Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:21])[CH:5]=[CH:6][CH:7]=1.[C:40](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:40][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 126 (370 mg, 0.68 mmol), potassium carbonate (235 mg, 1.70 mmol), and DMF (4 mL). The resulting mixture was stirred for 5 min, and methyl iodide (435 mg, 3.10 mmol) was then added. After stirring for a further 1 h at ambient temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give an 82% yield of compound 127 as a light yellow oil. 1H NMR (CD3OD) δ (ppm) 8.20 (m, 2H), 6.99-7.66 (m, 7H), 5.58 (s, 2H), 5.15 (bs, 1H), 3.62 (dt, 2H, J=1.8, 8.0 Hz), 3.32 (s, 3H), 2.78 (s, 3H), 1.55 (m, 3H), 0.88 (m, 2H), −0.07 (s 9H); m/z=558 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)C3CC3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added cyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide as an off-white solid (233 mg, 42% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.01 min (98.4%); mp, 281-283° C.; 1HNMR (DMSO-d6) δ 0.64-0.74 (m, 4H, CH2CH2 of cyclopropane ring), 1.57-1.66 (m, 1H, CH of cyclopropane ring), 2.15-2.21 (m, 1H, CH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.39 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53, 120.01, 123.78, 126.58, 134.02, 138.34, 145.78, 154.55, 160.44, 169.47, 172.62, 172.70. LCMS MH=413; Anal Calcd For C19H20N4O4: C, 61.95; H, 5.47; N, 15.21. Found: C, 61.86; H, 5.49; N, 15.04.
Reaction SMILES: C(C1C=CC(CN2C(C)=C(C3C=CC=C(C(F)(F)F)C=3)C(=O)C(C(O)=O)=C2)=CC=1)#N.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.BrC1C(=O)C(C(O)=O)=CN(CC2C=CC(C#N)=CC=2)C=1C.Br[C:66]1[C:67](=[O:86])[C:68]([C:83]([OH:85])=[O:84])=[CH:69][N:70]([CH:73]([C:75]2[CH:80]=[CH:79][C:78]([C:81]#[N:82])=[CH:77][CH:76]=2)[CH3:74])[C:71]=1[CH3:72]>>[C:81]([C:78]1[CH:77]=[CH:76][C:75]([CH:73]([N:70]2[CH:69]=[C:68]([C:83]([OH:85])=[O:84])[C:67](=[O:86])[C:66]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)=[C:71]2[CH3:72])[CH3:74])=[CH:80][CH:79]=1)#[N:82]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Product: Cc1c(-c2ccnc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1

Procedure:
Preparation 4 is prepared following the procedure described for preparation 1d, substituting 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid and substituting preparation 1c with preparation 2b as starting material. ESI mass spectrum: [M+H]+=428; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 51% yield.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1>C([Mg]Br)(C)C.[Zn+2].[Br-].[Br-]>[Br:19][C:20]1[N:21]=[C:22]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Agent: CC(C)[Mg]Br
Agent: [Br-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (1.09 g, 3.0 mmol), i-PrMgBr/ZnBr2 and commercially available 2,6-dibromopyridine (2.13 g, 9 mmol) according to the general procedure IVc protocol b. Obtained as a light yellow solid (0.826 g, 70%). MS (ISP) 393.0 [(M+H)+] and 394.8 [(M+2+H)+].
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.307 g, 5.75 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.75 mmol) dissolved in water (2 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.75 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.682 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.83-1.94 (m, 1H), 2.16-2.29 (m, 2H), 2.34-2.43 (m, 1H), 3.06-3.18 (m, 1H), 3.51 (ddd, 1H), 3.64 (s, 3H), 4.12 (ddd, 1H), 5.10-5.22 (m, 1H), 5.57 (s, 1H), 7.40 (d, 2H), 7.58 (d, 2H). MS m/z 371 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([CH3:9])[C:7](=[O:10])[CH2:6][O:5][CH2:4]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[CH3:9][N:8]1[C:7](=[O:10])[CH2:6][O:5][CH2:4][C@H:3]1[CH2:2][O:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)COC[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COCC(=O)N2C)cc1
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
Dissolve (R)-5-hydroxymethyl-4-methyl-morpholin-3-one (767 mg, 5.29 mmol) in pyridine (18 mL). Cool the reaction to 0° C., add 1.3 g (6.9 mmol) of p-toluenesulfonyl chloride (1.3 g, 6.9 mmol), and stir for 90 min. Pour into 1N HCl (50 mL) and extract with EtOAc (2×100 mL). Wash the combined organic layers with brine (50 mL), dry over Na2SO4, and concentrate to give the crude product. Purify via silica gel chromatography using a 0-100% EtOAc/hexanes gradient to yield 684 mg (43%) of the title compound. MS/ES m/z 300.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(F)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 81.8 %

