Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14](=[N:20]O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:10]1[O:11][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2cccc(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
2-(3-methoxyphenyl)acetyl chloride (1.18 mL; 7.57 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.146 g (15%) of ethyl 5-(3-methoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].OS(O)(=O)=O.[BrH:16].N(C(C)(C)C#N)=NC(C)(C)C#N.C(OO)(=O)C>ClC1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:16])([O-:3])=[O:2]
Reactant: Br
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)OO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccccc1CBr

Procedure:
13.7 g of o-nitrotoluene, 38.8 g of chlorobenzene, 0.24 g of conc. H2SO4 and 19.8 g of 47% strength aqueous hydrobromic acid were mixed at 62° C. in a 250 ml stirred apparatus, 2.32 g of 2,2'-azobis(2-methylpropionitrile) were added and, while stirring vigorously, 11.6 g of peroxyacetic acid (32% strength) were added dropwise in small portions over the course of 25.5 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:25]([NH2:27])=[O:26])=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)[N:17]=3)[C:9]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][NH:36][CH3:37]>[I-].[K+].CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([N:10]3[C:9]4[CH:28]=[C:5]([O:4][CH2:3][CH2:2][N:36]([CH3:37])[CH3:35])[CH:6]=[CH:7][C:8]=4[N:12]=[CH:11]3)[S:14][C:15]=2[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2c1
Reaction time: 6 h
Yield: 76.9 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.150 mL (0.3 mmole) of dimethylamine was stirred at 100 degrees for 6 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.034 g of 4-(3-chloro-phenyl)-2-[6-(2-dimethylamino-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.29) as a white powder. MH+/Z=442
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[C:2]1=[O:11].N1C2=NC=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>>[CH2:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[C:2]1=[O:11])[CH2:14][CH2:15][CH2:20][CH3:19]
Reactant: O=C1Nc2ccncc2C1=O
Reactant: c1cnc2[nH]ccc2c1
Product: CCCCCN1C(=O)C(=O)c2cnccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using 1H-pyrrolo[3,2-c]pyridine-2,3-dione (see Rivalle, C., et al, J. Heterocyclic Chem. (1997), 34:441) to replace 1H-pyrrolo[2,3-b]pyridine, the title compound was obtained (36%): 1H NMR (300 MHz, CDCl3) δ 8.71-8.64 (m, 2H), 6.90 (d, 1H), 3.71 (t, 2H), 1.74-1.62 (m, 2H), 1.41-1.27 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z 219.3 (M+1).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]([N:10]=[C:11]=[S:12])([CH3:9])[CH2:7][CH3:8]>C(O)C>[C:2]([NH:3][C:11]([NH:10][C:6]([CH3:9])([CH3:5])[CH2:7][CH3:8])=[S:12])#[N:1]
Reactant: N#CN
Reactant: CCC(C)(C)N=C=S
Agent: [Na]
Solvent: CCO
Product: CCC(C)(C)NC(=S)NC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a suspension of monosodium cyanamide (0.64 g, 10 mmol) in absolute ethanol (30 mL), 1,1-dimethylpropylisothiocyanate (1.29 g, 10 mmol) was added slowly at room temperature. Exothermic reaction occurred during addition and near the end of the addition, the initially heterogeneous mixture became a homogeneous solution. It was allowed to stir at room temperature for 2 hours and then heated at 75° C. for 1 hour. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate solution was concentrated to yield the title A compound (1.6 g) as a colorless solid.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30])=O)C1C=CC=CC=1.Br>C(OCC)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Agent: Br
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0 g, 7.4 mmol) and hydrobromic acid (45% in acetic acid, 6.2 ml) was stirred for 1 h at room temperature under an atmosphere of nitrogen. The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and it was stirred at 0° C. for 45 min. The white precipitate was collected by filtration, washed with cold diethyl ether (4×30 ml) and then dissolved in a mixture of water (30 ml) and aqueous sodium hydroxide (2M, 15 ml). The basic aqueous phase was extracted with ethyl acetate (3×70 ml) and the combined organic layers were washed with brine (30 ml), dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 94:6, dichloromethane: methanol as the eluant, to afford the title compound (1.6 g, 80%) as pale pink solid. mp 133-136° C. 1H NMR (360 MHz, CDCl3)δ1.02-1.40 (4H, m), 1.47-1.56 (1H, m), 1.61-1.74 (3H, m), 1.84-1.91 (1H, m), 1.96-2.06 (1H, m), 2.17 (2H, br s), 2.70-2.80 (1H, m), 3.39 (3H, s), 4.29 (1H, s), 7.20-7.27 (2H, m), 7.44-7.54 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][CH:3]=1.S(OCC)(O[CH2:25][CH3:26])(=O)=O.CC(C)([O-])C.