Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].[CH3:32][O:33][C:34](=[O:55])[C:35]1[C:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[O:49][CH2:50][CH2:51][CH2:52][CH2:53][NH2:54]>>[CH3:32][O:33][C:34](=[O:55])[C:35]1[C:40]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[O:49][CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:6](=[O:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Product: COC(=O)c1c(OCCCCNC(=O)[C@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)NC(C)=O)cccc1OCc1ccccc1

Procedure:
The title compound is prepared using (S)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid and 2-(4-aminobutoxy)-6-benzyloxybenzoic acid methyl ester (Example 110, step C) analogous to Example 131, step C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].Cl>CN(C)C=O.O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(CCc2ccc(O)cc2)S1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Oily sodium hydride (60%, 0.10 g) was added to a solution of 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.30 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 4-chloromethyl-5-methyl-2-phenyloxazole (0.29 g) was added, and the mixture was stirred at 90 to 100° C. for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-chloroform (1:9, v/v) gave 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-2,4-thiazolidinedione (0.30 g, 59%). This product was recrystallized from dichloromethane-isopropyl ether. Colorless needles. mp: 146-147° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][CH:31]1[CH2:34][N:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:38]4[CH2:39][CH2:40][CH:35]([N:33]5[CH2:32][CH:31]([F:30])[CH2:34]5)[CH2:36][CH2:37]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1CN(C2CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.155 g, 0.395 mmol), 4-(3-fluoroazetidin-1-yl)piperidine (0.075 g, 0.474 mmol) and 4 Å molecular sieves (0.5 g) in DCE (6 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.168 g, 0.79 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 608 as a white solid (0.177 g, 84%). LCMS (Method I): RT=2.25 min, [M+H]+ 534.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.27-7.21 (m, 2 H), 5.20-5.00 (m, 1 H), 4.50-3.96 (m, 4 H), 3.80 (s, 3 H), 3.80-3.74 (m, 4 H), 3.75 (s, 2 H), 3.56-3.45 (m, 2 H), 3.26 (q, J=7.4 Hz, 2 H), 3.06-2.94 (m, 2 H), 2.78-2.68 (m, 2 H), 2.19-2.09 (m, 2 H), 2.07 (s, 1 H), 1.66-1.57 (m, 2 H), 1.33 (t, J=7.4 Hz, 3 H), 1.25-1.12 (m, 2 H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][C@H:27]12>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:30][CH2:29][N:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]5[CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1C[C@@H]2CNCCN2C1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN5CCC[C@@H]5C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-octahydropyrrolo[1,2-a]pyrazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 4H) 2.33 (d, J=2.53 Hz, 3H) 2.81-4.24 (m, 9H) 7.64 (br. s., 1H) 7.75 (t, J=7.45 Hz, 1H) 7.95-8.83 (m, 4H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)=[O:7].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:18])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccc(CO)cc1)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(CCl)cc1)c1cccs1
Reaction time: 8 h

Procedure:
To a stirred and cooled suspension of 31 parts of α-hydroxy-p-tolyl 2-thienyl ketone in 160 parts of dry benzene are added dropwise 24 parts of thionyl chloride at 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is evaporated twice more from toluene. The latter residue is triturated in petroleumether. The product is filtered off and dissolved in 320 parts of ether. This solution is stirred with charcoal, filtered and the filtrate is evaporated. The residue is crystallized from ethanol at -20° C, yielding α-chloro-p-tolyl 2 -thienyl ketone.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[OH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28]>>[OH:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][OH:28])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: OCCNCCO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N(CCO)CCO)cc2c1=O
Yield: 55 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-(2-hydroxy-ethylamino)-ethanol according to the GPA affording 21 mg (55%) of a red powder. Rt=2.36 min.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:6][CH2:7][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]5[NH:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:3][CH2:4]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
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: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To the solution (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (99 mg, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and stirred at room temperature for 1 h. The solvent was removed in vacuo, dichloromethane added (15 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to yield the title compound (59 mg, 61%) as white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.71-0.89 (m, 4H), 1.00 (s, 3H), 1.28-1.46 (m, 5H), 1.50-1.68 (m, 2H), 1.68-1.89 (m, 8H), 1.89-2.00 (m, 2H), 2.11-2.31 (m, 2H), 2.86-3.02 (m, 2H), 3.02-3.14 (m, 2H), 3.47-3.70 (m, 4H), 3.75-3.91 (m, 1H). MS (M+1): 389.2.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:4]=[N:5][N:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].C([OH:15])C>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:11][N:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:3]([CH:2]=[O:15])[CH:4]=[N:5]1
Reactant: Cn1ncc(C(Cl)Cl)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: Cn1ncc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 41 %

