Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[NH:14][C:25](=[O:27])[O:1][N:2]=2)=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(=O)[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)—N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (30 g, 153.71 mmol, 1.00 equiv) and DIEA (39.7 g, 307.18 mmol, 2.00 equiv) in tetrahydrofuran (300 mL) was added dropwise to a solution of triphosgene (18.2 g) in tetrahydrofuran (50 mL). The reaction was stirred for 1 hour at room temperature then heated to reflux for an additional hour. The resulting solution was poured into 500 mL of water and extracted with 3×300 mL of ethyl acetate. The combined organic layers were washed with brine (3×200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by flash chromatography (DCM/MeOH=20:1) to afford of 3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one as a pale yellow solid (106). MS m/z 222.1 (M+1)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20](Cl)(=[O:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>ClCCl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:20]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][CH:19]=[C:10]3[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:22])=[O:21])=[CH:35][CH:34]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2cccc3c(NC(=O)c4ccccc4)cccc23)cc1

Procedure:
To a solution of 5-benzoylamino-naphthalene-1-sulfonyl chloride 44 (0.1 g, 0.29 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.06 ml, 0.43 mmol) and p-anisidine (0.05 g, 0.3 mmol). The resultant solution stirred at room temperature for 3 hours. The reaction mixture was quenched with water and the compound extracted into ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the crude product as a yellow oil. 1H NMR (300 MHz, DMSO) δ 8.65 (d, 1H), 8.19 (d, 1H), 8.06 (m, 3H), 7.70 (m, 2H), 7.54 (m, 2H), 6.84 (d, 2H), 6.69 (d, 2H), 3.56 (s, 3H); LC/MS (M+H)+ m/z 433.
Reaction SMILES: [F:1][C:2]([F:44])([C:6]([F:43])([F:42])[C:7]([F:41])([F:40])[C:8]([F:39])([F:38])[O:9][C:10]([F:37])([F:36])[C:11]([F:35])([F:34])[C:12]([F:33])([F:32])[C:13]([F:31])([F:30])[O:14][C:15]([F:29])([F:28])[C:16]([F:27])([F:26])[C:17]([F:25])([F:24])[C:18]([F:23])([F:22])[C:19]([NH2:21])=O)[C:3]([NH2:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([F:44])([C:6]([F:42])([F:43])[C:7]([F:40])([F:41])[C:8]([F:38])([F:39])[O:9][C:10]([F:36])([F:37])[C:11]([F:35])([F:34])[C:12]([F:32])([F:33])[C:13]([F:30])([F:31])[O:14][C:15]([F:29])([F:28])[C:16]([F:26])([F:27])[C:17]([F:25])([F:24])[C:18]([F:23])([F:22])[C:19]#[N:21])[C:3]#[N:5]
Reactant: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C#N
Temperature: 210 °C
Yield: 96 %

Procedure:
the perfluoro-6,11-dioxahexadecanediamide (16.6 g, 0.023 mole) was mixed with an excess of phosphorus pentoxide, placed in a distillation flask and heated to 210° C for 2 hours. The reaction mixture was cooled, a vacuum of 105 mm was applied and heat was reapplied. The fraction boiling between 120°-125° C at 105 mm was collected (15.3 g, 96% yield). Analysis of the product confirmed the dinitrile structure. Infrared and nuclear magnetic resonance 1H and 19F were consistent with the structure. Mass spectral analysis, calculated M+684, found M+684 and elemental analysis were consistent with the proposed dinitrile structure.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[C:15]([C@H:19]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49]([NH:51][C@:52]2([C:57](=[O:66])[NH:58][S:59]([C:62]3([CH3:65])[CH2:64][CH2:63]3)(=[O:61])=[O:60])[CH2:54][C@H:53]2[CH:55]=[CH2:56])=[O:50])[O:41][C:31]2=[N:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39](O)=[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[CH2:67][C@H:23]2[O:22][C:21](=[O:68])[NH:20]1)([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:15]([C@H:19]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49](=[O:50])[NH:51][C@:52]2([C:57](=[O:66])[NH:58][S:59]([C:62]3([CH3:65])[CH2:63][CH2:64]3)(=[O:60])=[O:61])[CH2:54][C@H:53]2[CH:55]=[CH2:56])[O:41][C:31]2=[N:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]([O:1][CH2:2][C@H:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)=[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[CH2:67][C@H:23]2[O:22][C:21](=[O:68])[NH:20]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CCN(C(=O)OC(C)(C)C)C1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 75, using the tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (Example 120). The method was slightly modified as triphenylphosphine was used instead of trimethylphosphine and the reaction was done at a 0.3 M concentration LRMS (ES+) m/z 949.5 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:31])[C:18]3[C:23]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:22][N:21]([CH3:30])[C:19]=3[N:20]=2)=[C:11]([O:32][CH3:33])[CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[CH:24]1([C:23]2[C:18]3[C:17](=[O:31])[NH:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=4[O:32][CH3:33])=[N:20][C:19]=3[N:21]([CH3:30])[N:22]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 99.5 %

Procedure:
To a 50 ml methanol/50 ml tetrahydrofuran mixed solution of 1.16 g (2.61 mmol) of the compound obtained in Example 35, 300 mg of 5% palladium carbon was added. The mixture was stirred for 3 hours at room temperature at atmospheric pressure in an atmosphere of hydrogen. Then, the catalyst was removed by filtration to obtain 0.92 g (99%) of the captioned compound.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[N:30]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(=O)c2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N=[N+]=[N-])c2ccccc2n1
Temperature: 100 °C

Procedure:
A solution of the compound prepared in Example 272 (0.032 g) in N,N-dimethylformamide (1 mL) was treated with diphenyl phosphoryl azide (0.037 mL), followed by triethylamine (0.028 mL) at room temperature. The mixture was heated at 100° C. overnight. The solvent was evaporated in vacuo and the resulting oil was purified by column chromatography on silica gel (1-10% diethyl ether in dichloromethane) to obtain the title compound (0.016 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH4+:16].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:16])=[O:8]
Reactant: [NH4+]
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2sc(C(N)=O)c(Cl)c2c1

Procedure:
To a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (1.52 g, 5.82 mmol) [Connor D. T., et al., J. Med. Chem. 35, 935 (1992)] in 80 mL of toluene at 50° C. is added dropwise 10 mL of aqueous NH4OH. The resulting precipitate is collected by filtration and recrystallized from methanol to provide 3-chloro-5-methoxybenzo[b]thiophene2-carboxamide; mp=220°-222° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]12O[C:14]([CH3:18])([CH:15]=[CH:16]1)[CH:13]1[CH:9]2[C:10](=O)[O:11][C:12]1=[O:19].[OH-].[Na+]>O1CCCC1>[OH:11][CH2:10][C:9]1[C:8]([CH3:7])=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH2:12][OH:19]
Reactant: CC12C=CC(C)(O1)C1C(=O)OC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CO)c1CO
Temperature: -78 °C
Reaction time: 45 h

Procedure:
A 1 L 3-necked RBF is charged with a 1.0M lithium aluminium hydride solution in tetrahydrofuran (175 mL, 0.175 mol) and anhydrous tetrahydrofuran (100 mL) under nitrogen. The solution is cooled to −78° C. and a solution of 1,7-dimethyl-4,10-dioxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 2 (12.3 g, 0.070 mol) in anhydrous tetrahydrofuran (150 mL) is added from a dropping funnel over a period of 30 minutes The reaction mixture is heated to reflux and stirred for 45 h. The reaction mixture is cooled to 0° C. using an ice bath and 2M sodium hydroxide solution (20 mL) is slowly added dropwise. The mixture is allowed to warm up to 22° C. and the precipitate is filtered off and washed thoroughly with diethyl ether and tetrahydrofuran. The filtrate is concentrated in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[N:26]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=3)=[O:23])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCOC(C)=O.Cl>C(Cl)Cl>[C:30]([C:28]1[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:20]=2)=[O:23])[N:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccnc(OC3CCNCC3)c2)cc1
Reaction time: 0.5 h

Procedure:
Treat a solution of 4-{4-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (877 mg, 1.6 mmol) in 1:1 EtOAc:DCM (100 mL) with a bubbling stream of HCl (g) for 3 min. Allow the resulting mixture to stand for 30 min, then concentrate under reduced pressure. Dissolve the residue in MeOH and load onto a 20 g Varian SCX column, rinsing well with MeOH. Elute the free base with 1:1 DCM:2 M ammonia in MeOH. Concentrate the solution under reduced pressure to give the title compound in quantitative yield. LCMS ES+(m/z) 449 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:32])[CH2:20][CH2:19]1)=[O:17].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[C:24]4[CH3:32])[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Reactant: Nc1ccccc1
Product: CCOC(=O)c1cnn2c(Nc3ccccc3)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 77.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.220 g, 0.488 mmol) obtained in step 2 and aniline (0.054 mL, 0.585 mmol), the title compound (0.191 g, 79%) was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([N:9]=[C:10]=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH3:30])[C:16]=1[C:17]([OH:19])=O>C(OCC)C>[CH2:28]([O:27][C:25]([C:21]1[C:20]([CH3:30])=[C:16]2[C:15](=[CH:23][C:22]=1[CH3:24])[NH:14][C:10](=[O:11])[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:12])[F:13])[C:17]2=[O:19])=[O:26])[CH3:29]
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
α,α,α-Trifluoro-o-tolyl isocyanate (434 mg) was added to a solution of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid (500 mg) in diethyl ether (22 ml), and the mixture was stirred overnight. The resulting precipitate was filtered off and dissolved in ethanol (15 ml). Then, hydrogen chloride (1 g) was introduced into the solution. The reaction mixture was refluxed for 3 hours and the solvent was evaporated off. The residue was recrystallized from diethyl ether to give 6-ethoxycarbonyl-5,7-dimethyl-3-[2-(trifluoromethyl)phenyl]-2,4-(1H,3H)-quinazolinedione (575 mg, 67%) melting at 175°-176° C. MS: m/e, 406(M+), 377, 361, 357, 337, 332, 314, 309. NMR: δ(ppm, CDCl3) 1.40 (3H, t), 2.30 (3H, s), 2.68 (3H, s), 4.44 (2H, q), 6.70 (1H, b), 7.2-8.0 (4H, m), 10.25 (1H, s).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:19][N:20](C)C=O>O>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:19]#[N:20])=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Sc1cc(Br)ccc1O2
Reactant: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)Sc1cc(C#N)ccc1O2

Procedure:
A mixture of 2-acetyl-8-bromophenoxathiin (from Example 4, Step 1) (1.73 g, 5.39 mmol) and cuprous cyanide (1.94 g, 21.6 mmol) in N,N-dimethylformamide (DMF, 15 mL) was refluxed for 7 hours. After cooling, the mixture was diluted with water and the precipitated solid filtered. This solid was boiled with ethyl acetate (100 mL) and filtered. The process was repeated with THF (100 mL, then 50 mL) and the combined filtrates evaporated to afford a yellow solid. This was purified by column chromatography on silica gel, eluting with a 1:3 mixture of ethyl acetate-hexane, to afford the title nitrile (774 mg) as a yellow solid, m.p.: 179°-183° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(C(F)(F)F)c1
Yield: 88.8 %

Procedure:
This compound was prepared according to the procedure used in Example 75. A mixture of 18.4 g (0.114 mole) of α, α, α-trifluoro-m-cresol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 22.5 g (82%) of a white solid, mp 100°-102° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[CH:16]=[C:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:18]=O.O>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([C:9]([F:10])([F:11])[F:12])=[N:1][CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=CC(=CCl)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (1.55 g; prepared by the method of Swarts, Bull. Sci. acad. roy. Belg., 1926, 12 (5), 679) in dry dimethylformamide (2 ml) was added dropwise to a suspension of sodium hydride (0.20 g) in dimethylformamide (20 ml). The mixture was then stirred for 30 minutes and 3-chloro-2-(p-chlorophenyl)prop-2-enal (1.7 g) was added dropwise. The mixture was stirred for 2 hours, allowed to stand overnight and poured into water. The resulting mixture was twice extracted with diethyl ether and the combined extracts washed with water, dried and filtered through charcoal. The filtrate was concentrated and the residue recrystallised from aqueous ethanol to give the title compound (1.1 g), m.p. 84°-5°.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Nc1ccccc1Br
Product: Nc1ccccc1-c1nccs1
Yield: 24.1 %

Procedure:
2-Tributylstannanyl-thiazole (600 mg, 1.6 mmol) was reacted with 2-bromoaniline (200 mg, 1.2 mmol) according to general procedure [B] for the preparation of substituted anilines described above, which gave the title compound (51 mg, 25%). [M+1] 177.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=C(NC2C=CC(NC(C3CN(C(OC(C)(C)C)=O)C=CC=3)=O)=CC=2)N=CC=1CC(N)=O)C1C=CC=CC=1.[ClH:83].C(OCC)(=O)C>CO>[ClH:83].[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Agent: CC(C)(C)OC(=O)N1C=CC=C(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)Cc1cnc(Nc2ccc(NC(=O)C3CCCNC3)cc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
25.9 mg of 4-(benzylamino)-6-[(4-{[1-(tert-butoxycarbonyl)piperidin-3-ylcarbonyl]amino}phenyl)amino]pyridine-3-carboxyamide (the compound of Example 308) was dissolved in 1 mL of methanol, to which 1 mL of 4 mol/L hydrochloric acid-ethyl acetate was added, and stirred at room temperature for 30 minutes. The solvent was evaporated, ether was added to the residue, the deposited crystals were filtered to obtain 20.7 mg (91%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=2)[CH3:21])=[O:16])=[CH:11][CH:12]=1
Reactant: Cc1ncoc1-c1ccc(CC(=O)O)cc1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncoc1-c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a solution of 3.00 g (14.0 mmol) 4-bromophenyl acetic acid in 25.0 ml DMF was added 3.60 g (27.9 mmol) 4-methyl-1,3-oxazole-5-carboxylic acid, 6.80 g (20.9 mmol) cesium carbonate, 4.1 g (14.0 mmol) tetrabutyl ammonium chloride monohydrate, and 0.400 g (0.700 mmol) bis(tri-t-butylphosphine)palladium(0). After 3.00 h at 140° C., the reaction mixture was diluted with CH2Cl2, washed with 10% citric acid, washed twice with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 50×150 mm) afforded 0.730 g (24%) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid. 1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H); 7.61 (d, 2H, J=8.32 Hz); 7.41 (d, 2H, J=8.33 Hz); 3.65 (s, 2H); 2.41 (s, 3H). ESMS+1 for C12H11NO3: 218.1. To a solution of 0.725 g (3.34 mmol) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid in 7.00 ml CH2Cl2 was added 0.978 g (3.34 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.591 g (4.34 mmol) HOAT, 0.832 g (4.34 mmol) EDC, and 1.75 mL (10.0 mmol) DIEA. After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 20-100% EtOAc:hexane) afforded 0.720 g (51.4%) 2-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H, J=2.38 Hz); 7.83 (s, 1H); 7.59 (dd, 2H, J=1.83 Hz, 6.59 Hz); 7.36 (d, 2H, J=8.42 Hz); 7.22 (m, 2H); 6.72 (br d, 1H, J=7.51 Hz); 5.12 (m, 1H); 4.38 (q, 2H, J=8.06 Hz); 3.62 (s, 2H); 2.45 (s, 3H); 1.41 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H20F3N3O3: 420.1540, Found: 420.1530.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:8]=1[Br:18])[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:21]3[S:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:22]=3)[CH:13]=2)[C:8]=1[Br:18])[CH3:2]
Reactant: CCOC(=O)COc1ccc2cc(Br)ccc2c1Br
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Temperature: 70 °C
Yield: 41.5 %

Procedure:
A mixture of (1,6-dibromo-naphthalen-2-yloxy)-acetic acid ethyl ester (6.9 g, 18 mmol), benzothiophene-2-boronic acid (4.78 g, 26.8 mmol) in two portions, palladium (II) acetate (0.11 g, 0.49 mmol), potassium carbonate (6.2 g, 45 mmol), tetrabutylammonium bromide (5.8 g, 18 mmol) in water (90 mL) and THF (35 mL) was heated at 70° C. for 3.5 hours. The reaction mixture was allowed to cool to ambient temperature and then poured into excess 2N hydrochloric acid. It was extracted with chloroform. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered hot (due to limited solubility) and solvent evaporated. The residue was purified by flash chromatography using 25–45% methylene chloride in hexane and 100% chloroform as eluent. Drying at 60° C. in vacuo for 30 minutes yielded (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester as a buff-colored solid (3.3 g, 42%) MP: 178–81° C.; mass spectrum (+EI, M+) m/z 440/442. 1H NMR (500 MHz, DMSO-d6): δ8.32 (d, 1H,J=1.83 Hz), 8.18 (d, 1H, J=8.86 Hz), 8.07–8.12 (m, 2H), 8.01 (d, 2H, J=7.33 Hz), 7.88 (dd, 1H, J=7.63 Hz and 1.07 Hz), 7.47 (d, 1H, J=9.16 Hz), 7.36–7.43 (m, 2H), 5.09 (s, 2H), 4.18 (q, 2H, J=7.08 Hz), 1.22 ppm (t, 3H, J=7.11 Hz). Elemental Analysis for C22H17BrO3S: Calcd: C, 59.87; H, 3.88; N, 0.00; Found: C, 60.03; H, 3.83; N, 0.00.