodium hydrogen carbonate (14.1 g) in water (220 ml) was added during 5 minutes with stirring and cooling to 20° C. After 30 minutes the mixture was refluxed for 41/2 hours, cooled to 25° C., extracted with dichloromethane (3×300 ml), the extract dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil (21.4 g). The brown oil (20.09 g) was dissolved in 1,4-dioxane (500mi) and hydrogen chloride gas bubbled in for 31/4 hours, with stirring, at 23° C. The mixture was left in a stoppered flask for 20 hours, concentrated under reduced pressure, dissolved in dichloromethane (400 ml), neutralised with a minimum of saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated under reduced pressure to a brown oil (21.9 g). The oil was subjected to column chromatography on silica gel, gradient eluting with dichloromethanet-butyl methylether mixtures to give the crude product as a yellow gum (4.7 g). The gum was crystallised from hexane solution to give a yellow solid. 1H NMR (CDCl3): δ 4.43(1 H,bs); 5.49(1 H,s); 5.68(2 H,m); 7.49-7.8(4 H,m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (271 mg, 70%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[C:16]1([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(C(OCC2CCNC2)c2ccccc2)cc1
Yield: 78.5 %

Procedure:
A solution of 1-benzyl-3-(diphenylmethoxymethyl)pyrrolidine (1.43 g, Preparation 8) in ethanol (50 ml) containing acetic acid (1.0 ml) was stirred at room temperature for six days under an atmosphere of hydrogen in the presence of 5% palladium on charcoal. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution and water, dried over magnesium sulphate and evaporated to give the title compound (0.84 g) as a pale yellow oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[N:13]1([C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc([N+](=O)[O-])c1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 73.1 %

Procedure:
To a suspension of 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (300 mg, 1.75 mmol), azetidine (354 μl, 5.25 mmol) and diisopropylethylamine (920 μl, 5.26 mmol) in ethyl acetate (7.5 ml) was added 1-propanephosphonic acid cyclic anhydride (3.68 ml, 6.13 mmol; 50% in ethyl acetate) at 0° C. The ice bath was removed and stirring at r.t. was continued for 40 h. The reaction mixture was poured into ethyl acetate (100 ml) and extracted with sodium bicarbonate (saturated aqueous solution) water and brine. The aqueous layer was back-extracted with ethyl acetate, the combined organic phases were dried, evaporated, and the product was purified by silica gel chromatography using an amine phase and a heptane/ethyl acetate gradient to yield a white solid (269 mg, 73%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)[CH2:9][C@@H:10]([CH3:14])[C:11]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1.304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDC.HCl (450 mg, 2.347 mmol), 1-hydroxy-7-azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN—H2O (0.1% NH4OH) over 10 min by X-bridge phenyl column] provides ((1S,3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333 mg, 55%). HPLC retention time=1.03 minutes (condition D), MS (m−1)=495.5, MS (m−55)=405.3, MS (m−99)=361.3.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28]\[OH:29])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=360.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19].[H-].[Na+]>>[CH2:10]([N:9]([CH2:12][CH3:13])[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:19][CH2:18][CH2:17][CH2:16][NH2:15])[CH:7]=1)=[O:14])[CH3:11]
Reactant: NCCCO
Reactant: CCN(CC)C(=O)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)C(=O)c1ccnc(OCCCN)c1

Procedure:
2-Chloro-4-diethylcarbamoylpyridine is reacted with 3-aminopropanol and sodium hydride to give 3-(4-diethylcarbamoyl-2-pyridyloxy)propylamine, which is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-(4-diethylaminomethyl-2-pyridyloxy)propylamine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].C([NH:38][CH:39]([CH3:53])[CH2:40][CH:41]([C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=1)[C:42]([OH:44])=[O:43])(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[NH2:38][CH:39]([CH3:53])[CH2:40][CH:41]([C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=1)[C:42]([OH:44])=[O:43]
Reactant: CC(=O)NC(C)CC(C(=O)O)c1ccc(C)c(C)c1
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Cc1ccc(C(CC(C)N)C(=O)O)cc1C

Procedure:
0.5 g of the acetamido acid prepared in Example 10 was refluxed for 18 hours with 20 ml of 6N hydrochloric acid. The excess acid was removed in the rotary evaporator, leaving a semi-solid residue. This was dissolved in five ml of water and sodium bicarbonate solution added to pH 6-7, whereupon a voluminous white precipitate formed. After chilling for an hour, the solid was recovered by filtration and recrystallized from aqueous ethanol. The white crystals of the above-named product thus obtained melted at 222.5°-223° with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>O1CCCC1>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[C:17](=[O:18])[NH:15]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Solvent: C1CCOC1
Product: CCOC(=O)CN1Cc2c(C)cccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cooled solution of 15.00 g (67 mmole) of N-(2-amino-6-methyl benzyl) glycine ethyl ester in 300 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere was added a solution of 11.72 g (72 mmole) of 1,1'-carbonyldiimidazole in 200 ml of anhydrous tetrahydrofuran at such a rate that the temperature did not exceed 5°. Upon complete addition, the solution was allowed to stir at room temperature for 2 hours, heated to reflux for 18 hours, cooled to room temperature and the tetrahydrofuran removed in vacuo. The residue was dissolved in methylene chloride (250 ml), washed with 5% aqueous hydrochloric acid (2×100 ml), then water (100 ml). The methylene chloride extract was dired (Na2SO4) and the solvent removed in vacuo affording 14.0 g (83% yield) of a colorless solid. purification was effected by crystallization from nitromethane; m.p.; 184°-5°.
Reaction SMILES: BrC(CC)C(O)=O.O.[C:9]1([S:15]([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)([Cl:26])=O>C(OCC)(=O)C.CN(C=O)C>[C:9]1([S:15]([CH:18]([CH2:22][CH3:23])[C:19]([Cl:26])=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCC(C(=O)O)S(=O)(=O)c1ccccc1
Agent: CCC(Br)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C(=O)Cl)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Bromobutyric acid, (200 g, 1.2 mol), sodium benzenesulfinate,(236 g, 1.44 mol) and water(1000 mL) were heated to 80° C. After about 1 hour the clear solution had turned cloudy and an oil had precipitated out. After heating at 80° C. for a total of 2 hours the mixture was cooled with good stirring. The oil solidifies and the crystals were filtered off, washed with water and air-dried. Yield 162.5 g. 2-Phenylsulfonylbutyric acid (47.8 g, 0.21 mol) was suspended/dissolved in ethyl acetate (400 mL) to which was added DMF (0.5 mL), thionyl chloride (76 mL, 1.05 mol) and the mixture heated to 70° C. for 2 hrs. After this period the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (×1). The resulting pale yellow oil was used as such in the preparation of inventive coupler IC-1.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH3:4].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:1][CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH:3]2[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=CC(C)N(CC=O)C(=O)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2C(CCN2Cc2ccccc2)C1C

Procedure:
11.6 g (62.6 mmol) of ethyl N-(1-buten-3-yl)-N-(2-oxoethyl)-carbamate and 10.4 g (62.6 mmol) of N-benzylglycine in 170 ml of toluene are heated under reflux overnight in a water separator. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([N:5]([CH:8]=[CH2:9])[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:11][CH2:12]CCCC.[Na+].[Cl-]>>[CH2:1]([N:5]([CH:8]=[CH2:9])[CH:6]=[O:7])[CH2:2][CH2:3][CH2:4][CH2:11][CH3:12]
Reactant: C=CN(C=O)CCCC
Reactant: CCCCCCBr
Agent: [Cl-]
Agent: [Na+]
Product: C=CN(C=O)CCCCCC
Yield: 63 %