Procedure:
To 600 mg (1.9 mmol) of the compound (133) obtained in Example 25, 5 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added, and the solution was heated at reflux for 2 hours. After air-cooling, 20 ml of water was added to the solution, and solids were filtered off and washed with ethanol and ether in this order to obtain 461 mg of the subject compound (134) in a 80% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[N:26][C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([C:33]3[CH:40]=[CH:39][C:36]([CH2:37][N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[CH:16]=[N:15][C:14]6[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=6)[N:8]=5)[CH2:5][CH2:6]4)=[CH:35][CH:34]=3)=[N:26][C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Product: Fc1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4cnc5ccccc5n4)CC3)cc2)cc1

Procedure:
The compound is prepared in analogy to example 33.0. 216 mg (0.756 mmol) 2-Piperidine-4-ylquinoxaline are reacted with 200 mg (0.63 mmol) 4-[6-(4-fluorophenyl)-imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde. After the usual work-up and purification 201 mg (58.9%) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
Under nitrogen atmosphere, 3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.) were added with THF (2 ml), and then further added dropwise with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2 eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at room temperature for 12 hr under nitrogen atmosphere. The residues obtained after concentrating the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder, 120 mg).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH2:3][CH2:2]1.C(=O)([O-])[OH:13].[Na+].OOS([O-])=O.[K+]>C(OCC)(=O)C.O.O>[O:13]1[CH:5]2[CH:4]1[CH2:3][CH2:2][O:1][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: O=C([O-])O
Reactant: C1=Cc2ccccc2OCC1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)OCCC1OC21
Reaction time: 1 h

Procedure:
To 0.5 g of 2,3-dihydro-1-benzoxepin (3.42 mmol), prepared according to the method described in J. Org. Chem., 1969, 34 (1), 207, dissolved in 30 ml of a mixture of ethyl acetate/water 50/50, there are added 1.44 g of sodium hydrogen carbonate (17.1 mmol) and then, over 1 hour, a solution of 2.1 g of Oxone® (3.42 mmol) in 15 ml of water. After the end of the addition, stirring is carried out for a further hour and then the organic phase is separated off. The aqueous phase is again extracted with 10 ml of ethyl acetate, and the combined organic phases are washed with water, dried, filtered and evaporated to dryness to yield the expected product in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccnc(-c2ccsc2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(c2ccnc(-c3ccsc3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-3-yl-pyridine (50 mg, 0.26 mmol), 1-methylpiperazine (100 mg, 1 mmol), 2-propanol (0.7 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28]([OH:30])=O)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:33][C:34]1[CH:35]=[C:36]([S:40]([NH:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[OH:46][CH2:45][C:44]([NH:43][S:40]([C:36]1[CH:35]=[C:34]([NH:33][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:23])([F:24])[F:22])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:13])([F:14])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:31])[F:32])[CH:6]=4)=[N:16][C:17]=23)=[O:30])[CH:39]=[CH:38][CH:37]=1)(=[O:42])=[O:41])([CH3:48])[CH3:47]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 698.3 [(M−H−]; mp 251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])=[CH:7][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)cn1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(NC(=O)CCl)cn1
Reaction time: 0.25 h

