Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[N:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([C:26]3[N:25]=[C:24]([CH3:23])[O:28][N:27]=3)=[CH:37][CH:36]=2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cc1nc(-c2ccc(C(=O)NC3CCN(CCn4c(=O)ccc5c(F)cc(F)cc54)CC3)cc2)no1
Yield: 44.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (80 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol). Solvent removed and the obtained solids were suspended in ethyl acetate and then filtered to give title compound (71.9 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14]C([O-])(C)C.[K+].CI>C(Cl)Cl>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH3:14])([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC(C)CC1=CCC(C)(C=O)C(C)C1
Temperature: -3 °C
Yield: 99.4 %

Procedure:
4-Isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (8 g, 44 mmol) was dissolved in methylene chloride (400 ml) and cooled to −3° C. with stirring and under nitrogen. KOtBu (6.7 g, 58 mmol) and MeI (19 g, 130 mmol) were added sequentially and the suspension stirred for 30 min before being allowed to return to room temperature. After stirring for a further 3 h the reaction crude was poured onto brine (400 ml), stirred for 10 min and the phases allowed to separate. The upper aqueous phase was extracted with methylene chloride (150 ml) and the organic phases combined, dried (Na2SO4) and concentrated in vacuo to give 8.5 g of an orange oil (8.5 g). The oil was purified by flash chromatography (MTBE/hexane 1:9) and combination of pure fractions gave 3c as a 7:3 mixture of diastereomers (7 g, colorless oil, 80% yield). 1 g of the oil was distilled to give a sample for olfactory assessment. (0.52 g, colourless oil, >99% pure).
Reaction SMILES: [N:1]1([CH2:11][C:12]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>ClCCl>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:12]([OH:30])([C:13]([F:14])([F:15])[F:16])[CH2:11][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([C:42]([C:38]3[O:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:3][CH2:2]2)[CH:26]=1
Reactant: O=C(Cl)c1ccco1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCNc2ccccc21)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCN(C(=O)c2ccco2)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.8 %

Procedure:
To a solution of 2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (0.50 g, 0.117 mmol) in dichloromethane (10 mL) was added pyridine (0.24 mL, 0.129 mmol) and 2-furoyl chloride (0.012 mL, 0.129 mmol). The reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane, washed with two 25 mL portions of a saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by flash column chromatography (5% MeOH/CH2Cl2) yielded the title compound as a white solid (14.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:12]/[C:13](/[C:23](OC)=[O:24])=[C:14](/OC(=O)C)\[C:15]([O:17][CH3:18])=[O:16])(=O)C>C(O)(=O)C.CO>[CH3:18][O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]2[C:23](=[O:24])[C:13]=1[OH:12])=[O:16]
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Yield: 2.1 %

Procedure:
2-Amino-5-bromo-pyridine (664 mg, 3.85 mmol), dimethyl diacetoxyfumarate (1.00 g, 3.84 mmol) and glacial acetic acid (10 drops) in dry methanol (10 mL) were combined and heated to reflux. After 48 h the reaction was cooled to room temperature and concentrated in vacuo. Ethyl acetate (2 mL) was added to the residue which was sonicated for 2 min and the resulting precipitate collected by filtration and washed with cold ethyl acetate (1 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester as a yellow solid (24 mg, 2%): 1H NMR (300 MHz, CDCl3) δ 4.19 (3H, s, OCH3), 7.53 (2H, d, J=1.4 Hz, H8 and H9), 9.00 (1H, d, J=1.4 Hz, H6), 10.53 (1H, br s, OH).
Reaction SMILES: CO[N:3]=[C:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]1=[O:16]>CO.[Pd]>[NH2:3][CH:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]1=[O:16]
Reactant: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: NC1C(=O)Nc2ccccc2NC1=O
Yield: 62 %

Procedure:
A solution of 3-methoxyimino-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (3.78 g, 17.4 mmol) and 10% Pd/C (1.8 g) in methanol (300 ml) is stirred for 15 hr under hydrogen gas. After removing the catalyst by filtration, the filtrate is concentrated under reduced pressure. The resultant residue is crystallized from methanol to obtain Compound 4 (2.062 g, 62%). M.p. =290°-291° C.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-])=O)[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O>C(O)(=O)C.[Fe]>[NH2:24][C:11]1[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=[C:2]([F:1])[C:12]=1[N:13]1[C:21](=[O:22])[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]1=[O:23]
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c2N1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c2c(cc(F)c1N1C(=O)C3=C(CCCC3)C1=O)OCC(=O)N2
Yield: 104.7 %

Procedure:
2-[7-Fluoro-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.25 g) was dissolved in acetic acid (13 ml) and iron powder (0.77 g) was added with stirring. Solution was stirred at ambient temperature for 12 hr and water was added. Product was extracted with ethyl acetate to afford the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH:26]([F:28])[F:27])=[N:9]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 90 °C

