Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Si@@]1(Cl)N(C)[C@H](C)C(C2C=CC=CC=2)O1)[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:17][CH:16]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[Si@]1(Cl)OC(c2ccccc2)[C@@H](C)N1C
Reactant: CC(C)(C)C=NNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
N′-(2,2-Dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester (12 g, 59.9 mmoles) was charged to a dried, 3-neck, 1 L round bottom flask with thermometer, magnetic stirrer, and nitrogen atmosphere. Anhydrous methylene chloride (200 mL) was charged to the flask using a catheter. The mixture was chilled to 0° C. with an ice bath. (R,R)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (24.07 g, 89.87 mmoles) was subsequently added to the flask under inert conditions. Within minutes, the originally light yellow solution turned transparent dark yellow. The reaction was stirred for 6 hr at 0° C., then allowed to warm to room temperature, and stirred overnight, while being monitored by TLC. The reaction was quenched by adding ca. 25 mL methanol, resulting in a lightening of color. The solution was concentrated and the residue was diluted with 100 mL of ethyl acetate and 100 mL of water. The phases were separated and the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography using 10% ethyl acetate in hexanes. Purified (S)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid tert-butyl ester was obtained as an oil (2.87 g, 24.4% yield). An impure fraction was also collected (3.17 g). Rf=0.44 (5:1 hexanes:ethyl acetate, 12 visualization); 1H NMR (400 MHz, CDCl3) δ 6.07 (br, 1H, NH), 5.85 (m, 1H), 5.0 (dd, 2H), 2.6 (m, 1H), 2.33 (m, 1H), 2.3 (m, 1H), 1.4 (s, 9H), 0.9 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)=[C:5]([CH3:32])[CH:4]=1)#[N:2].[Cl-].[Li+]>CC(N(C)C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])=[C:5]([CH3:32])[CH:4]=1)#[N:2]
Reactant: COc1c(-c2ccc(C#N)cc2C)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (27.3 mg, 0.063 mmol) and lithium chloride (13.41 mg, 0.316 mmol) in DMA (0.5 mL) then heated at 50° C. using a heating block for 24 hours. Additional portion of lithium chloride (8.05 mg, 0.190 mmol) was added and the reaction mixture was stirred at 50° C. for an additional 14 hours. The reaction mixture was cooled to 23° C., filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 30-60% ACN (with 0.035% TFA) in water (with 0.05% TFA). The product containing fractions were combined and concentrated via rotary evaporation to furnish an off-white solid which was collected by filtration, rinsed with water (5×2 mL), and dried in vacuo to give the title compound (8.2 mg, 31.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2H) 1.58-1.67 (m, 2H) 1.75-1.86 (m, 1H) 2.43 (s, 3H) 3.20 (t, J=6.32 Hz, 2H) 3.27 (td, J=11.75, 2.02 Hz, 2H) 3.81-3.90 (m, 2H) 7.60-7.69 (m, 1H) 7.73 (s, 1H) 7.78 (br. s., 1H) 8.05-8.25 (m, 1H) 8.35-8.45 (m, 1H) 8.69-8.80 (m, 1H) 8.89-8.95 (m, 1H) 13.21 (br. s., 1H). MS m/z [M+H]+ 418.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([OH:25])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:38][C:39]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].CN(C1C=CC=CN=1)C.Cl>C(N(CC)CC)C.CN(C)C=O>[Cl:38][C:39]1[CH:48]=[CH:47][C:46]([NH:49][C:23](=[O:25])[CH2:22][CH2:21][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:3]=2[O:2][CH3:1])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]
Reactant: COc1cc(OCCCCCc2ccccc2)ccc1CCC(=O)O
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCc2ccc(OCCCCCc3ccccc3)cc2OC)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a mixture of 3-[2-methoxy-4-(5-phenylpentyloxy)phenyl]propanoic acid (342 mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (288 mg), 1-hydroxybenzotriazole-1-hydrate (153 mg) and dimethylformamide (5 mL) was added methyl 2-chloro-5-aminobenzoate (265 mg) and triethylamine (0.7 mL). To the reaction mixture was added dimethylaminopyridine (50 mg). The reaction mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over an anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (300 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:18][C:15]12[CH2:17][CH:11]([N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:7][CH:6]=3)=[O:9])[CH2:16]1)[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]2
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)c3ccncc3)cc2)C1
Reaction time: 2 h