Procedure:
A solution of 3-amino-6-methoxypyridine (25.0 grams) in absolute ether (160 ml) was charged into a glass reaction flask equipped with a mechanical stirrer, dropping funnel and thermometer. The solution was cooled to a temperature of about 0° C and pyridine (18.1 ml) was added thereto. A solution of chloroacetyl chloride (17.0 ml) in ether (40 ml) was then slowly added to the flask with stirring over a period of about 15 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture was kept between about 0° to 5° C during the addition of the chloroacetyl chloride. After completion of the addition stirring was continued for a period of about 30 minutes. The solid precipitate which had formed was then recovered by filtration and was washed with aqueous sodium bicarbonate and then with water. The washed product was then dried to yield the desired product N-(6-methoxy-3-pyridyl)-α-chloroacetamide as a white solid having a melting point of 117° to 118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:14]2[C:33]([CH:34]3[CH2:36][CH2:35]3)=[CH:32][C:17]3[C:18]([C:28]([NH:30][CH3:31])=[O:29])=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[O:20][C:16]=3[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][B:45]1[O:49]C(C)(C)C(C)(C)[O:46]1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:14]2[C:33]([CH:34]3[CH2:36][CH2:35]3)=[CH:32][C:17]3[C:18]([C:28](=[O:29])[NH:30][CH3:31])=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[O:20][C:16]=3[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:44][B:45]([OH:49])[OH:46]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC1(C)OB(CBr)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCB(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 65 °C
Yield: 59.6 %

Procedure:
A mixture of 6-(N-(3-chloro-4-hydroxyphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (65.0 mg, 0.123 mmol), potassium carbonate (85.0 mg, 0.614 mmol), and 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.109 g, 0.492 mmol) in 4 mL of anhydrous MeCN in a sealed tube was heated to 65° C. with stirring. After 2 hours the mixture was cooled to RT, filtered to remove solids, and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/water to afford the title compound (43 mg, 60%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 8.05 (s, 2H) 7.97 (dd, J=8.7, 5.5 Hz, 2H) 7.65 (d, J=2.5 Hz, 1H) 7.53 (dd, J=8.9, 2.6 Hz, 1H) 7.40 (t, J=8.8 Hz, 2H) 7.14 (s, 1H) 7.00 (d, J=9.1 Hz, 1H) 3.73 (s, 2H) 3.32 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.20-2.35 (m, 1H) 0.90 (br. s., 3H) 0.45 (br. s., 1H). LCMS (m/z, ES+)=587 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([CH3:15])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H][H]>CN(C=O)C.[Pt]>[Cl:1][C:2]1[C:3]([C:8]2([CH3:15])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC1(c2ncccc2Cl)C=CC(=O)CC1
Agent: [Pt]
Solvent: CN(C)C=O
Product: CC1(c2ncccc2Cl)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A solution of the product of Example 38E (0.225 g, 1.015 mmol) in DMF was added to 5% Pt—C, wet (225 mg, 1.153 mmol) in a 50 ml pressure bottle. The mixture was pressurized with hydrogen (40 psi), stirred for 16 hours at ambient temperature, filtered to remove catalyst, and concentrated. The residue was chromatographed on silica gel eluting with 30% ethyl acetate-hexanes to give the title compound (90 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (dd, J=1.5, 4.6, 1H), 7.91 (dd, J=1.5, 8.0, 1H), 7.36 (dd, J=4.6, 8.0, 1H), 2.96-2.77 (m, 2H), 2.26 (dd, J=5.4, 8.1, 4H), 2.03-1.84 (m, 2H), 1.46 (s, 3H). MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14](O)=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18].S(Cl)([Cl:23])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14]([Cl:23])=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2

Procedure:
To a solution composed of 3.34 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.87 ml of thionyl chloride, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.56 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16](C3C=CC=CC=3)[CH2:15][C:14]3=[N:23][NH:24][CH:25]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26]1([CH2:32]C2CC(=O)CCN2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:32]([CH:16]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][C:13]2[CH:25]=[N:24][NH:23][C:14]=2[CH2:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2c[nH]nc2CC1c1ccccc1
Reactant: O=C1CCNC(Cc2ccccc2)C1
Product: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1Cc1ccccc1

Procedure:
Prepared as described for compound 55 in Example 1 using 2-(phenylmethyl)-4-piperidinone.