Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O[C:7]([C:10]1[CH:11]=[C:12]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:13]=[C:14]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:15]=1)([CH3:9])[CH3:8]>FC(F)(F)C(O)=O>[CH3:9][C:7]([C:10]1[CH:15]=[C:14]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:13]=[C:12]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])[CH:11]=1)([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:8]
Reactant: c1nc[nH]n1
Reactant: CC(C)(O)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1cc(C(C)(C)C#N)cc(C(C)(C)n2cncn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1,2,4-triazole (0.69 g) in trifluoroacetic acid (3.12 ml) was added to 2,2'-[5-(1-hydroxy-1-methylethyl)-1,3-phenylene]-di(2-methylpropiononitrile), (0.27 g), and the resulting solution was stirred at room temperature for 18 hr and then evaporated to dryness. The residue was treated with aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography using methanol (1% by volume) in dichloromethane as eluant, to give 2,2'-(5-[1-methyl-1-(1H-1,2,4-triazol-1-yl)ethyl]-1,3-phenylene)di(2-methylpropiononitrile), which was characterised as the hydrochloride salt, mp 185°-188°.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C.IN1C(=O)CCC1=O>[I:1][C:13]1[CH:12]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Yield: 242.7 %

Procedure:
N-iodosuccinimide (69.5 g, 0.309 moles) was suspended in acetic acid (257 mL) and cooled to 0° C. 4-Trifluoromethylphenol (50.0 g, 0.310 moles) was added followed by sulphuric acid (5.44 mL) dropwise over 5 minutes. The orange-brown suspension was stirred whist warming slowly to room temperature over 18 hours. A further portion of N-iodosuccinimide (2.5 g, 0.011 moles) was added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by adding water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organics were washed with a saturated aqueous solution of sodium metabisulphite (2×50 mL) and then with saturated aqueous sodium chloride solution (50 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude title product as a light yellow oil. This batch was combined with the products from two further identical reactions and purified by distillation in vacuo. The product was collected boiling at approximately 45° C. at 2mBar to give the title compound as a pink-orange semi-solid (216 g).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1S(=O)(=O)CCC1.[C:22]([C:25]1[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)([OH:24])=O.[OH-].[Na+]>C(O)C>[O:24]=[C:22]1[C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][C:30]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S1(=O)CCCC1
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h

Procedure:
To 49 ml. of absolute ethanol is added with vigorous stirring, 81 g. of phosphorus pentoxide. After addition, the mixture is allowed to stir at 95°-100° C. for 1 hour, 400 ml. of tetramethylene sulfone are added, and the temperature is adjusted to 86°-90° C. Then, 38.5 g. of 4-(2-carboxybenzyloxy)phenylacetic acid are added, the mixture is stirred for 4 hours and poured onto ice water. The aqueous mixture is made basic with sodium hydroxide and extracted with toluene. Cooling of the aqueous layer followed by acidification with concentrated hydrochloric acid gives light brown crystals. Recrystallization from acetic acid-water or from dimethoxyethane provides colorless crystals, m.p. 126°-128° C. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:11]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1OC(c2ccc(Cl)cc2)c2ccccc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A five-liter, 3-neck flask fitted with a reflux condensor and drying tube, an air-driven stirring blade, and thermometer and temperature controller was charged with 2-(4'-chlorobenzoyl)benzoic acid (130.3 grams; 0.5 mol), zinc dust (490.3 g; 7.5 gram-atom), glacial acetic acid (2500 milliliters (ml)), and water (500 ml). The resulting mixture was heated, with stirring, under reflux temperatures (about 105° C.) for about 2 hours. The acetic acid solution was then decanted from the zinc and poured into 4 liters of cold water and the resulting white, fluffy needles were collected by filtration and dried at 60° C. at 10 mm of pressure for 14 hours. As a result of such operations, the desired 3-(4'-chlorophenyl)phthalide compound of Formula I was obtained in a yield of about 88%. Recrystallization from ethanol gave a purified product having an m.p. of 123.5°-124° C. as compared to a literature reference (Rec. Trav. Chim., 82, 801-805 (1963)) of 122°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1ccc(I)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(I)cc1F
Yield: 66.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-fluoro-4-iodobenzamide (0.500 g, 1.8 mmol), oxalyl chloride (0.285 g, 2.2 mmol) and EDC (10 mL) to afford 0.350 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[OH:8])=[O:10])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Product: Cc1ccc(O)c(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c1
Yield: 32.1 %

