Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].C(=O)(O)[O-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[K+:35]>O>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[K+:35]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]

Procedure:
The soluble aspirin composition of the present disclosure is formulated so that all aspirin is bound to particles of bicarbonate, i.e., the composition contains no non-agglomerated aspirin. The granules, containing aspirin, powdered heat-treated bicarbonate salt, resin and surfactant, are in mixture with crystalline particles of pharmaceutically-acceptable acid, such as citric acid, and crystalline particles of heat-treated bicarbonate salt, e.g., potassium bicarbonate. When the soluble aspirin composition is introduced to water or other aqueous medium, the pharmaceutically acceptable acid crystals and the heat-treated bicarbonate salt crystals strongly react with one another to effect effervescence and mixing of the composition in the liquid volume, and the pharmaceutically acceptable acid crystals react with the heat-treated bicarbonate salt in the granules to reactively break up and disperse the granules, with the reaction involving the aspirin in the granules, to yield potassium acetylsalicylate, which immediately dissolves in the aqueous medium without residue.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH3:19])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:19])[CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(R)-tert-Butyl 4-(3-(2-chlorobenzamido)-N-methyl-2,3-dihydro-1H-indene-5-carboxamido)-piperidine-1-carboxylate (300 mg, 0.587 mmol, 1 eq) was dissolved in dichloromethane (10 ml). The solution was cooled to 0° C., and trifluoroacetic acid (2 ml) was added dropwise. The reaction mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The residue was taken up in dichloromethane (100 ml), washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. The desired product was in the form of a brown solid and was used in the next stage without being purified further. Yield: 95% (230 mg, 0.559 mmol)
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:19]1([C:24]2[N:29]=[N:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:30]([C:27]2[N:28]=[N:29][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)=[O:31])[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2ccnc2)nn1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ccnc4)nn3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-imidazol-1-yl-pyridazine-3-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 13): tR=2.44 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[OH:32]>CCOCC.CO>[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[O:32][CH2:3][C:2]([CH3:4])=[CH2:1]
Reactant: C=C(C)C=[N+]=[N-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CCOCC
Solvent: CO
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 150 ml of ether (prepared from 0.1 mole of N-(2-methyl-2-propenyl)-ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem., Soc., 91, 711 (1969)) is diluted with 50 ml of methanol and cooled to 0°C. A total of 7 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g -silica gel column. Elution with chloroform gives TLC pure material which crystallizes from acetone-hexane to give 5.4 g of 21-chloro-9-fluoro-11β,17 -dihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione, melting point 238°-240°C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([NH:38]C(=O)OC(C)(C)C)=[NH:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([NH2:38])=[NH:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=N)NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N=C(N)N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Reaction time: 0.02 h

Procedure:
To a solution of tert-butyl N—[N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamimidoyl]carbamate, 70c, (0.100 g, 0.156 mmol) in THF (20 mL) was added sodium methoxide (0.033 g, 0.156 mmol) at room temperature. After 1 minute, the reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 95 mg of the desired product. To 10 ml MeOH solution of the product was added hydrochloride/IPA (0.031 mL of 5 M solution, 0.156 mmol). The reaction mixture was stirred at room temperature for 1 hour after which the solvent was removed under reduced pressure to afford the product, as hydrochloride salt: 1H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.40 (dd, J=9.1, 2.7 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H), 3.78-3.53 (m, 1H), 2.41 (d, J=11.7 Hz, 1H), 2.28 (d, J=12.0 Hz, 1H), 2.18-1.98 (m, 2H), 1.69 (dd, J=23.6, 11.8 Hz, 2H), 1.56-1.28 (m, 2H); LCMS RT=1.45 (M+H) 387.06.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:20][C:21]2([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[O:31]CC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([N:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH:20][C:21]3([C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=4[OH:31])[CH2:22][CH2:23]3)[C:5]2=[O:19])[CH:9]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4cc(F)ccc4OCc4ccccc4)CC3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4cc(F)ccc4O)CC3)c2=O)c1
Temperature: 75 °C
Yield: 60.6 %

Procedure:
To 3-[5-bromo-3-[[1-[5-fluoro-2-(phenylmethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 278b, 2.8 g) in ethanol (200 mL) was added ammonium formate (5.0 g) and 10% Pd/C (1.0 g). The reaction was heated at 75° C. for 1 h, filtered through celite washing the celite with warm ethanol (100 mL) followed by dichloromethane (2000 mL). The combined filtrates were evaporated, diluted with dichloromethane (1000 mL) and washed with water, dried (MgSO4) and evaporated to give the subtitle compound (1.2 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1

Procedure:
80 mg of solid yellow 3-{4-[3-(2-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-trifluoromethylphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:34][C@H:33]([CH2:35][O:36]CC4C=CC(Cl)=CC=4Cl)[C@@H:22]([O:23]CC4C=CC(Cl)=CC=4Cl)[C@@:20]3([CH3:46])[OH:21])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:22]([OH:23])[C@@:20]3([CH3:46])[OH:21])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cn([C@@H]3O[C@H](COCc4ccc(Cl)cc4Cl)[C@@H](OCc4ccc(Cl)cc4Cl)[C@@]3(C)O)c2n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)c2n1
Temperature: -72.5 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of compound 15.2 (7.03 g, 8.43 mmol) in CH2Cl2 (200 mL) at −75° C. was added boron trichloride (1M in CH2Cl2; 83.4 mL, 83.4 mmol). The mixture was stirred at −75 to −70° C. for 2 hr and then at −30 to −20° C. for 3 hr. The reaction was quenched by addition of MeOH/CH2Cl2 (1/1, 9 mL) and the resulting mixture stirred at −20 to −15° C. for 30 min., then neutralized with aq. ammonia (28%, 35 mL) at 0° C. and stirred at room temperature for 10 min. The solid which separated was filtered and washed with MeOH/CH2Cl2 (1/1, 500 mL). The combined filtrates were evaporated and the residue was purified on a silica gel column using CH2Cl2/MeOH (50/1, 40/1) as the eluents to furnish the target compound 15.3 as an off-white solid (2.93 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=O)[O:21]C3C(F)=C(F)C(F)=C(F)C=3F)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:43][C:44]1[CH:45]=[C:46]2[C:67](=[CH:68][CH:69]=1)[CH2:66][C@:48]1([C:56]3[C:51](=[N:52][CH:53]=[CH:54][CH:55]=3)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:49]1=[O:65])[CH2:47]2.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=[O:21])[O:43][C:44]3[CH:45]=[C:46]4[C:67](=[CH:68][CH:69]=3)[CH2:66][C@:48]3([C:56]5[C:51](=[N:52][CH:53]=[CH:54][CH:55]=5)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:62])([CH3:63])[CH3:64])[C:49]3=[O:65])[CH2:47]4)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(O)cc3C2)c2cccnc21
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)C(=O)C12CCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2
Temperature: 150 °C

Procedure:
A mixture of tert-butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-9-[2-oxo-2-(pentafluorophenoxy)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate from Step A (119 mg, 0.197 mmol), (2R)-5-hydroxy-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (77 mg, 0.201 mmol, described in Intermediate 35), and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) in DMF (0.5 mL) was heated at 150° C. in a microwave reactor for 30 min. The reaction mixture was cooled and partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to provide the title compound. MS: m/z=803.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Br.C1(O)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Product: Fc1ccc(Cn2c(SC3CCNCC3)nc3ccccc32)cc1
Yield: 99 %

Procedure:
A mixture of 4.95 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 225 parts of a hydrobromic acid solution 48% in water and 5 parts of phenol was stirred and refluxed for 2 hours. The reaction mixture was evaporated and the residue as taken up in water and treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (99%) of 1-[(4-fluorophenyl)methyl]-2-[(4-piperidinyl)thio]-1H-benzimidazole (55).
Reaction SMILES: [CH3:1][C:2]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: Cc1cccc(C(=O)Nc2cc(-c3ccc(OC(=O)OC(C)(C)C)cc3)ccc2C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc(O)cc3)ccc2C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2,3-dimethylbenzamido)-4-(4-(tert-butoxycarbonyl)oxyphenyl)benzoate and stirred ah room temperature for 2 hours. The solvent was evaporated under reduced pressure and ethyl acetate was added to the obtained residue and a solid substance was separated by filtration to obtain 20 mg of 2-(2,3-dimethylbenzamido)-4-(4-hydroxyphenyl)benzoic acid as white solid.
Reaction SMILES: C[Si](C)(C)O[C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.OC1C=[CH:39][C:27]([C:28]([O:30]C2C=CC(CC)=CC=2)=[O:29])=[CH:26]C=1.C(OC(=O)C(C)=C)(=O)C(C)=C.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[C:28]([O:30][C:19]1[CH:20]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=[O:9])(=[O:29])[C:27]([CH3:39])=[CH2:26]
Reactant: CCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Reactant: CCc1ccc(OC(=O)c2ccc(O[Si](C)(C)C)cc2)cc1
Agent: C=C(C)C(=O)OC(=O)C(=C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1ccccc1C(=O)Oc1ccc(CC)cc1
Temperature: 100 °C

Procedure:
A solution of 16.9 g of 4-ethylphenyl 4-trimethylsilyloxybenzoate (prepared by the procedure in EP-A-358,208, page 9, sec. C) in 15 ml of toluene and 10 ml of ethanol was refluxed for 1 hour and then freed from volatile components by heating at 100° C. for 60 minutes. The remaining 13.3 g of 4-ethylphenyl 4-hydroxybenzoate were dissolved in 15 ml of toluene together with 30 g of methacrylic anhydride and 1.2 g of toluenesulfonic acid, and the mixture was heated at 100° C. for 1 hour. After cooling, the product was precipitated with hexane and recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[F:33][C:34]1[CH:41]=[CH:40][C:37](CO)=[CH:36][CH:35]=1>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(F)cc2)CC1

Procedure:
Compound 21 was prepared in a similar manner to compound 7, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+1)=430.40
Reaction SMILES: CCCN([C:8]1[C:9]([N+:21]([O-:23])=[O:22])=[CH:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])CCC.FC(F)(F)C1C=CC([Cl:32])=CC=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O>>[F:18][C:17]([F:20])([F:19])[C:11]1[CH:10]=[C:9]([N+:21]([O-:23])=[O:22])[C:8]([Cl:32])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
The preparation of, for example, trifluralin is carried out by nitrating 1-trifluoromethyl-4-chlorobenzene with nitric acid in the presence of sulfuric acid to give 1-trifluoromethyl-3,5-dinitro-4-chlorobenzene, from which 2,6-dinitro-4-trifluoromethyl-N,N-dipropylaniline is obtained by amination with the secondary amine, di-n-propylamine. This synthesis can be represented by the following reaction scheme: ##STR1##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[CH2:21]([O:23]CCO)[CH3:22].[H-].[Na+].[H-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH2:20][O:23][CH2:21][CH3:22])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOCCO
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: [H-]
Agent: [Na+]
Product: CCOCCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 2-ethoxyethanol is added sodium hydride. After the hydride is reacted, the mixture is heated on a steam bath for 12 hours. The solvent is removed and the residue is acidified with dilute acetic acid to give the product of the example.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][C:28]([C:31]([O-:33])=[O:32])=[CH:27][N:26]=5)[CH2:21][CH2:20]4)[N:15]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Na+].Cl>CO>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[N:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[CH:29][N:30]=5)[CH2:23][CH2:24]4)[N:15]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C([O-])c1cnc(N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)nc1
Temperature: 60 °C

Procedure:
Ethyl 4-(2-(4-(4-((6-(1H-tetrazol-1-yl)pyridin-3-yloxy)methyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxylate (0.8 g, 0.00167 mol) (Example 60) was dissolved in MeOH (20 mL). An aqueous solution of NaOH (10 eq., 40 mL) was added and the reaction mixture was heated at 60° C. for three hours. The methanol was removed in vacuo and the remaining reaction mixture was cooled to 0° C. and concentrated HCl was added drop wise until the pH reached 2-3. The aqueous solution was extracted with DCM, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[N:23]=[C:22]([NH2:32])[N:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2ccnc3c2CCN3)c(F)c1
Product: Nc1nc(Nc2ccc(Oc3ccnc4c3CCN4)c(F)c2)cc(-c2ccncc2)n1

Procedure:
Analogously to example 25, the title compound is prepared from 19.7 mg (0.08 mmol) of [4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoro-phenyl]amine (from example XLVI) and 17.4 mg (0.08 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX). Purification by preparative HPLC gives the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 62%).