[K+]>C(O)C>[CH2:25]([O:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][CH:3]=1)[CH3:26]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)CSc1cccc(O)c1CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1cccc(OCC)c1CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-hydroxy-2-(ethoxycarbonylmethylthio)-phenylacetate (20.0 g) in anhydrous ethanol (200 mL) is added diethyl sulfate (10.3 g). To this is added in portions solid potassium t-butoxide (7.52 g), keeping the temperature below 30° with a cold-water bath. After stirring overnight at room temperature, the solvent is removed in vacuo and the residue is mixed with ether and water. The layers are separated and the organic layer is washed with ice-cold sodium hydroxide (0.5N, 40 mL) to remove starting material. The ether layer is washed with water to neutrality, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give (as shown by NMR) ethyl 6-ethoxy-2-(ethoxycarbonylmethylthio)-phenylacetate as an oil.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2)C1CC1
Yield: 103.8 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.55 mmol) and and cyclopropane carboxylic acid (64 mg, 0.62 mmol) according to the procedure described for example 93. Obtained the title compound as a brown solid (195 mg, 99%), MS (ISP) m/e=342.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:13])([CH3:11])[CH3:12])=[CH:9][C:2]=1[F:1]
Reactant: CC(C)(O)c1ccc(C#N)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CN)c(F)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 1.95 g (0.011 mol) 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzonitrile in 30 mL anhydrous THF at 0° C. was added dropwise 34 mL (0.034 mol) 1.0M LiAlH4. The mixture was warmed to room temperature then heated to reflux for 30 minutes. The mixture was then cooled to 0° C. and quenched with 20 mL MeOH added dropwise. Next, it was diluted with 700 mL CHCl3 and washed with 100 mL water. The resulting suspension was filtered through Celite and the organic layer dried over MgSO4 and concentrated to give 1.6 g of an amber oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:8]([O:9][CH3:10])[C@@H:7]([O:11][CH3:12])[C@H:6]([CH3:13])[O:5][C@H:4]1[O:14][NH2:15].CCN(C(C)C)C(C)C.Cl[CH:26]([C:31]([O-])=[O:32])[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C:31]([NH:15][O:14][C@H:4]1[C@H:3]([O:2][CH3:1])[C@H:8]([O:9][CH3:10])[C@@H:7]([O:11][CH3:12])[C@H:6]([CH3:13])[O:5]1)=[O:32]
Reactant: COC(=O)C(Cl)C(=O)[O-]
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON)[C@@H]1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(=O)NO[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (P-4; 157 mg, 0.71 mmol) in dichloromethane (CH2Cl2; 8 mL) was added DIEA (230 μL, 1.3 mmol) followed by a solution of methyl chloromalonate (137 mg, 1.0 mmol) dissolved in CH2Cl2 (2 mL). This mixture was allowed to stir at room temperature for 4 h. The mixture was then diluted with CH2Cl2 and washed with 1 N HCl. The aqueous fraction was extracted with CH2Cl2. The organic fractions were combined, dried with anhydrous Na2SO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 75% EtOAc in Hexane). The title product (132 mg, 58%) was isolated as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 10.00-9.38 (m, 1H), 5.06 (d, J=55.9 Hz, 1H), 4.02-2.92 (m, 18H), 1.39 (t, J=20.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 189.13, 101.59, 81.56, 77.24, 75.39, 69.66, 59.26, 57.89, 52.86, 39.75, 26.47, 17.85; ESIMS m/z 320 (M−H).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][NH:18][CH2:19][CH3:20])[CH3:7].[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH2:32][NH:33][CH2:34][CH3:35])[CH3:22].[N:36]#[C:37][NH2:38]>CC(C)=O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][N:18]([CH2:19][CH3:20])[C:37]([NH2:38])=[NH:36])[CH3:7].[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH2:32][N:33]([CH2:34][CH3:35])[C:37]([NH2:38])=[NH:36])[CH3:22]