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (400 mg, 1.47 mmol) in dry THF (25 ml) was added dropwise a solution of isonicotinoyl chloride (312 mg, 2.20 mmol) in dry THF (20 ml). The mixture was stirred for 2 hrs. and evaporated followed by addition of water 20 (ml). The aqueous phase was extracted with EtOAc (2×20 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using first EtOAc (300 ml) followed by a 4% mixture of TEA in EtOAc as eluents. Pure fractions were collected and evaporated to dryness. The residue was crystallized from a mixture of diethyl ether (20 ml) and EtOAc (5 ml) affording after filtering and drying in vacuo at 50° C. 200 mg (36%) of the title compound as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:29]=[CH:30][C:31]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:32])=[CH:34][CH:35]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1
Yield: 68.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), 4-fluorocinnamic acid (1.9 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (2.5 g, 69%) as an amorphous solid product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:32])[C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC=CC=1.[O:39]([C:44]([N:46]1[CH2:52][CH2:51][CH2:50][C@H:47]1[CH:48]=O)=[O:45])[C:40]([CH3:43])([CH3:42])[CH3:41].[BH4-].[Na+]>C(O)C>[OH:32][C@@H:3]([C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH2:48][CH:47]1[CH2:50][CH2:51][CH2:52][N:46]1[C:44]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN)C(C)C)C2=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCC3CCCN3C(=O)OC(C)(C)C)C(C)C)C2=O)cs1
Temperature: 70 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of the product of Example 274C (59 mg) in ethanol:benzene (1 mL, 1:1) was treated with N-t-butoxylcarbonyl-(L)-prolinal (26 mg, 1 equivalent), stirred at 70° C. for 1 hour, cooled at 25° C., treated with NaBH4 (14 mg, 3 equivalents) at 25° C. and stirred for 16 hours. The mixture was quenched with saturated NH4Cl and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 85 mg of the crude title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.FC(F)(F)S(O[C:66]1[CH:75]=[CH:74][CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][C:70]([CH3:76])=[N:71]2)(=O)=O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:76][C:70]1[CH:69]=[CH:68][C:67]2[C:72](=[CH:73][CH:74]=[CH:75][C:66]=2[N:50]2[CH2:51][CH2:52][N:47]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48][CH2:49]2)[N:71]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Temperature: 25 °C

Procedure:
A stirred mixture of Pd(OAc)2 (243 mg), CsCO3 (6.63 g), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.01 g) in dry toluene (60 mL) was heated under reflux for 15 min, under argon. After cooling, a solution of tert-butyl piperazine-1-carboxylate (3.03 g, 16.3 mmol) and the 2-methylquinolin-5-yl trifluoromethane-sulfonate prepared in example 5 (3.95 g, 13.6 mmol) in toluene (100 mL) was added, and the resulting mixture was heated under reflux for 8 h. The reaction mixture was cooled to room temperature, concentrated to half of its value, and then quenched with saturated solution of NH4Cl (50 mL). The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic solutions were concentrated in vacuo. The residue was purified by column chromatography using CH2Cl2 as eluent. Yield: 4.29 g (96.6%), brown oil. Rf=0.64 (CH2Cl2-MeOH (19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c[nH]c(C(=O)O)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (11 g, 41.7 mmol) in methanol (140 mL,) and tetrahydrofuran (140 mL) was added sodium hydroxide (140 mL, 6M aqueous solution) and the reaction was stirred at 110° C. for 4 hrs. The reaction mixture was allowed to cool and the organics removed under vacuum. The resulting residue was slurried in water (200 mL) and acidified with acetic acid to pH4. The resulting precipitate was collected by filtration and washed with water to afford the title compound as a grey solid (9.8 g, 99% yield)
Reaction SMILES: [Br:1]Br.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11]2)[N:6]=[CH:5]1.O.[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]2[C:18]([CH:10]([CH2:9][C:7]3[N:6]=[CH:5][NH:4][CH:8]=3)[CH2:11][CH2:12]2)=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Reactant: BrBr
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc2c(cc1Br)CCC2Cc1c[nH]cn1
Temperature: 21.5 °C
Reaction time: 3 h