Procedure:
A hot solution of silver nitrate (4.7 g, 27.4 mmol) in ethanol (15 mL) and water (4 mL) was added to a stirring solution of 4-dichloromethyl-1-methyl-5-nitro-1H-pyrazole (1.44 g, 6.85 mmol) in ethanol (50 mL) at 50° C. The mixture was stirred vigorously under reflux for 1 h, cooled to room temperature, and diluted with water (14 mL). The aqueous layer was extracted with chloroform and filtered through a layer of celite. Concentration and chromatography on a silica gel column with hexane and ethyl acetate (6:1) gave 1-methyl-5-nitro-1H-pyrazole-4-carbaldehyde (0.42 g, 41%): 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 8.08 (s, 1H), 4.36 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([Cl:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) (0.2 g, 0.53 mmol) was dissolved in DCM (10 ml) and treated with oxalyl chloride (1.5 g, 12 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 14 hours and the solvent was then removed in vacuo. The crude material was dissolved in toluene and evaporated. Crude 2,4-bis-benzyloxy-5-isopropyl-benzoyl chloride was obtained as an oil (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:11][C:7]1[CH:8]=[C:2]([Cl:1])[C:3]([O:9][CH3:10])=[CH:4][C:5]=1[NH2:6]
Reactant: COc1cc(N)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1Cl
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 4-chloro-3-methoxyaniline (1.0 equivalent) dissolved in CH2Cl2 (15 volumes) at 5° C. was treated portion wise with N-bromosuccinimide (1.03 equivalents), warmed to 20° C. and mixed for 5 minutes. A 5% aqueous Na2SO3 solution (10 volumes) was added and the mixture was stirred for 10 minutes. The layers were separated and the organic layer was washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with a minimal volume of heptane and the solid was collected by filtration and dried to constant mass (80% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: Fc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of p-fluorophenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for four hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1N hydrohloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated. The residue, containing 2-p-fluorophenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5% palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2p-fluorophenylnaphthalene.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:30][C:31]4[O:35][CH:34]=[CH:33][CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (400 mg) and furfural (485 mg) in 1,2-dichloroethane (15 ml) was added sodium triacetoxyborohydride (536 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (319 mg) as yellow oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37]N)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(S(=O)(=O)C(F)(F)F)c1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-trifluoromethanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=531.1 (M+H)+
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[Cl:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([C:20](=[CH:26]N(C)C)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O>C(O)C>[Cl:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a stirred solution of 3.45 g of benzamidine hydrochloride in 50 cc of ethanol was added 1.50 g of sodium ethoxide at room temperature and the mixture was stirred for 10 minutes. The resulting suspension was added to 6.2 g of compound D in 50 cc of ethanol and the resulting mixture was heated under reflux for 6 hours. After cooling, the solvent was distilled off, and AcOEt and water were added to the residue. The organic layer was further washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/8) to obtain 5.80 g of compound E. Yield: 77.6%.
Reaction SMILES: [H-].[Na+].I[CH3:4].[OH:5][CH:6]1[C:12]2[CH:13]=[C:14]([CH2:17][N:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([CH:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[O:20])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:34]([N:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([O:5][CH3:4])[C:12]=2[CH:13]=1)[C:19]([CH:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]1)=[O:20])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CN(Cc1ccc2c(c1)C(O)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCCc2ccc(CN(CC(C)C)C(=O)C3CN(C(=O)OC(C)(C)C)CCO3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.8 %