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (200 mg, 0.49 mmol) was dissolved in DMF (5 mL), 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (263 mg, 0.74 mmol) and cesium carbonate (240 mg, 0.74 mmol) were added and the mixture heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with DCM (×3). The combined organic extract was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant yellow oil was purified by flash chromatography on silica eluting with 0-2% MeOH in DCM. The appropriate fractions were collected and evaporated to afford 4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester a yellow oil. The crude product was taken onto the next step without further purification. LCMS (Method 4) [M+Na]+=610.0; RT=4.30 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1
Reactant: [H][H]
Reactant: CSc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=[O:13])[CH2:3][CH2:2]1
Reactant: OCCC1CCOc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethanol (1.45g, 8 mmol), N-methylmorpholine-N-oxide (1.41 g, 12 mmol) and 4 A molecular sieves (4.0 g) in methylene chloride (20 ml), tetrapropylammonium perruthenate (0.140 g, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 15 min., diluted with an equal volume of ethyl acetate (20 ml) and flash filtered through silica gel (eluant: methylene chloride/ethyl acetate 1:1). Concentration of the filtrate in vacuo afforded the title compound as an oily gum (0.92 g, 64%). NMR (300 MHz/CDCl3) 9.87 (1 H, s).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl>CN1CCN(C)C1=O.O>[F:11][C:9]1[CH:10]=[C:2]([OH:12])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1ccc(F)cc1O
Temperature: 135 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 2,4-difluorobenzoic acid (100 g, 0.63 mol) in 1,3-dimethyl-2-imidazolidinone (1,400 mL, 0.45 M) was treated with sodium hydroxide (88 g, 2.2 mol) and heated to 135° C. After stirring for 4 h, the solution was cooled 0° C., dissolved in water (100 mL), and transferred to a 5 L Erlenmeyer flask and carefully treated with aq HCl (2,800 mL, 2 N). After filtering off the crude product, the precipitate was dissolved in ethyl acetate, dried over sodium sulfate and decolorizing charcol, and filtered. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate and heptane to give 4-fluorosalicylic acid (2 crops, 67 g, 68%) as off-white needles. mp: 188-189° C.; Rf 0.26 (20% methanol in dichloromethane).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=C\CCCCC.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=[O:39].CC/C=C\C/C=C\C/C=C\CCCCCCCC(OO)=O.C1OC1=C.CC/C=C\C[C@@H]1C(=O)C=C[C@@H]1CCCCCCCC(O)=O>CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(O)=O>[CH3:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:7]1[C:6](=[O:39])[CH2:5][CH2:4][C@@H:3]1[CH2:2][C:1]([OH:20])=[O:19]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: C=C1CO1
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)OO
Agent: CC/C=C\C[C@@H]1C(=O)C=C[C@@H]1CCCCCCCC(=O)O
Product: CC/C=C\C[C@@H]1C(=O)CC[C@@H]1CC(=O)O

Procedure:
The first step in jasmonic acid biosynthesis is the formation of linoleic acid (Chemical Abstracts name: (Z,Z)-9,12-Octadecadienoic acid) and linolenic acid (Chemical Abstracts name: (Z,Z,Z)-9,12,15-Octadecatrienoic acid) from membrane lipid breakdown, catalysed by phospholipase. Linoleic and linolenic acid are converted to 13-hydroperoxylinolenic acid by the action of lipoxygenase. 13-hydroperoxylinolenic acid is converted into 12,13 expoxy-octadecatrienoic acid in the presence of allene oxide synthase (AOS), and then converted into 12-oxo-phytodienoic acid by allene oxide cyclase (AOC). Following reduction and three steps of β-oxidation, (+)-7-iso-jasmonic acid is formed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:18].[CH3:19][C:20](OC(C)=O)=[O:21]>N1C=CC=CC=1>[Cl:18][C:3]1[CH:4]=[C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][C:2]=1[NH:1][C:20](=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 10 h
Yield: 96.4 %

Procedure:
A solution of 1 g (3.4 mmol) of 2-(4-amino-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 5 mL of pyridine was treated with 0.42 mL (4.4 mmol) of Ac2O and stirred at 70° C. for 10 hours. The solvent was evaporated, the residue dissolved in THF, treated with a 2M aqueous solution of NaOH and stirred for 1 h at RT. After acidification of the mixture to a pH of ca. 7 by adding aqueous HCl, Et2O and H2O were added, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.1 g (ca. 94%) of crude N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide, which was dissolved in 20 mL of DMF and treated with 0.65 mL (4.37 mmol) of DBU and then at 0° C. dropwise with 0.73 mL (4.37 mmol) of TESCl. The mixture was stirred overnight and poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.53 g (93%) of crude N-[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide, yellow oil, MS: 450 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cnccc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-c]pyridin-1-yl amine (223 mg, 1.52 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (329 mg, 1.52 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol) in DMF (8 mL) is stirred at 150° C. for 1 h. The reaction is quenched with water and NaHCO3 (168 mg, 2 mmol). The mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% meOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide (91 mg, 17%). MS: 345 (M+H); 1H NMR (300 MHz, DMSO-d6): δ=9.34 (s, 2H), 8.79 (d, 1H), 8.53 (d, 1H), 8.45 (d, 1H), 8.13 (d, 1H), 8.02 (t, 1H), 7.86 (s, 1H), 7.59 (t, 1H), 2.77 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[CH3:10][C:11](=[CH2:13])[CH3:12]>>[C:11]([C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7])([CH3:12])([CH3:10])[CH3:13]
Reactant: Cc1ccc(N)cc1N
Reactant: C=C(C)C
Product: Cc1cc(C(C)(C)C)c(N)cc1N
Temperature: 180 °C

Procedure:
The procedure of Example 1 was followed to produce toluenediamine (5tBTDA) by using 15 grams of powdered montmorillonite clay in place of the silica-alumina catalyst and using 150 g (1.23 moles) of the 2,4-toluenediamine isomer as opposed to the 2,6-isomer. As in Example 1, the reaction contents were purged with nitrogen and then the contents were heated to 180° C. with stirring. Approximately 278 grams or 4.95 moles of isobutylene were then added to the reaction mixture over 20 minutes. The initial reaction pressure increased to 1210 psig and the contents maintained 180° C. for 23 hours. At that time the contents were cooled 150° C. and the reactor vented. The catalyst then was removed by hot filtration.
Reaction SMILES: [OH-].[K+].[CH2:3]([SH:6])[CH2:4][CH3:5].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15]>CN(C)C=O>[CH2:3]([S:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:4][CH3:5]
Reactant: CCCS
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1S(N)(=O)=O
Yield: 82.1 %

Procedure:
To a solution of potassium hydroxide (85%, 12 gm, 0.2 mole) and n-propylmercaptan (18.1 ml, 0.2 mole) in 100 ml dimethylformamide at 90° C. was added a solution of 2-chlorobenzenesulfonamide (19.1 gm, 0.1 mole) in 100 ml dimethylformamide. The reaction mixture was heated to reflux for five hours, cooled, and the solvent was removed in vacuo. The residue was diluted with water, made acidic with concentrated hydrochloric acid and extracted with ether. The ether extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield the crude product. Recrystallization from a suitable solvent such as toluene afforded 19 gm (82%) product: m.p. 58°-64°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:23]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1OC
Yield: 60 %

Procedure:
4-[2-(3,4-Dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl was prepared analogous to Example I from 4-[2-amino-ethyl]-4'-hydroxy-biphenyl and 3,4-dimethoxybenzoyl chloride. Yield: 60% of theory; m.p. 170° C.
Reaction SMILES: Cl.[CH2:2]([NH:14][NH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+].[CH3:18][N:19]=[C:20]=[O:21]>C(OCC)C>[CH3:18][NH:19][C:20]([N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[NH2:15])=[O:21]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCNN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCCCN(N)C(=O)NC
Yield: 94.1 %

Procedure:
A stirred, degassed suspension of dodecylhydrazine hydrochloride (4.62 g, 0.017 mole) in diethyl ether (15 mL) was cooled under nitrogen and 4N aqueous potassium hydroxide (8.7 mL, 0.035 mole) was added. Stirring was continued as methyl isocyanate (0.97 g, 0.017 mole) in 5 mL diethyl ether was added dropwise. The mixture was filtered to yield 4.12 g (94.7%) N-methyl-1-dodecyl-hydrazinecarboxamide (m.p. 73°-75° C.). NMR analysis confirmed the structure.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[CH2:10]([N:12]=[C:13]=[O:14])[CH3:11]>ClCCCl>[CH2:10]([NH:12][C:13](=[O:14])[O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH3:9])[CH3:11]
Reactant: C/C=C(/C=C/CO)CC
Reactant: CCN=C=O
Solvent: ClCCCl
Product: C/C=C(/C=C/COC(=O)NCC)CC
Yield: 80 %

Procedure:
A solution of (E,E)-4-ethyl-2,4-hexadien-1-ol (2.0 g) and ethyl isocyanate (1.13 g) in 1,2-dichloroethane (12 ml) was stirred at 0° C. for 3 hours and at room temperature for 12 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (chloroform) to give (E,E)-4-ethyl-2,4-hexadien-1-yl ethylcarbamate (2.5 g) as an oil.