Procedure:
2-Hydroxy-5-methylacetophenone (200 mg, 1.33 mol) and 4-benzyloxy-3-nitrobenzaldehyde (350 mg, 1.36 mmol) were reacted according to the same procedure as Preparation 1 to give 170 mg (Yield 29%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 15m (1.26 g, 1.59 mmol) in anhydrous methanol (30 mL) was added sodium borohydride (120 mg, 23.18 mmol) in portions at 0° C. The mixture was warmed up to room temperature and stirred for 30 min. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15n as yellow oil (570 mg, 46.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3OD) δ(ppm): 7.58 (dd, 1H), 7.54 (d, 1H), 7.39 (d, 1H), 7.32 (m, 5H), 7.25 (m, 8H), 7.16 (d, 2H), 7.09 (m, 4H), 4.94 (d, 1H), 4.90 (d, 1H), 4.80 (s, 1H), 4.76 (d, 1H), 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (dd, 2H), 4.07 (s, 3H), 4.00-3.93 (m, 2H), 3.77 (d, 1H), 3.37 (dd, 1H), 3.18 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:32]=[C:31]([C:33]([CH3:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])[O:30][N:29]=4)=[O:26])=[CH:20][CH:19]=3)=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[C:41](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:42]>>[CH2:41]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:32]=[C:31]([C:33]([CH3:39])([CH3:38])[C:34]([F:37])([F:35])[F:36])[O:30][N:29]=4)=[O:26])=[CH:22][CH:23]=3)=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1)[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Reactant: CC(C)(c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1)C(F)(F)F
Agent: Cl
Product: CCN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)cc3)nc2)CC1
Yield: 68 %

Procedure:
5-(1-Ethylpiperidin-4-yloxy)-N-(4-(3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)picolinamide (79 mg, 68%) was prepared using a procedure analogous to that described in Example 2, substituting 5-(piperidin-4-yloxy)-N-(4-(3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate in absolute ethanol (500 mL) and potassium carbonate (18 g, 0.13 mol) was stirred for 3 h at 60° C. The mixture was diluted with 500 mL of dichloromethane and the suspension was filtered. The precipitate was washed with 200 mL of dichloromethane. The combined solutions was washed with 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The crude product introduced into a silica gel column and eluted with hexane/ethyl acetate mixture (2:1) to give 20 g (91 mmol, 95%) of desired compound as a yellow solid. 1HNMR (DMSO d-6): 1.30 (t, 3H), 2.45 (s, 3H), 4.30 (qt, 2H), 6.65 (s, 1H), 7.28 (2, 1H) 7.53 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1([C:17]2[S:21][C:20]([NH2:22])=[N:19][N:18]=2)[CH2:16][CH2:15]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:22][C:20]2[S:21][C:17]([C:14]3([CH3:13])[CH2:16][CH2:15]3)=[N:18][N:19]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CC1(c2nnc(N)s2)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1(c2nnc(NC(=O)Cc3ccc(Br)cc3F)s2)CC1
Reaction time: 14 h
Yield: 47.2 %