Procedure:
Bromine (130 mg, 1 eq.) is added dropwise to a stirred suspension of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol hydrochloride (130 mg) in acetic acid (6 ml). The mixture is stirred at 20-23° C. for 3 hours. The reaction mixture is then poured into water and is made alkaline with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The product is purified by flash chromatography using methylene chloride-methanol as eluent and is then converted to the hydrochloride salt in ethyl acetate-ethanol solution.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CNCc2ccco2)cc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Yield: 93.4 %

Procedure:
A solution of 600 mg (1.75 mmol) of tert-butyl 3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example I-5), 323 mg (0.87 mmol) of tetra-n-butylammonium iodide and 265 mg (2.62 mmol) of triethylamine in 10 ml of THF is treated with 438 mg (2.62 mmol) of ethyl bromoacetate and heated at reflux overnight. After cooling, the mixture is concentrated under reduced pressure, the residue is taken up in water and ethyl acetate, the aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are washed with NaCl solution and dried over sodium sulphate. The solvent is removed under reduced pressure, and chromatographic purification on silica gel (cyclohexane→cyclohexane/ethyl acetate 10:1) then gives 702 mg (94%) of tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:35][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1ccc(F)cc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(F)cc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methoxy-5-fluorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 6.93 (m, 1H), 6.77 (m, 3H), 5.36 (s, 2H), 3.77 (s, 3H), 3.59 (m, 4H), 3.07 (m, 2H), 2.98 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 435.1, found 435.0.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:7]=1[N+:13]([O-:15])=[O:14]>>[N:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[N+:13]([O-:15])=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [Na+]
Product: [N-]=[N+]=Nc1cccc(F)c1[N+](=O)[O-]

Procedure:
reacting sodium azide with 1,3-difluoro-2-nitrobenzene to form 1-azido-3-fluoro-2-nitrobenzene; and
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=O)[CH2:3]1.F[B-](F)(F)F.[CH3:13][O+:14]([CH3:16])C>>[CH2:3]([CH:2]1[CH2:1][C:13]([O:14][CH3:16])=[N:5][CH2:6]1)[CH3:4]
Reactant: C[O+](C)C
Reactant: CC1CNC(=O)C1
Agent: F[B-](F)(F)F
Product: CCC1CN=C(OC)C1

Procedure:
The product of EXAMPLE 180 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](Cl)(=[O:18])[CH3:17].FC(F)(F)C(O)=O>O>[C:16]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: OC(c1ccccc1)c1cccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OC(c1ccccc1)c1cccnc1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.39 g 2-chloro-α-phenyl-3-pyridinemetanol (see Ex. 20), 3.14 g acetyl chloride and 8 ml trifluoroacetic acid is stirred for 1 hr. at room temperature. The reaction liquid is added dropwise to water, and the solid formed is filtered, washed, dried and crystallised from cyclohexane. Yield: 4.46 g title product, m.p. 100°-2° C.; Cl 13.82 (13.55).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH2:18][C:19]1([CH3:22])[CH2:21][CH2:20]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH2:18][C:19]2([CH3:22])[CH2:20][CH2:21]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)CC1(C)CC1
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1(C)CC1)Sc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 4-bromothiophenol (455 mg, 2.4 mmol) in DRY (3 mL) was added sodium hydride (101 mg of 60% oil disp., 2.5 mmol). The resulting suspension was stirred at 0° C. for 30 min. A solution of ethyl 2-bromo-3-(1-methylcyclopropyl)propanoate (465 mg, 2.0 mmol) in DMF (2 mL) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using Et2O in hexane to afford ethyl 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Product: COc1c(OCCOCCNS(=O)(=O)c2ccc(C)cc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 31, Step 5 was used to prepare the title compound from N-{8-[2-(2-aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Example 31, Step 4) and (4-methylphenyl)sulfonyl chloride. HPLC MS RT=2.35 min, MH+=579.5.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([C:39]([F:42])([F:41])[F:40])=[O:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:42][C:39]([F:40])([F:41])[S:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1)=[O:38]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with water, 10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) to yield 99 mg colorless powder that was further purified by HPLC-MS.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:2]([NH:1][S:40]([C:37]2[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=2)(=[O:42])=[O:41])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 77, by condensing methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with 4-(trifluoromethyl)-benzenesulphonyl chloride there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoate and therefrom by treatment with 5.5M HCl there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoate.