Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br.O>CC(OC)(C)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: O=C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Valerolactam (60 g) was dissolved in MTBE (1.5 L) at room temperature. To this solution was added Bu4NSO4 (4.9 g) as a phase transfer catalyst. The cloudy solution was stirred at room temperature for 5 minutes. Then, NaOH (50 wt %; 300 mL) was slowly added as to keep the internal temperature below 30° C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) was then added slowly to this biphasic mixture, again as to keep the internal temperature under control. The reaction was then aged for 4 hours at room temperature. At this time LC showed the reaction to be complete. Water (500 mL) was then added. After phase cut, the organic layer was washed with brine (300 mL), dried under MgSO4 followed by solvent switch to heptane (400 mL). The slurry obtained was stirred at room temperature. for 1 hour and then filtered to afford the title product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:18])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[ClH:19].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:18][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Oc1ccc(Cl)cc1
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccc(OC(Cn2ccnc2)c2ccc3ccccc3c2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1.00 g of 1-[2-(2-naphthyl)-2-hydroxyethyl]imidazole, 0.81 g of p-chlorophenol and 0.92 g of diethyl azodicarboxylate in 20 ml. of dry tetrahydrofuran at room temperature was added 1.65 g of triphenylphosphine (with stirring). The resulting yellow solution was stirred overnight, the solvent evaporated and the residual oil dissolved in ether. The hydrochloride salt of the product was precipitated as a gum by dropwise addition of ethereal hydrogen chloride, and crystallized from ethyl acetate to give 1[2-(2-naphthyl)-2-(4-chlorophenoxy)ethyl]imidazole hydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2N1
Product: CC(=O)N1C(=O)Cc2ccccc21
Yield: 93.7 %

Procedure:
Indoline-2-one (6.65 g, 50 mmol) and acetic anhydride (9 mL) were heated at reflux for 15 h. After cooling, the product was filtered and rinsed with Et2O to give 2a as solids after vacuum drying (8.2 g, yield: 93.7 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.Br[CH2:37][CH2:38][N:39]1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)C(C2C=C(Cl)C=CC=2OC(F)F)=N1.N1C=CC(CN)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:42]=[CH:43][N:39]=[CH:38][CH:37]=3)[N:9]=2)[CH:7]=1
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: NCc1ccncc1
Product: O=C(Nc1cn(CCNCc2ccncc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and pyridin-4-ylmethanamine. LCMS (Method 25) [M+H]+=539.1, RT=1.45 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.4 Hz), 8.45 (d, 2H, J=6.0 Hz), 8.38 (s, 1H), 7.64-7.59 (m, 2H), 7.44 (d, 1H, J=8.8 Hz), 7.32-7.28 (m, 3H), 7.07 (t, 1H, J=73.2 Hz), 4.26 (t, 2H, J=6.0 Hz), 3.76 (s, 2H), 2.93 (t, 2H, J=6.0 Hz).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[S:3])[NH2:2].Br[CH:25]([CH2:35][CH3:36])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][C:25]([CH2:35][CH3:36])=[C:26]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[N:2]=3)[CH2:5][C@H:6]2[O:21][CH2:22][CH3:23])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCO[C@@H]1CN(C(N)=S)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1CC
Yield: 89 %

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-ethoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained in Example (76b) (104 mg, 0.29 mmol) and butyl 3-bromo-2-oxopentanoate obtained by the method described in Example (110a) (113 mg, 0.45 mmol), to obtain 132.1 mg of the title compound (89%).
Reaction SMILES: [NH:1]([C:14]([O:16]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.[F:39][C:40]([F:52])([F:51])[S:41]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>>[F:39][C:40]([F:52])([F:51])[C:11]([OH:13])=[O:12].[OH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@H:2]2[N:1]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[C:14](=[O:16])[N:48]([C:47]3[CH:49]=[CH:50][C:44]([S:41]([C:40]([F:52])([F:39])[F:51])(=[O:43])=[O:42])=[CH:45][CH:46]=3)[C:11]2=[O:13])=[CH:9][CH:8]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=Cc1ccncc1
Product: O=C(O)C(F)(F)F
Product: O=C1[C@@H](Cc2ccc(O)cc2)N(Cc2ccncc2)C(=O)N1c1ccc(S(=O)(=O)C(F)(F)F)cc1
Yield: 1.8 %

Procedure:
The compound is prepared from 0.05 mmol of resin, 0.15 mmol of N-Fmoc-D-Tyr(OH), 0.25 mmol of 4-pyridinecarboxaldehyde and 0.125 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 0.7 mg of expected product is obtained.
Reaction SMILES: ClS([C:5]1[C:6]([Cl:15])=[C:7]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(N)CCC>C1(C)C=CC=CC=1.Cl>[Cl:14][C:11]1[CH:12]=[CH:13][CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: O=C(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Part B: 3-(Chlorosulfonyl)-2,6-dichlorobenzoic acid (1.5 g; 5.2 mmol) was dissolved in anhydrous toluene (35 ml) to which was added powdered K2CO3 (1.44 g: 10.4 mmol) and n-butylamine (1.0 ml, 10.4 mmol). The reaction mixture was stirred at 25° C. for 12 hours. The solution was diluted slowly with 1 M ethereal HCl (20 ml) and was then stirred for 30 minutes. The solution was filtered and the resulting filtrate was evaporated to dryness to give crude product. Further purification of the material by silica gel chromatography using EtOAc as the eluent provided 3-N-butylsulfonamidoyl)-2,6-dichlorobenzoic acid (Formula 3) (1.43 g, 85%. 1H NMR (DMSO) d 8.11 (t, 1H), 7.98 and 7.71 (doublets, 1H each), 2.75 (m, 2H), 1.55 (m, 2H), 1.32 (m 2H), 0.87 (t, 3H)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])(=[O:31])=[O:30])[CH2:8]1)=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Reaction time: 14 h
Yield: 86.4 %

Procedure:
To a solution of 3.87 g piperidine-3-carboxylic acid ethyl ester hydrochloride (commercially available) (20 mmol) in 40 mL DCM was added 10 mL of DIPEA (60 mmol). At room temperature 2.72 mL 2-chloro-benzenesulfonyl chloride (20 mmol) was added drop wise and stirred for 14 h. The mixture was diluted with 30 mL of DCM, washed with water (3×50 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography on silica eluting with 10% ethyl acetate in hexane to yield 5.73 g (86.3%) of the title compound. (MH+) 332.16.
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C1(C)C(C)=CC=CC=1>[C:1]1([S:7][CH:8]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CSc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(Sc2ccccc2)C1(C)C
Reaction time: 1 h

Procedure:
Alternately, when no catalyst is used, the reaction is carried out at a higher temperature (approx. 150° ) for thermal decomposition. Xylene is heated to reflux and a mixture of 2-methyl-1-propenyl phenyl sulfide and ethyl diazoacetate is added dropwise over 2 hr. Reflux is continued an additional 1 hr or until nitrogen evolution has ceased. The reaction is then filtered, dried and solvent is removed, giving ethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:24])[CH2:20][CH2:21]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-{[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (40 mg, 0.12 mmol) was added 1-[2-(trifluoromethyl)phenyl]methanamine (22 mg, 0.12 mmol), EDCl (24 mg, 0.12 mmol), HOBt (17 mgs, 0.12 mmol), and N-methylmorpholine (13 mg, 0.12 mmol). The mixture was stirred at rt for 20 h. The solvent was removed under vacuum, and the resulting residue was purified by HPLC to provide 20 mg (34% yield) of the desired material. MS (ES+): m/e 485.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH3:18]>>[NH2:18][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: N
Product: Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 200 °C