Procedure:
Combine (4-bromo-2-fluoro-phenyl)-acetic acid (3.81 g, 16.35 mmol) and 5-(1-Methyl-cyclopropyl)-[1,3,4]thiadiazol-2-ylamine (2.54 g, 16.35 mmol) in THF (45 mL). Under N2, add 4-methyl-morpholine (2.16 mL, 19.62 mmol), then 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium; chloride (5.43 g, 19.62 mmol). Stir the reaction mixture for 14 hours under N2. Extract with ethyl acetate versus water. Wash with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate. Triturate the resulting solid from ethyl acetate/hexanes, filter, and dry to give fluffy white solid as the title compound (2.86 g, 47%). MS (ES), mm/z 370, 372 (M+1).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][N:28]=2)=[O:26])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][O:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[N:28]([C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[CH:49]=3)[N:29]=[C:30]3[C:35]=2[CH:34]=[CH:33][CH:32]=[CH:31]3)=[O:26])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C(=O)c2n[nH]c3ccccc23)c1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(-n2nc3ccccc3c2C(=O)c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To solution of (3-{[tert-butyl(diphenyl)silyl]oxy}phenyl)(1H-indazol-3-yl)methanone (0.10 g, 0.21 mmol)) in dry CH2Cl2 (4 mL) in a flame-dried flask was added dry pyridine (0.034 mL), anhydrous copper (II) acetate (0.057 g, 0.32 mmol), 3-methoxyphenylboronic acid (0.064 g, 0.42 mmol) and powdered 4 Angstrom molecular sieves (0.25 g). Stir at room temperature for seven days.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(F)cc4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,4-difluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 555.2 ([M+H]+)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](Br)[C:10]([O:13][CH:14](F)F)=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[NH:18]1[CH:22]=[CH:21][C:20](B(O)O)=[N:19]1>>[CH3:14][O:13][C:10]1[C:9]([C:21]2[CH:22]=[N:18][NH:19][CH:20]=2)=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][N:11]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Product: COc1ncc(Cn2cncn2)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared in a manner analogous to Example 4, from Intermediate 13 and the appropriate pyrazole boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.07 (s, 1H), 8.01 (q, J=2.3 Hz, 2H), 7.99 (s, 1H), 5.37 (s, 1H), 3.94 (s, 3H), 2.52 (s, 1H). [M+H]=257.26.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[NH:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9])([O-])=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[NH:18][C:17]3[CH:16]=[CH:15][C:6]([NH:7][C:8]([C:10]4[S:11][CH:12]=[CH:13][CH:14]=4)=[O:9])=[CH:5][C:4]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cccs1
Product: COc1ccc(-c2nc3cc(NC(=O)c4cccs4)ccc3[nH]2)cc1

Procedure:
Compound 210 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(thien-2-oyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C19H15N3O2S: 350.09; found: 349.89.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[ClH:10].[Cl:11][CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[ClH:11].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1.[ClH:10]
Reactant: COc1ccc(S)cc1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(SCCN)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 4-methoxybenzenethiol (25 g), 2-chloroethylamine HCl (1.1 eq.) and Cs2CO3 (2.4 eq.) in DMF (200 mL) was stirred at 60° C. for 2 days. The solvents were removed by evaporation under reduced pressure and the crude product was dissolved in 300 mL of EtOAc. The organic phase was washed with H2O (2×50 mL) and concentrated under reduced pressure. The residue was dissolved in 200 mL 1N HCl and washed with EtOAc (2×50 ml). Evaporation of the aqueous phase gave the desired product as HCl salt and white solid. Yield: 34.8 g, 91%. (The free amine can be obtained by treatment of the salt with 1N NaOH).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.O.[OH-].[Na+]>CO>[C:15]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCOc1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCOc1cccc(-c2ccccc2)c1
Reaction time: 3.5 h
Yield: 89.5 %