Reactant: CCNCC1Cc2ccccc2N1CC
Reactant: N#CN
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCN(CC1Cc2ccccc2N1CC)C(=N)N
Temperature: 120 °C

Procedure:
A mixture of 25.3 g of 1-ethyl-2-ethylaminomethylindoline hemisulphate and 25 g of cyanamide is heated at 120° C. for 20 minutes. After cooling, acetone is added and the mixture is filtered. The crystals are taken up in icecold sodium bicarbonate solution and the aqueous phase is extracted with chloroform. The oily base obtained after drying and evaporating the chloroform phase is dissolved in a little methanol and the pH of the solution is adjusted to 6 with sulphuric acid. The solution is evaporated. The residue is triturated with acetone and 1-ethyl-2-(1-ethyl-guanidinomethyl)-indoline hemisulphate is obtained, m.p. 230° C.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>C1COCC1>[CH3:22][O:21][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:3]/[C:4]#[N:5])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(/C=C/C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.8 %

Procedure:
Diethylcyanomethyl phosphonate (28.6 mL, 176 mmol) was added to a suspension of NaH (7.0 g, 176 mmol, washed with hexanes to remove oil) in 450 mL of THF at RT and the resulting mixture was stirred at RT for 30 min. A solution of m-anisaldehyde (20.0 g, 140 mmol) in 50 mL of THF was added and the resulting mixture was stirred at RT overnight, resulting in the formation of a thick brown oil at the bottom of the mixture. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and methylene chloride. The organic phase was separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were then dried over MgSO4, filtered, and concentrated in vacuo to provide 27.6 g of a brown oil (99% crude yield) which was carried on without further purification. 1H NMR (CDCl3) δ 7.30-7.40 (m, 2H), 6.92-7.05 (m, 3H), 5.86 (d, J=24 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][NH:18][CH3:19]>CS(C)=O>[CH3:11][N:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:13][CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][NH:18][CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCN(C)CCNC
Solvent: CS(C)=O
Product: CNCCN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In 7 ml of dimethyl sulfoxide were dissolved 1.41 g of p-fluoronitrobenzene and 14 g of N,N',N"-trimethyldiethylenetriamine, and the mixture was then stirred at 120° C. for 3 hours.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24]Cl)=[N:22][C:18]=2[CH:17]=1.[OH-].[Na+].O>CO>[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24][N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[N:22][C:18]=2[CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
4 cc (0.022 mole) of 1-benzylpiperazine is added to a solution of 7.2 g (0.02 mole) of 5-bromo-2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole hydrochloride and 40 cc (0.04 mole) of 1N NaOH in 100 cc of hot methanol, and the obtained reaction mixture is heated under an argon atmosphere at reflux temperature for several hours. When the reaction, which is followed by thin layer chromatography, is completed, the solvent is boiled off and the obtained residue is taken up with a small amount of water, filtered and dried. Yield 8.87 g. M.p. 155°-157° C.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1>C(O)C.[Pd]>[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1
Reactant: Cc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Oc2ccc(N)cn2)c1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2,3-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 37, 640 mg) was dissolved in ethanol (10 mL) to give a pale yellow solution. Hydrazine hydrate (0.463 mL, 4.72 mmol) and palladium on carbon (25.10 mg, 0.236 mmol) were added. The reaction mixture was stirred at 90° C. After 1 hour, the reaction was complete. The reaction mixture was filtered and the organic phase was evaporated in vacuo affording the title compound as a pale yellow oil (573 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCc1cc(-c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)s2)c(C)[nH]c1=O
Yield: 75 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and 4-trifluoromethyl-benzylamine to afford the title compound (75% yield). LC/MS: RT 3.15 min; m/e 421 (M+H).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:5]=1[C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7].O>CN(C=O)C>[F:18][C:14]1[C:15]([F:17])=[CH:16][C:4]2[O:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6](=[O:7])[C:5]=2[CH:13]=1
Reactant: CN(CCO)C(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCOc2cc(F)c(F)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium hydride (52 mg, 1.29 mmol) was added portionwise to a solution of 2,4,5-trifluoro-N-(2-hydroxyethyl)-N-methylbenzamide (300 mg, 1.29 mmol) in DMF (13 mL) and reaction was allowed to stir at RT for 2 hours. Water (30 mL) was added and the white solution was extracted with ethyl acetate (3×30 mL) and dried (MgSO4), filtered and evaporated to give the desired compound as a colourless oil (275 mg). The compound was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[H-].[Na+].[C:12]([C:16]1[N:20]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]2[CH:28]=[CH:29][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:31][C:18]=2[N:17]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([C:16]1[N:20]([CH2:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]2[CH:28]=[CH:29][C:30]([S:32]([N:1]3[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]3)(=[O:33])=[O:34])=[CH:31][C:18]=2[N:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: COC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 26.8 %

Procedure:
Following the same procedure in Example 29, using methyl 1H-pyrrole-3-carboxylate (0.16 g, 1.3 mmol) (see following step B for preparation), sodium hydride (0.18 g, 60%, 4.5 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.48 g, 1.3 mmol) in THF (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.16 g (27%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.46-1.54 (m, 4 H), 1.56 (s, 9 H), 2.15-2.32 (m, 1 H), 3.25-3.37 (m, 2 H), 3.79 (s, 3 H), 3.93-4.03 (m, 2 H), 4.22 (d, J=7.42 Hz, 2 H), 6.62 (dd, J=3.32, 1.56 Hz, 1 H), 7.15 (dd, J=3.32, 2.34 Hz, 1 H), 7.42 (d, J=8.79 Hz, 1 H), 7.74-7.81 (m, 2 H), 8.33 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=459.8; Anal. Calcd for C23H29N3O5S+0.10 EtOAc+0.30H2O (474.98): C, 59.43; H, 6.45; N, 8.85. Found: C, 59.34; H, 6.60; N, 8.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2C2C(F)=CC=C(F)C=2F)=[CH:4][CH:3]=1.FC1C=CC(N2C(C=O)=CN=[C:33]2[C:39](C)([CH3:50])[CH2:40][C:41]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=2[F:49])=CC=1.CC(=CC)C.Cl([O-])=O.[Na+].OP([O-])(O)=O.[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[C:39]([CH3:50])([CH3:33])[CH2:40][C:41]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=2[F:49])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CC(C)(Cc1c(F)ccc(F)c1F)c1ncc(C=O)n1-c1ccc(F)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(Cc1c(F)ccc(F)c1F)c1ncc(C(=O)O)n1-c1ccc(F)cc1

Procedure:
1-(4-fluorophenyl)-2-(2-methyl-1-(2,3,6-trifluorophenyl)propan-2-yl)-1H-imidazole-5-carboxylic acid (37) was prepared in a similar manner as that described for the synthesis of compound 27 using 1-(4-fluorophenyl)-2-(2-methyl-1-(2,3,6-trifluorophenyl)propan-2-yl)-1H-imidazole-5-carbaldehyde (36) (59.2 mg, 0.16 mmol), 2-methyl-2-butene (2M in THF, 0.53 mL, 1.05 mmol), sodium chlorite (80%, 59.6 mg, 1.6 mmol), sodium phosphate mono-basic (14.7 mg, 0.12 mmol), tert-butanol (1.6 mL), and water (0.8 mL).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:18])[CH:12]=1)(=O)C>O.CO>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:18]
Reactant: CC(=O)Oc1cccc(C(=O)NCc2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(NCc1ccccn1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.4 %

Procedure:
11.7 g (0.85 mol) of potassium carbonate in solution in 86 ml of water are added to 11.5 g (0.43 mol) of 3-{[(pyridin-2-ylmethyl)amino]carbonyl}phenyl acetate (stage A) in solution in 340 ml of methanol. The mixture is stirred at ambient temperature for 3 hours and then concentrated to dryness. The residue is taken up in ethyl acetate and the product is neutralized with 85 ml of a molar solution of hydrochloric acid. The two phases are separated. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulphate. The solid obtained after concentration under vacuum is washed with ethyl ether and filtered. After drying, 6.3 g (65%) of a white solid are obtained.