Procedure:
To a stirred mixture of 25 mg (0.62 mmol, 1.2 equiv) of 60% sodium hydride/mineral oil dispersion and 0.047 mL (0.75 mmol, 1.5 equiv) of iodomethane in 1 mL of anhydrous tetrahydrofuran under nitrogen was added a solution of 230 mg (0.50 mmol) of (±)-tert-butyl 2-{[[(9-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)methyl](isobutyl)amino]-carbonyl}morpholine-4-carboxylate in 1 mL of anhydrous tetrahydrofuran over five minutes. The mixture was stirred at ambient temperature in a sealed flask for three days. The mixture was diluted with 2 mL of saturated sodium bicarbonate solution and extracted with 2×10 mL of ethyl acetate. The extract was washed with 3 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated to give 263 mg of a gum. Purification by flash chromatography (10-50% ethyl acetate in hexanes) gave 171 mg (72%) of product as a solid white foam. MS (m+1)=475.4; H NMR (400 MHz, CDCl3) 7.06 (m, 2H), 6.96 (m, 1H), 4.7 (m, 1H), 4.50 (d, 1H, J 16 Hz), 4.28 (m, 1H), 4.18-4.02 (m, 2H), 3.97-3.80 (m, 2H), 3.50 (m, 1H), 3.31 (d, 3H, J 10 Hz), 3.22 (m, 2H), 2.99 (m, 3H), 2.65 (m, 1H), 2.01 (m, 2H), 1.86 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.45 (d, 9H, J 14 Hz), 0.89 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])([O-:3])=[O:2].[NH3:18]>>[N+:1]([C:4]1[CH:13]=[C:12]([C:14]([NH2:18])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reactant: N
Product: NC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
This invention provides as new compositions of matter 2- and 3-nitroterephthalamic acids. This invention further provides a new process for the preparation of 2- and 3-nitroterephthalamic acids comprising the steps of reaction of a 1-4 carbon dialkyl nitroterephthalate with 20-51% by weight aqueous ammonia at 100°-200° C. under at least autogenous pressure for 1-6 hours at a dialkyl nitroterephthalate concentration of 10-40% by weight. Preferably 30-51% by weight aqueous ammonia is reacted at 150°-175° C. for 2-4 hours. For the preparation of 3-nitroterephthalamic acid it is preferred that the reaction be carried out using 20% by weight dimethyl nitroterephthalate and 25-51% by weight aqueous ammonia for 2-4 hours at 125°-175° C., most preferably at 150° C. 3-Nitroterephthalamic acid is isolated from the reaction mixture by cooling, removal of by-product nitroterephthalamide by filtration, adjustment of the pH of the filtrate to about 4 and removal of 3-nitroterephthalamic acid by filtration. For the preparation of 2-nitroterephthalamic acid, it is preferred that the reaction be carried out using about 10% by weight dimethyl nitroterephthalate and 25-51% by weight aqueous ammonia for 2-4 hours at 150°-200° C., most preferably at 175° C. 2-Nitroterephthalamic acid is isolated from the reaction mixture by cooling, removal of by-product nitroterephthalamide by filtration, adjusting the pH of the filtrate to about 4, removal of by-product 3-nitroterephthalamic acid by filtration, adjustment of the pH of the filtrate to about 2 and removing 2-nitroterephthalamic acid by filtration. The reaction may be summarized as follows: ##STR1##
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].C(O)(=[O:35])C.ClC1C=CC=C(C(OO)=O)C=1>O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N+:6]1([O-:35])[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: N#CC(CC[N+]1([O-])CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
6.3 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid was dissolved, at room temperature, in 100 ml. of glacial acetic acid. To that mixture was added 3.1 grams of m-chloroperbenzoic acid (85% by weight) and the resultant mixture was stirred at room temperature for a period of 11/2 hours, thereafter diluted with 500 ml. of water, cooled and filtered. The residual solid was washed successively with water chloroform, ether and warm methanol. Upon drying for 6 hours at 65° C. was afforded 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-N-oxidopiperidine-4-carboxylic acid, melting at about 186°-189° C., with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.F>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: F
Solvent: c1ccccc1
Product: Cc1ccc(C(c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 64 h

Procedure:
1290 g of 2-(4-methylphenyl)hexafluoropropan-2-ol and 780 g of benzene were placed in a 5-liter steel autoclave and 1500 g of anhydrous hydrogen fluoride was pumped into the sealed autoclave. The reaction mixture was heated at 170°-175° C. with stirring for 64 hours. After completion of the reaction, hydrogen fluoride gas was allowed to escape at 80° C., and the liquid product was then washed twice with water, dried over calcium chloride, and fractionally distilled. Boiling point 135°-136° C./1.4 mbar. Yield: 1424 g (89.5%).