Procedure:
To a solution in methanol (7.5 mL) of 5-(3-phenylphenoxy)pentanoic acid methyl ester (1.42 g, 5.0 mmol), prepared as in step 1, was added water (3.75 mL) and aqueous 4N sodium hydroxide (3.75 mL). The reaction mixture was stirred for 3.5 hours and then was concentrated in vacuo. The residue was partitioned between water and ethyl ether. The aqueous phase was taken to pH 2 with concentrated HCl and extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. Trituration of the solid with 1:1 ethyl ether-hexanes gave 5-(3-phenylphenoxy)pentanoic acid (1.21 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([N:19]([CH3:26])[S@@](C(C)(C)C)=O)[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[ClH:30]>CO.O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH:19][CH3:26])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N(C)[S@](=O)C(C)(C)C)nc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)OC)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-2,2-dimethyl-4-(2-{(R)-1-[methyl-((R)-2-methyl-propane-2-sulfinyl)-amino]-ethyl}-quinolin-7-yl)-but-3-enoic acid methyl ester (77 mg, 0.19 mmol) in methanol (10 mL) was treated with hydrochloric acid in 1,4-dioxane (4 M, 5 mL). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residual solvent was removed by azeotroping with toluene (3×10 mL) to give crude (E)-2,2-dimethyl-4-[2-((R)-1-methylamino-ethyl)-quinolin-7-yl]-but-3-enoic acid methyl ester hydrochloride.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:18])=O>>[CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCc1ccc(C(=O)Cl)cc1

Procedure:
A solution of 3 g of para-n-hexyl benzoic acid is refluxed in 7 ml of thionyl chloride for 2 hours. The thionyl chloride is eliminated by distillation under atmospheric pressure, followed by the distillation of the acid chloride under reduced pressure and under a dry nitrogen stream. This gives a product with a boiling point of 153° C. under 1.2 mm Hg.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.Cl.[NH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][C:30]([C:34]3[S:35][C:36]([CH2:39][O:40][CH3:41])=[CH:37][N:38]=3)([OH:33])[CH2:29][CH2:28]2)[CH2:23]1>CN(C=O)C>[CH3:41][O:40][CH2:39][C:36]1[S:35][C:34]([C:30]2([OH:33])[CH2:29][CH2:28][CH:27]([N:24]3[CH2:25][CH2:26][C@@H:22]([NH:21][C:14](=[O:16])[CH2:13][NH:12][S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=4)(=[O:10])=[O:11])[CH2:23]3)[CH2:32][CH2:31]2)=[N:38][CH:37]=1
Reactant: COCc1cnc(C2(O)CCC(N3CC[C@@H](N)C3)CC2)s1
Reactant: O=C(O)CNS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1cnc(C2(O)CCC(N3CC[C@@H](NC(=O)CNS(=O)(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reaction time: 2 h

Procedure:
To a solution of ({[3-(trifluoromethyl)phenyl]sulfonyl}amino)acetic acid (64 mg, 0.22 mmol) and 4-[(3R)-3-aminopyrrolidin-1-yl]-1-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexanol dihydrochloride (72 mg, 0.19 mmol) in DMF (5 mL) at 0° C. was added TEA (38 mg, 0.38 mmol) and BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (99 mg, 0.22 mmol). The reaction mixture was stirred for 2 h, and quenched with water (5 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with saline solution (10 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 1% ammonium hydroxide in ethyl acetate/methanol (100/0 to 90/10). The appropriate fractions were combined to provide two isomers of the desired compound in 1 to 1 ratio with the following characteristics: MS: 577.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[NH:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:13]2[C:17]([N:18]=1)=[N:16][CH:15]=[N:14]2>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[NH:11][C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:13]3[C:17]([N:18]=2)=[N:16][CH:15]=[N:14]3)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1ccc(CNc2[nH]c(Cl)nc3ncnc2-3)cc1
Product: N[C@H]1CC[C@H](Nc2nc3ncnc-3c(NCc3ccc(F)cc3)[nH]2)CC1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
570 mg of trans-1,4-diaminocyclohexane are heated to its melting point 70° C., 290 mg of the product obtained in stage 1 above are added and the medium is then heated at approximately 140° C. for about 4 hours and then left overnight at room temperature. After purification by chromatography on silica with, as eluent, a mixture of CH2Cl2:MeOH:NH4OH (75:22:3) 93 mg of the expected product are obtained in the form of a beige crumbly foam.