Procedure:
The synthetic procedure was identical to that described for the preparation of 1a, where 1-bromohexane is used in place of 1-bromobutane. Yield: 63%; IR (NaCl, v: cm−1): 1698 (—NHC(═O)H); 1630 (C═C); 1H-NMR (CDCl3, δ: ppm): 8.31, 8.14 (2s, 1H, —C(═O)H); 7.25–7.16, 6.61–6.52 (m, 1H, H2C═CH—); 4.65–4.54 (m, 1H, HaHbC═CH—); 4.45–4.42 (s, 1H, HaHbC═CH—); 3.60–3.44 (t, 2H, —NCH2CH2—); 1.65–1.56 (m, 2H, —CH2CH2CH2—); 1.31 (m, 6H, —CH2(CH2)3CH3); 0.90–0.88 (t, 3H, —NCH2CH2(CH2)3CH3).
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-isopropyl-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[BH4-].[Na+].B(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O.O1CCCC1>[C:13]1([CH2:12][OH:17])[C:14]([CH2:15][OH:16])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)c2ccccc21
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1ccccc1CO
Temperature: 20 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
A 2-liter, 4-necked glass reaction vessel equipped as described in Example 1 was charged with 44.6 grams (1.12 moles plus 5% excess) of sodium borohydride, 0.75 liter of tetrahydrofuran, and 0.185 liter (1.5 moles) of boron trifluoride diethyl etherate at 0°-5°C using the procedure described in Example 1. In a separate 3-liter, 4-necked glass reaction vessel equipped as described in Example 1 was placed 148 grams (1.0 mole) of phthalic anhydride and 0.25 liter of tetrahydrofuran. The resulting slurry was cooled to 0°-5°C using an external ice/water bath. The sodium borohydride-boron trifluoride reaction mixture was then transferred under nitrogen pressure to the anhydride/tetrahydrofuran slurry over a 1.5 hour period while maintaining a temperature of 5°-10°C. After stirring the reaction mixture for 12 hours at 20°C, 0.25 liter of water was added dropwise over a one hour period followed by one liter of diethyl ether. The aqueous layer was saturated with anhydrous potassium carbonate and the organic layer was removed. The aqueous layer was extracted with diethyl ether (2 × 0.25 liter) and the combined organic extracts were dried over anhydrous potassium carbonate, filtered, and concentrated on a rotary evaporator giving 131 grams (95% yield) of 1,2-benzene dimethanol as a crystalline solid, mp 58°-60°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
o-Nitrophenol (111.2 g., 0.8 mole), 1-bromopropane (98.4 g., 0.8 mole), anhydrous potassium carbonate (121.4 g., 0.88 mole) and any acetone (800 cc) are refluxed for 70 hrs., filtered the reaction mass, the residue was washed with acetone, and the filtrate rotoevaporated. To the residue of the evaporation was added 200 cc of dichloromethane and rotoevaporated again; the residue was washed with 100 cc of water and separated into two layers. The dichloromethane layer was washed with 100 cc of 10% Na2CO3, separated again, washed again with 100 cc of water, and the dichloromethane layer was fractionated under vaccum. The main fraction distilled at 103°-106° C. at 0.2-0.3 mm Hg., giving 130 g. of product (87% yield).
Reaction SMILES: Br[C:2]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[N:12][C:5]2[O:6][CH2:7][C:8](=O)[N:9]([CH3:10])[C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:15]=3)=[N:12][C:5]3[O:6][CH2:7][CH2:8][N:9]([CH3:10])[C:4]=3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CN1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccc(F)cc3)cc21
Temperature: 80 °C
Yield: 23.1 %

Procedure:
In a sealed tube was added tert-butyl 1-(4-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (82 mg, 0.168 mmol), 4-fluorophenylboronic acid (35.2 mg, 0.252 mmol), triphenylphosphine (13.21 mg, 0.05 mmol) and cesium fluoride (128 mg, 0.84 mmol) in 1,2-dimethoxyethane (2 ml). The reaction mixture was degassed by bubbling nitrogen for 10 min and palladium acetate (5.65 mg, 0.025 mmol) was added and the mixture was heated at 80° C. overnight. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and the suspension was pass through silica. The filtration was concentrated and to the residue was added methanol (2.5 ml) to form a suspension. The solid was filtered and dried to give tert-butyl 1-(4-(7-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (19 mg). LCMS (Method D): RT=1.54 min, M+H+=504.