Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Cl:35])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
184 mg (0.5 mmol) {4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol are suspended in 15 ml toluene. Pyridine (44 μl, 0.55 mmol) and thionyl chloride (40 μl, 0.55 mmol) are added and the mixture is stirred at RT for 16 h. A second portion of the same amounts of pyridine and thionyl chloride are then added and the mixture stirred for 1 additional hour. The solvent is evaporated and the residue suspended in water containing a small amount of sodium bicarbonate (pH ˜8). After filtration, the product was thoroughly washed with water and ether and dried to give crude title compound; m.p.>300° C.; Rf(dichloromethane/ethanol 95:5 plus 1% conc. ammonia)=0.42; HPLC tR=11.33 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[F:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.7 %

Procedure:
368 mg (corresponding to 1.1 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 15 mL of N,N-dimethylformamide, and 453 mg (corresponding to 3.3 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 280 μL (corresponding to 1.6 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1), and further by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 222 mg (corresponding to 0.580 mmol) of 2-[4′-(2″-fluoroethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-7, Step 3).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:20]=[CH:19]2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(-c2ccc3[nH]ccc3c2)c(C#N)c2ccc(OC)cc21
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2ccc3c(ccn3S(C)(=O)=O)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1-ethyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile (70 mg, 0.22 mmol), prepared as described in Example 1Gb, in pyridine (2 mL) is treated with methanesulfonyl chloride (0.034 mL, 0.44 mmol) and stirred overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-80%) to afford 70 mg (81%) of 1-ethyl-1′-methanesulfonyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile as a tan solid.
Reaction SMILES: C([O-])C.[Na+].C(O)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:15]([NH2:17])=[NH:16].C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25]CC)=O)C>O>[CH2:31]([O:30][C:28]([C:22]1[C:23]([OH:25])=[N:16][C:15]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:17][CH:21]=1)=[O:29])[CH3:32]
Reactant: N=C(N)c1ncccn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(-c2ncccn2)nc1O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a fresh prepared solution of sodiumethanolate in ethanol (prepared from 0.44 g (18.92 mmol) Na in 20 ml Ethanol) 1.50 g (9.46 mmol) pyrimidine-2-carboxamidine hydrochloride was added. After 10 min. 1.89 ml (9.46 mmol) diethyl ethoxymethylenemalonate was added at 0° and the resulting suspension was stirred for 12 hrs. After addition of 20 ml H2O, the pH was adjusted to 5 and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was triturated with 5 ml diisopropylether, filtered off and dried to give 1.62 g (70%) 4-hydroxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester as a light yellow powder, MS (EI): 246.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.Br[C:18]1[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=1.O1CCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:18]2[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: FC(F)(F)c1nnc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Sc2nnc(C(F)(F)F)s2)c1
Yield: 94.9 %

Procedure:
8.5 g (0.061 mole) of 3,5-dimethylthiophenol, 6.2 g (0.061 mole) of triethylamine and 14.3 g (0.061 mole) of 2 -bromo-5-trifluoromethyl-1,3,4-thiadiazole in 150 mole of tetrahydrofuran were stirred for 30 minutes under reflux. The salt (by-product) which had precipitated was filtered off and washed thoroughly with tetrahydrofuran. After distilling off the solvent in vacuo, a colorless oil passed over on distillation. 16.8 g (95% of theory) of 2-(3',5'-dimethylphenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of boiling point 107°-108° C/10.2 mm Hg were obtained. 22.8 g (0.201 mole) of hydrogen peroxide (30% strength) in 100 ml of glacial acetic acid were added thereto and the reaction mixture was stirred for 15 hours at 60° C, and poured onto ice water. The precipitate was filtered off and recrystallized from ethanol. 12.7 g (54% of theory) of 2-(3',5'-dimethylphenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 110° C were obtained.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18]CC(O)=O)(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(NC2CCCCC2)CCCCC1.C([O:45][C:46](=[O:59])[CH2:47][CH2:48]NS(C1SC(N)=NC=1)(=O)=O)C>>[CH:1]1([N:7]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:48][CH2:47][C:46]([OH:59])=[O:45])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Agent: C1CCC(NC2CCCCC2)CC1
Product: O=C(O)CCNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:47])[CH2:35][CH2:36][O:37][C:38](=[O:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:47])[CH2:35][CH2:36][O:37][C:38](=[O:46])[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)NC(C)CCOC(=O)Cc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)Cc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6-yl)benzoic acid and rac-phenyl-acetic acid 3-isopropylamino-butyl ester as described for example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13]1>O1CCOCC1.C(N(C(C)C)CC)(C)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: NCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCCC(CNc2cc(I)cc(Cl)n2)C1
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dichloro-4-iodopyridine (1.5 g, 5.5 mmol) and benzyl 3-(aminomethyl)piperidine-1-carboxylate (2.7 g, 11 mmol) in dioxane (10 mL) in a microwave tube was added ten drops of diisopropylethyl amine and sealed. The tube was heated at 150° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography eluting with EtOAc/hexane=1:3 to 1:2 to give the title compound. Yield: 1.0 g (38%). MS (DCI/NH3) m/z 486 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][OH:9].N1C=CN=C1.C(N(CC)CC)C.[S:22](Cl)(Cl)=[O:23]>ClCCl>[S@@:22]1(=[O:23])[N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][O:9]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@@H]1CCCCN1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[S@@]1OCC2CCCCN21
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-1-Piperidin-2-yl-methanol hydrochloride (3.43 g, 22.63 mmol), imidazole (6.1 g, 88.72 mmol) and triethylamine (7.33 g, 72.42 mmol) in anhydrous dichloromethane (120 mL) at 0-5° C. was added a solution of thionyl chloride (3.2 g, 25.86 mmol) in anhydrous dichloromethane (10 mL) over a period of 45 min. The reaction mixture was stirred at 0-5° C. for 45 min, partitioned with H2O and the aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layer was washed with H2O dried over Na2SO4, and concentrated in vacuo to give an orange liquid. Flash column chromatography purification (silica gel, 2% EtOAc in dichloromethane) afforded the title product as a clear, colorless liquid (1.31 g, 36%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].I[CH3:23]>CN(C=O)C>[CH3:23][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc([N+](=O)[O-])c1)S(=O)(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 114.9 %

Procedure:
A 60% suspension of NaH (0.47 g, 11.75 mmol) was added to a solution of N-(3-nitrophenyl)benzenesulfonamide (2.56 g, 9.20 mmol) and iodomethane (2.61 g, 18.4 mmol) in DMF (50 mL) at room temperature. The yellow solution changed to a bright brown color. After 1.5 h at room temperature, the reaction mixture was quenched with careful addition of water (100 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with saturated NH4Cl, brine, dried (MgSO4) and concentrated to give N-methyl-N-(3-nitrophenyl)benzenesulfonamide (3.09 g). LCMS: (M+MeCN+Na)+=356.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, ddd, J=8.03, 2.26, 1.25 Hz), 7.94 (1H, t, J=2.13 Hz), 7.70-7.76 (1H, m), 7.66 (1H, t, J=8.03 Hz), 7.57-7.62 (3H, m), 7.52-7.56 (2H, m), 3.21 (3H, s).
Reaction SMILES: [C:1]([C:5]([CH2:7]Br)=[O:6])([F:4])([F:3])[F:2].[C:9]([C:13](OCC)=[O:14])([F:12])([F:11])[F:10].O1CCCC1>[Zn].CN(C)C=O>[C:1]([C:5]([CH2:7][C:13]([C:9]([F:12])([F:11])[F:10])=[O:14])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F

Procedure:
CF3COCH2Br (1.91 gr, 10 mmol), CF3CO2C2H5 (1.42 gr, 10 mmol), and zinc powder (1.3 gr) were put into a flask (100 ml) together with a mixed solvent comprising tetrahydrofuran (20 ml) and dimethylformamide (10 ml), and they were subjected to the reaction for a period of one hour while being irradiated with ultrasonic waves by means of an ultrasonic cleaner (35W, 32 kHz). After the reaction, impurities contained in the mixed liquid were filtered, then water (500 ml) was added to the filtered liquid, whereby an oil layer generated was extracted by means of diethylether. After drying the extracted liquid with magnesium sulfate, the solvent was removed. The product (CF3COCH2COCF3) (bp: 70° to 72° C.) was obtained through distillation with a yield by 69%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(F)(F)F)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].Cl.Cl.[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][NH:26][CH2:27]2.C(N(C(C)C)C(C)C)C>CC#N>[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:16]([F:17])([F:18])[F:19])[CH2:27]2
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CN1C2CCCC1CNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1C2CCCC1CN(Cc1ccc(N)cc1C(F)(F)F)C2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of 296 mg (0.85 mMol) N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (WO 2005/051366; Step 14.2) in 5 ml of CH3CN is added at 5° C. within 30 min to a solution of 213 mg (1.00 mMol) 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane dihydrochloride (synthesized according to Barnes, Roderick A. et al.: J. Am. Chem. Soc. 1953, 75, 975) and 0.7 ml (4 mMol) ethyldiisopropylamine in 10 ml CH3CN. After 1.5 h at 5-10° C., the solvent is evaporated off under reduced pressure. The residue is dissolved in EtOAc and washed with NaHCO3. The aq. phase is re-extracted with EtOAc and the combined organics are washed with water, brine and dried over Na2SO4. The solvent is evaporated off under reduced pressure and the residue is dissolved in a mixture of 10 ml MeOH and 2 ml of a 2 M NaOH solution and stirred at 50° C. for 3 h. The MeOH is evaporated off under reduced pressure, the mixture is diluted with water and extracted 3 times with EtOAc. The combined organics are washed with water and brine and dried (Na2SO4). The solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a crystalline solid.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[I-:29].[Na+]>CC(C)=O>[I:29][CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCI
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane (1.05 g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8 g, 12 mmole) and the mixture was stirred for 36 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed with 10% sodium thiosulfate solution and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 1.04 g=81%
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M89) (0.35 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (114 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209°-210 ° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
According to the recently released paper in line with the direct manufacture of amide compound formed by the NASH reaction, it is reported that benzamide is reacted with nitrobenzene in the presence of TMA(OH) to isolate N-(4-nitrophenyl)benzamide, a relatively stable intermediate, and then methanol and ammonia are added to the mixture and reacted under a pressure reactor to prepare 4-nitroaniline as a final product, while regenerating benzamide (J. Org. Chem., 1993, 58(24), 6883-8; WO No. 93/24447).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:22].C[OH:24].[OH-].[Na+]>O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=2[F:10])=[C:14]([CH2:13][C:12]([OH:24])=[O:22])[CH:15]=1)[CH3:21]
Reactant: CCc1ccc2c(c1)CC(=O)N2c1c(F)c(F)cc(F)c1F
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol, is slurried in water containing a little methanol (10% v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture is stirred at 80-85° for 2-4 hours, then cooled to ambient temperature. The reaction solution is partially concentrated under reduced pressure (25-30 mm). After removal of 50 ml of the solvent, the mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml). The cooled mixture is acidified to pH 6.5-7.0 with aqueous HCl (12.1 N; 19.5 ml), keeping the temperature at 0-5°. The aqueous layer is discarded and the organic layer is washed with water (250 ml). The organic layer is concentrated under reduced pressure (20-100 mm) while exchanging the solvent to toluene. After the more volatile components have been removed, the batch volume is adjusted to 400-450 ml. This mixture is warmed to 70°, clarified, concentrated to one-half volume, and cooled to 0°. After stirring at this temperature for 2 hours, the product is collected and is washed with toluene/heptane (10:90; 100 ml). The resulting solid is dried under reduced pressure at 50-60° for 4-8 hours to give 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid of Example 3.
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14](=[NH:2])[NH2:15])[CH:11]=[CH:10][N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1ccnc(Cl)c1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a suspension of ammonium chloride (10.7 g, 200 mmol) in 250 mL of dry toluene. was added a 2 M solution of Al(CH3)3 (100 mL, 200 mmol) in toluene dropwise under nitrogen at 0° C. The resulting reaction mixture was stirred at rt until no more evolution of gas was observed and then 2-chloropyridine-4-carbonitrile (13.86 g, 100 mmol) was added. The mixture was stirred at 90° C. overnight. It was then cooled down to 0° C. and 300 mL of methanol were added with subsequent stirring for 1 h at rt. After filtration, the solid was washed with methanol for several times, the solution was evaporated to dryness under vacuum. The residue was washed with methanol to give 2-chloropyridine-4-carboximidamide. (18.3 g, 95%). 1HNMR δ (400 MHz, d6-DMSO): 8.70 (dd, J=4.8, 0.4 Hz, 1H), 8.00 (dd, 0.4 Hz, 1H), 7.84 (dd, J=5.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.53 (t, J=8.1 Hz, 1H); MS (ESI) m/z (M+H)+ 156.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].ClCC#N.[CH3:14][C:15]([NH:17][CH2:18][CH2:19]C1C2C=C(OC)C=CC=2NC=1)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH2:19][CH2:18][NH:17][C:15](=[O:16])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: COc1cccc(N)c1
Agent: N#CCCl
Product: COc1cccc(NCCNC(C)=O)c1

Procedure:
N-cyanoalkylation of 3-methoxyaniline (3l) using chloroacetonitrile, followed by hydrogenation and N-acetylation of the intermediate nitrile 4l [Yield (4l): 58%; 1H-NMR (CDCl3): δ 3.80 (s, 3H), 4.05 (s, 2H), 6.25-6.48 (m, 2H), 7.18 (t, 1H)], according to the procedure previously described for the preparation of 5a, provided the title compound 5l; oil. 1H-NMR (CDCl3): δ 2.00 (s, 3H), 3.27 (m, 2H), 3.53 (m, 2H9, 3.78 (s, 3H), 5.84 (brs, 1H), 6.17-6.32 (m, 3H), 7.09 (t, 1H).