Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:59])([CH3:58])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([F:35])=[CH:30][CH:29]=4)=[C:20]2[N:19]=[C:18]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH:17]=1>CC#N.C(Cl)Cl>[CH3:57][Si:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][O:51][CH2:50][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:58])[CH3:59])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([F:35])=[CH:30][CH:29]=4)=[C:20]2[N:19]=[C:18]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[C:17]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccc(F)cc5c4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NBS (410.9 mg, 2.31 mmol) was added to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate (1547 mg, 2.09 mmol) in CH3CN (50 mL) and CH2Cl2 (50 mL). After stirring at room temperature for 2 h, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate: LCMS tR=1.88 Min (5 min run, UV254nm), Mass calculated for M+815.3, observed m/z 816.1 (M+H).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][C:12]=2[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1.O>[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:23][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.79 g, 18.77 mmol) was added to a stirred solution of phenylmethyl 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoate (may be prepared as described in Description 78; 0.81 g, 1.88 mmol) in tetrahydrofuran (50 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After the reaction mixture was cooled to room temperature, the solvent was removed and the residue was dissolved in water (100 ml) and stirred in an ice-water bath. 1N HCl (aq) was added to adjust the pH to 4. The solid was filtered, and dissolved in ethyl acetate (80 ml). The solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as a white solid, 486 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]3[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccc(F)cc3)c21
Temperature: 80 °C
Yield: 47.6 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.247 g, 0.82 mmol) in anhydrous dioxane (6 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.015 g, 0.016 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene HCl (0.014 g, 0.033 mmol). 4-Fluorophenylmagnesium bromide (0.74 mL, 1.48 mmol, 2M in diethyl ether) was added and the reaction heated to 80° C. for 18 hours. After this time an additional 50% of reagents were added and the reaction heated for an additional 18 hours. The reaction mixture was treated with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.139 g, 0.39 mmol, 47%).
Reaction SMILES: C1(S([C:10]2(SC)[CH2:15][C@H:14]3[C@:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C[OH:27].Cl>C(OCC)(=O)C.CCCCCC>[Cl:23][C:18]1[CH:17]=[C:16]([C@:12]23[CH2:13][C@H:14]2[CH2:15][C:10](=[O:27])[CH2:11]3)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Yield: 99 %

Procedure:
(1S,5S)-3-Benzenesulfonyl-1-(3,4-dichlorophenyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (3.5 g, 8.4 mmol), methanol (15 mL) and concentrated hydrochloric acid (3 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane(20:80)). The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 3 g of crude oil, which was purified by preparative HPLC to give 900 mg (45%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.68-0.70 (1H,t, J=4 Hz), 1.25-1.35 (1H,m), 1.94-2.15 (1H,m), 2.36-2.42 (1H, d, J=10 Hz), 2.59-2.66 (1H,d,J=10 Hz), 2.83-2.89 (2H,m), 6.99-7.03 (1H,dd,J=9,3 Hz), 7.25-7.26 (1H,d,J=3 Hz), 7.36-7.39 (1H,d,J=9 Hz). 13CNMR(CDCl3)δ: 215.28, 143.49, 132.57, 130.4, 130.07, 128.09, 125.41, 45.35, 42.08, 27.20, 23.31, 22.23.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: BrCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c2c1OCCO2
Reaction time: 6 h

Procedure:
3-bromo-6-methoxycatechol (16 g) was dissolved in DMF (50 ml), mixed with 1,2-dibromoethane (15 ml) and potassium fluoride (21 g), stirred for 6 hours while heating at 110EC. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed withan aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate anhydride, and then, evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbo-a (5.9 g, 34%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([F:27])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[C:4]([F:27])[CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccccc2C)c2ccc(Br)cc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-2-fluoro-phenyl)-1-(6-methoxy-pyridin-3-yl)-3-o-tolyl-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=414.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[CH:10]1([CH2:13][N:14]2[C:22]3[N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[CH:26][CH:25]=4)[NH:19][C:18]=3[C:17](=[O:32])[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[C:15]2=[O:41])[CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1>[CH:10]1([CH2:13][N:14]2[C:22]3[N:21]=[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]([CH3:31])[C:7]([C:5]5[CH:4]=[N:3][CH:2]=[N:1][CH:6]=5)=[O:9])=[CH:28][CH:29]=4)[NH:19][C:18]=3[C:17](=[O:32])[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[C:15]2=[O:41])[CH2:12][CH2:11]1
Reactant: O=C(O)c1cncnc1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1cncnc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 72 %

Procedure:
This compound was prepared by a method similar to that described in example 79 except that pyrimidine-5-carboxylic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.75 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1.5 equivalent of 4-dimethylaminopyridine was added as the final reagent to the reaction mixture. Purification was performed by chromatography using silica eluted with 94:6 ethyl acetate/methanol followed by trituration with hot acetonitrile to give the product as a colorless solid (72%). MS, m/z(M+H)=540.2161.
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:24]([F:37])=[CH:23][C:22]=3[F:38])[C:14](=[O:20])[N:15]2[CH2:18][CH3:19])=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([NH:4][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:21]3[C:22]([F:38])=[CH:23][C:24]([F:37])=[C:25]([NH:27][C:28]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:29])[CH:26]=3)[C:14](=[O:20])[N:15]2[CH2:18][CH3:19])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N(C(C)=O)C(C)=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of N-acetyl-N-{3-[2,4-difluoro-5-(3-phenyl-ureido)-phenyl]-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-yl}-acetamide (100 mg, 0.19 mmol) in MeOH (2 mL) was added K2CO3 (79 mg, 0.57 mmol) and water (1 mL), and the mixture was stirred overnight at RT. MeOH was removed under reduced pressure and the residue was diluted with water (8 mL). The mixture was extracted with EtOAc to give a crude product which purified by prep-HPLC to give 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (32 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 8.21-8.16 (m, 1H), 8.07 (s, 1H), 7.45-7.40 (m, 3H), 7.30-7.26 (m, 2H), 7.00-6.96 (m, 1H), 4.24-4.18 (q, J=6.8 Hz, 2H), 2.16 (s, 3H), 1.28-1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 478.3 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.CS(C)=O.[OH:14][CH2:15][CH:16]1[CH2:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[CH2:17]1>C(N(CC)CC)C>[O:27]=[C:18]1[N:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH:16]([CH:15]=[O:14])[CH2:17]1
Reactant: O=C1CC(CO)CN1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CC(=O)N(c2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Oxalyl chloride was added to a dichloromethane solution of DMSO at −78° C. and stirred for 20 minutes. Successively, this was mixed with a dichloromethane solution of 4-(hydroxymethyl)-1-phenylpyrrolidin-2-one and then with triethylamine 15 minutes thereafter, and stirred for 30 minutes. Thereafter, work-up and purification were carried out to obtain 5-oxo-1-phenylpyrrolidine-3-carboaldehyde. EN: 188.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5](C(O)=O)[CH2:4]1.C1(P([N:26]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C[Si](C)(C)[O-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.C(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH2:26])[CH2:4]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC1CCCC(C(=O)O)C1
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC1CCCC(N)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methoxycyclohexanecarboxylic acid, mixture of cis and trans 97% (1.50 g, 9.5 mmol), diphenylphosphoryl azide (2.043 mL, 9.5 mmol), and triethylamine (1.582 mL, 11.4 mmol) in anhydrous toluene (65 mL) was heated at reflux for 3 hrs. The mixture was cooled to 0° C., sodium trimethylsilanolate (18.964 mL of a 1 M solution in tetrahydrofuran, 19.0 mmol) was added, and the mixture stirred for 30 mins at room temperature. The reaction was quenched with 5% aqueous citric acid (100 mL), stirred, concentrated to approximately half volume under reduced pressure, washed with diethyl ether (2×), adjusted to basic pH with sodium hydroxide, and extracted with methylene chloride (3×). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (5-12% methanol/methylene chloride) to give partially purified material. The residue was dissolved in methylene chloride and extracted with 1 N aqueous hydrochloric acid (3×). The combined aqueous layers were adjusted to basic pH with 15% aqueous sodium hydroxide and extracted with methylene chloride (3×). The combined organic fractions were dried (anhydrous sodium sulfate), filtered, concentrated, suspended in hexanes/methylene chloride, and filtered. Concentration of the organics gave a yellow liquid (0.272 g). 1H NMR (300 MHz, CDCl3) (mixture of diastereomers) δ 3.52 (m, 1H), 3.28 (s, 3H), 2.99 (m, 1H), 1.95-1.00 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OS(C1C=CC(C)=CC=1)(=O)=O)[C@H:12]1[O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]2[CH2:13][O:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OC[C@@H]1CO1
Yield: 107.6 %

Procedure:
Preparation according to Preparation 1 using 5-bromo-2-hydroxybenzaldehyde (6 g, 30 mmol), (S)-glycidyltosylate (8.2 g, 36 mmol), K2CO3 (4.9 g, 36 mmol) and DMF (12 ml). Water (100 ml) was added and the solution was extracted with EtOAc (3×100 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1 N, 100 ml), brine, were dried and concentrated to give the crude title compound (8.3 g). MS m/z (rel. intensity, 70 eV) 257 (M+, 38), 256 (M+, 39), 200 (bp), 199 (87), 57 (88).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)cc3OC)CC2)c(OC)nc1C
Yield: 77 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14].O>C(O)(=O)C>[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[C:24]([F:33])[C:23]=2[Cl:34])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])(=[O:14])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.07 ml (0.011 mol) of acetic anhydride and 0.45 ml (0.0106 mol) of 98 percent strength nitric acid are added successively to a solution of 3.8 g (0.01 mol) of 5-methanesulphonamido-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole in 20 ml of glacial acetic acid at approximately 15° C. The mixture is stirred at room temperature for approximately 16 hours, and the reaction solution is then poured into 100 ml of water. The precipiate thus formed is filtered off with suction, washed until neutral and dried in vacuo. 3.5 g (80% of theory) of 5-methanesulphonamido-4-nitro-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 107°-115° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
To a solution of 0.64 g (2.75 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL 4N HCl was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring at 180° C. for 6 hours. The solution was cooled to room temperature before the addition of 10% NaHCO3 (10 mL) and then extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and vacuum concentrated. The residue thus obtained was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>>[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:35])=[CH:32][N:31]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-{[4-(methylsulfonyl)benzyl]oxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 16 Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (151 mg, 77%): HPLC MS RT=2.00 min, MH+=521.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.24 (3H, s), 4.02 (3H, s), 4.23-4.28 (2H, m), 4.50-4.55 (2H, m), 5.56 (2H, s), 7.06 (1H, d), 7.58 (1H, d), 7.79 (2H, d), 8.01 (1H, d), 8.05 (1H, d), 8.50 (1H, dd), 8.79 (1H, d).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:5]=1.[Li+].[BH4-].O.Cl>C1COCC1>[I:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(I)c(Oc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(I)c(Oc2ccc3ccccc3c2)c1

Procedure:
4-Iodo-3-(naphthalen-2-yloxy)-benzoic acid methyl ester (0.10 g, 0.25 mmol) dissolved in THF (2 mL) was treated with LiBH4 (2 M solution in THF) (0.247 mL, 0.495 mmol) and heated at reflux for 1.5 hr. The reaction mixture was cooled, added to H2O (50 mL)- concd HCl (4.3 mL), and extracted with EtOAc (3×30 mL). The organics were combined, washed with H2O, aq saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[S:30]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cnccc1Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cnccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and 4-chloro-pyridine-3-sulfonyl chloride. Off-white solid. MS (ESI): 490.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[CH:29][CH:28]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[O:34][CH:35]=[CH:36][N:37]=3)=[CH:31][CH:32]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncco2)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCC[C@H]1CO
Yield: 79.7 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-hydroxymethylcyclopentyl)benzenesulfonamide (145 mg, 0.5 mmol), cesium carbonate (326 mg, 1.0 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (143 mg, 0.6 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 2) to give 4-chloro-N-(trans-2-(hydroxymethyl)cyclopentyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (178 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.31 Hz), 7.66-7.78 (3H, m), 7.43-7.50 (4H, m), 7.22 (1H, s), 4.70 (1H, d, J=16.12 Hz), 4.15 (1H, d, J=16.12 Hz), 3.97-4.08 (1H, m), 3.57 (1H, dd, J=11.58, 4.28 Hz), 3.42 (1H, dd, J=11.46, 3.65 Hz), 1.34-1.71 (8H, m). LC/MS R.T.=2.14 min; [M+H]+=447.12. HRMS [M+H]+ calc'd 447.1145, found 447.1139.