Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(OCC)(=O)C>O1CCCC1.ClC(OCC(C)C)=O.CN1CCOCC1>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([NH:26][C:11](=[O:13])[C@@H:9]([N:8]([CH3:14])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10])[CH:27]=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@@H](C(=O)Nc1cccc(OCc2ccccc2)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of N-Boc-N-methyl-L-alanine (561 mg) in tetrahydrofuran (14 mL), isobutyl chloroformate (362 μL) and N-methylmorpholine (303 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 3-benzyloxyaniline (500 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-(benzyloxy)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E15, 903 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via PH paper indicator. The crude is concentrated and diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). HPLC retention time=0.58 minutes (condition D); MS (m+1)=144.0.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH:15]=[CH:16]3)[N:9]1[C:20](=[O:43])[CH2:21][NH:22][C:23](=[O:42])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][CH2:16]3)[N:9]1[C:20](=[O:43])[CH2:21][NH:22][C:23](=[O:42])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(C2CC3C=CC2C3)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)[C@@H]1CSC(C2CC3CCC2C3)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 41 %

Procedure:
The procedure is as in Example 1, but starting with 0.2 g of benzyl (4R)-3-[3-{2-[4-tert-butoxycarbonyl-2-[(2RS)-5-norbornen-2-yl]-3-thiazolidinyl]-2-oxoethyl}ureido]phenylacetate (mixture of isomers C and D), 0.13 g of Ammonium formate and 0.2 g of palladium on charcoal (10% Pd). 0.07 g of (4R)-3-[3-{2-[4-tert-butoxycarbonyl-2- ((2RS) -2-norbornyl)-3-thiazolidinyl]-2-oxoethyl}ureido]phenylacetic acid (mixture of isomers C and D) is thereby obtained in the form of a white product, melting point 115° C.
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C([O-])(O)=O.[Na+].O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:29]1[CH:33]=[CH:32][C:31]([C:2]2[CH:28]=[CH:27][C:5]3[N:6]([CH2:9][C:10]4[CH:26]=[CH:25][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]6[OH:24])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)=[N:30]1
Reactant: OB(O)c1cc[nH]n1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-c5cc[nH]n5)ccc43)cc2s1
Temperature: 90 °C
Yield: 4.5 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.20 mmol) from Step 5 of Example 183 in DMF (2 mL) were added (1H-pyrazol-3-yl)boronic acid (90 mg, 0.80 mmol), NaHCO3 (100 mg 1.2 mmol), bis(triphenylphosphine) palladium(II) dichloride (28 mg, 0.04 mmol), and water (0.4 mL). The mixture was flushed with argon and heated in a sealed vessel at 90° C. for 15 h. The reaction mixture was cooled to rt and partitioned between DCM and water. The aqueous layer was extracted twice with DCM and the combined organic phases were washed three times with a 1:1 mixture of water and brine. The organic phases were then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH/DCM to afford (1R,2R)-2-((6-((5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (4 mg, 5%) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 12.53 (br s, 1H), 8.29 (br s, 1H), 8.03 (m, 1H), 7.58-7.74 (m, 3H), 7.53 (d, J=7.9 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.63 (br s, 1H), 5.47 (s, 2H), 4.42 (d, J=4.4 Hz, 1H), 3.51 (br s, 1H), 3.41 (tt, J=4.5, 8.8 Hz, 1H), 2.06 (m, 1H), 1.90 (d, J=11.8 Hz, 1H), 1.57-1.71 (m, 2H), 1.19-1.36 (m, 4H); LCMS (ESI) m/z 445 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]#[N:15])(=O)C.CO.Cl>C1COCC1.O.CCOC(C)=O>[NH2:15][CH2:14][C:7]1[C:8]([Cl:13])=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(Cl)cc(Cl)c1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NCc1c(Cl)cc(Cl)cc1CO
Temperature: 75 °C

Procedure:
To a soln. of 3,5-dichloro-2-cyanobenzyl acetate (11.7 mmol) in 50 mL THF was added a soln. of BH3 (50 mmol, 1M in THF). The reaction mixture was heated to 75° C. for 7 h and then cooled to 0° C. Water was added followed by MeOH and the mixture was conc. The residue was taken up in water and EtOAc, acidified with 1N HCl solution and extracted with DCM. The aq. phase was then basified with 1M NaOH soln. and extracted with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo. Purification with CC (0-10% MeOH/DCM; 1% Et3N) gives the desired compound as pinkish solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CN(C=O)C>[Br:27][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Cc1cc(-c2cccc(CO)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 3-(3-hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (246 mg, 0.644 mmol; see step (d)), CBr4 (534 mg, 1.61 mmol) and PPh3 (422 mg, 1.61 mmol) in DMF (5.0 mL) was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried and concentrated in vacuo. The crude product was purified on column chromatography (Hex/EtOAc 9:1) to give the sub-title compound as a white solid in 95% yield (273 mg, 0.612 mmol).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:31]1[C:36]2=[CH:37][N:38]=[C:39]([CH:41]=O)[CH:40]=[C:35]2[CH2:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:31]1[C:36]2=[CH:37][N:38]=[C:39]([CH2:41][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:23])[CH2:8][CH2:9]3)[CH:40]=[C:35]2[CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Yield: 76 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride (145 mg, 0.399 mmol) in chloroform (5 ml) and MeOH (0.1 ml) was treated with triethylamine (161 μl, 1.162 mmol) and stirred for 0.25 h before addition of 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (59 mg, 0.363 mmol). The reaction was stirred for 0.5 h before addition of NaBH(OAc)3 (231 mg, 1.089 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (132 mg, 76%).
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[F:29][C:30]([F:41])([F:40])[CH:31]([C:36]([F:39])([F:38])[F:37])[CH2:32][C:33](O)=[O:34]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:33](=[O:34])[CH2:32][CH:31]([C:30]([F:40])([F:41])[F:29])[C:36]([F:37])([F:39])[F:38])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Reactant: O=C(O)CC(C(F)(F)F)C(F)(F)F
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(C3CCN(C(=O)CC(C(F)(F)F)C(F)(F)F)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 4,4,4-trifluoro-3-(trifluoromethyl)butyric acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1>Cl.O1CCOCC1>[NH:28]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 N HCl-1,4-dioxane (200 mL) was added to 40.6 g tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate produced in Reference Example 17, and stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was triturated with methanol. The insoluble solid was collected through filtration, and dried under reduced pressure to obtain 6-(1H-tetrazol-5-yl)-spiro[chroman-2,4′-piperidine]-4-one as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[O:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[O:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzoxazole.
Reaction SMILES: [C:1]([OH:17])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:20])=O>>[C:1]([Cl:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCC(=O)Cl

Procedure:
Pentadecanoic acid (24.2g) was treated with thionyl chloride (13.1g) at 80°-90° C. Pentadecanoyl chloride, thus obtained, was added slowly under ice cooling into the mixture of β-phenoxyethylalcohol (13.8g), pyridine (10.3g) and benzene (100ml) with stirring. After having been stirred, the reaction mixture was treated with an ordinary method (washed with dilute hydrochloric acid, the benzene layer was dried over Glauber's salt, and then benzene was removed under reduced pressure, giving a crude product). Solid (33g) was obtained. The solid was recrystalized from n-hexane, from which it formed colourless crystals (26g), m.p. 45.0°-47.0° C., of β-phenoxyethyl pentadecanoate.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:3]=[O:4])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCCc3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To dimethylformamide (1.7 ml, 0.022 mol) at 0° C. was added dropwise POCl3 (2.0 ml, 0.022 mol) and the mixture allowed to warm and stirred at ambient temperature for 20 minutes, then diluted with 1,2-dichloroethane (5 ml). 1-Benzyl-1,2,3,4-tetrahydroquinoline (4.5 g, 0.020 mol) dissolved in 5 ml of 1,2-dichloroethane was then added and the mixture refluxed 1 hour, then cooled to room temperature. Sodium acetate (9.0g, 0.11 mol), dissolved in the minimum necessary water, was added and the mixture refluxed for 15 minutes. The layers were separated and the aqueous layer extracted 2×10 ml ether.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.[C:31]([NH2:35])(=[O:34])[CH:32]=[CH2:33].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:35][C:31](=[O:34])[CH2:32][CH2:33][N:23]1[CH2:24][CH2:25][C:20]2[C:19]([C:27]([NH2:29])=[O:28])=[C:18]([NH:17][C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)=[O:30])[S:26][C:21]=2[CH2:22]1
Reactant: C=CC(N)=O
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of compound A4 (200 mg, 0.431 mmol), acrylamide (156 mg, 2.19 mmol), and diisopropylethylamine (0.400 mL, 2.25 mmol) in N,N-dimethylformamide (2.5 mL) was heated at 50° C. for 8 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 10% methanol/methylene chloride to afford compound D1 as a yellow solid (180 mg, 99%): 1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.19 (s, 1H), 7.59-7.29 (m, 6H), 6.90-6.73 (m, 2H), 3.48 (s, 2H), 2.83-2.65 (m, 6H), 2.33-2.25 (m, 2H). MS (M+H) 422.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:13]3[C:12](=[O:14])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=3[N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:6]=2)[CH2:3][CH2:2]1.CC[OH:27].CS(C)=O>[OH-].[Na+].OO.[Cl-].[Na+].O>[CH:1]1([CH2:4][C:5]2[C:13]3[C:12](=[O:14])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=3[N:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:27])=[CH:23][CH:24]=3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc(C#N)cc3)c2C1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc(C(N)=O)cc3)c2C1
Reaction time: 1.5 h
Yield: 43 %

Procedure:
After dissolving the nitrile in 10 mL of 4:1 EtOH-DMSO, approximately 0.1 mL of 1 N NaOH (aq.) and 0.1 mL of 30% H2O2 (aq.) were added and the solution stirred for 1.5 hours. The reaction mixture was poured into brine, extracted with EtOAc (×3), and the combined organics washed with brine (×2). The organic extracts were dried over Na2SO4 and concentrated in vacuo to afford 73.2 mg (43% yield) of 4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide as an off-white solid. LCMS (m/z): M+H=339.4.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)[CH:3]([F:5])[F:4].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:5])[F:4])[CH:8]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: FC(F)C(F)(F)Oc1cccc(CNc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a 1,2-dichloroethane (30 mL) solution of 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (2.00 g, 9.0 mmol) was added 3-bromoaniline (0.98 mL, 9.0 mmol), NaB(OAc)3H (2.48 g, 11.7 mmol) and acetic acid (0.57 mL, 10 mmol). The cloudy mixture was stirred at room temperature for 1 hour . The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 3.27 g (96%) of the desired N-(3-bromophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil which was used without further purification. MS m/z=377 [M+].
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([CH3:25])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:25][C:7]1[CH:6]=[C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)C(=O)O)ccc1OCCOc1ccc2ccccc2c1
Yield: 86.7 %

Procedure:
A solution of 3-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na25O4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.5 g of purified 3-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 167°-169° C.
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:20])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCCC(CCCCCC)C(=O)O

Procedure:
The synthetic fuel was prepared by using a 1000 ml glass reactor, provided with thermostat, mechanical stirring, sampling outlet, and condensation system. Octanol-1 (300 g) was charged to the reactor and ZnO (2 g), KOH (6 g), CaO (5 g) and Cu Bronze (1.5 g) were added. The above reaction mixture was heated at 200° C. for 8 hours to complete the reaction. The reaction mixture was filtered and purified by distillation to get 2-hexyl-1-decanol (250 g). 2-Hexyl-1-decanol (250 g) was reacted with Jones reagent (200 ml) in acetone (200 ml) to get 2-hexyl-1-decanoic acid. 2-Hexyl-1-decanoic acid produced (200 g) was again charged to the above reactor and subsequently, methanol (200 g) and sulfuric acid (6.0 g) were added slowly to the reactor with stirring. The reaction mixture was refluxed till completion of the reaction. The reaction mixture was passed through basic alumina to get rid of residual catalyst. The catalyst free mixture was fractionated to separate un-reacted methanol and synthetic diesel. Prepared synthetic fuel was evaluated for fuel properties and results were tabulated.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: CCc1cc2c(Cl)ncnc2s1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)ncnc2s1
Yield: 92 %

Procedure:
1-BOC-3-(R)-methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=92%, ES-MS: (M+H)+ 363.