Procedure:
A 12.5 g sample of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine was placed in a steel cylinder with liquid ammonia and the sealed cylinder (bomb) was heated at 200° C. The chilled cylinder was opened and the ammonia allowed to evaporate. The solid residue was heated and stirred with chloroform, then filtered. The filtrate was concentrated and the residue recrystallized, first from chloroform-hexane, then twice from chloroform to give 1.8 g of 3-amino-6-[3-(trifluoromethyl)phenyl]pyridazine as white crystals, mp 143°-145° C.
Reaction SMILES: FC(F)(F)C1C=C(NC(N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@@H]2CC3CCN2CC3)=O)C=C(C(F)(F)F)C=1.C=CC.[N+:43]([CH3:46])([O-:45])=[O:44].[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])/[CH:60]=[C:61](\[C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)/[C:62]([F:65])([F:64])[F:63])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]>O>[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])[CH2:60][C@@:61]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)([CH2:46][N+:43]([O-:45])=[O:44])[C:62]([F:64])([F:63])[F:65])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: COc1ccc2nccc([C@H](NC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]3CC4CCN3CC4)c2c1
Solvent: C=CC
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Alternatively, to a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(S)-(6-methoxy-4-quinolyl)-[(2S)-quinuclidin-2-yl]methyl]urea; prop-1-ene (09 mg, prepared according to the literature: Organic Letters 2007, 9, (14), 2621-2624) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 3 days at 50° C. then allowed to stand at room temperature for 2 days. Water was then added and the resulting mixture was extracted with diethyl ether and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.43 minutes (major enantiomer), 7.78 minutes (minor enantiomer) indicated that the reaction proceeded with 95% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:28]1[NH:33][C:32](=[O:34])[N:31]([CH:35]([CH3:37])[CH3:36])[C:30](=[O:38])[CH:29]=1>CN1C(=O)CCC1.CS(C)=O>[CH:35]([N:31]1[C:30](=[O:38])[CH:29]=[C:28]([NH:10][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:9])[NH:33][C:32]1=[O:34])([CH3:37])[CH3:36]
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Reactant: Cc1ccccc1[C@H](C)N
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1ccccc1[C@H](C)Nc1cc(=O)n(C(C)C)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50 equiv) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol, 1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath, cooled to room temperature, and then diluted with DMSO (2 mL). The solids were filtered and the filtrate was purified by Flash-Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: H2O/0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min. This afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions: Column, Chiralpak IC, 2*25 cm, Sum; mobile phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of the title compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): δ ppm 9.76 (br s, 1H), 7.28 (d, J=7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d, J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J=6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([O:35]C)=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([OH:35])=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1
Reactant: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(C(=O)O)c4)c3)c2)n(C)n1
Yield: 66.2 %

Procedure:
A 50 ml THF solution of methyl 3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoate (228 mg, 0.41 mmol) and 0.5M NaOH (6.6 ml, 3.28 mmol) was stirred at room temperature for 3 hours. The reaction was quenched with acetic acid (0.188 ml, 3.28 mmol) and rotary evaporated to remove the THF solvent. The aqueous solution was partitioned between EtOAc and dilute HCl/brine mixture, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to white solid foam. The solid was combined with impure product from another lot (14 mg) and recrystallized from EtOAc/hexane to give the title compound as a white solid (147 mg, 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][O:16][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Br:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Cc1cccc(Br)c1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(Br)c1OCC[C@H]1CN(Cc2ccccc2)CCN1
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.5 g, 6.8 mmol), 2-bromo-6-methylphenol (1.4 g, 7.5 mmol), di-tert-butyl azodicarboxylate (DBAD, 2.4 g, 10.2 mmol), polymer supported-triphenylphosphine (3.8 g, 13.6 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)c2OC
Yield: 34.2 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (163 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (156 mgs) were combined to give the title compound as off-white solid (101 mgs) 1H-NMR (CDCl3, 400 MHz): 9.67 (s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.69 (t, J=8.1 Hz, 1H), 7.60-7.58 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 4.49-4.43 (m, 1H), 4.40-4.31 (m, 1H), 3.87 (s, 3H), 3.59-3.52 (m, 1H), 3.31-3.28 (m, 1H), 3.18-3.13 (m, 1H), 2.80-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.06-1.99 (m, 1H), 1.37-1.33 (m, 6H), 1.22 (t, J=6.1 Hz, 3H), LC/MS: found (M+H)+=655.57; MP:245-247° C.
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CC(C(F)(F)F)CC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=CC=1)#N.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][CH:69]=3)[CH2:63][C:62]=2[OH:78])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]>>[C:38]([C:40]1[CH:41]=[CH:42][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[CH:69]=[CH:70][C:71]([C:74]([F:75])([F:76])[F:77])=[CH:72][CH:73]=3)[CH2:63][C:62]=2[O:78][CH2:1][CH3:3])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:44][CH:45]=1)#[N:39]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3ccc(C(F)(F)F)cc3)CC2=O)cc1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-ethoxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 13), using 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)-methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 16, 930 mg, 1.62 mmol) as starting material. Yield: 825 mg; ESI mass spectrum [M+H]+=602, Retention time HPLC: 1.37 min (V011_S01).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1C=NO.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:15]#[N:17])=[CH:8][CH:9]=1)([OH:2])=[O:14]
Reactant: COC(=O)c1ccc(N)cc1C=NO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: N#CNc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In 180 ml of tetrahydrofuran was dissolved 17.12 g of 4-amino(N-hydroxyimino)methylbenzoic acid methyl ester. To the solution was added 12.12 g of triethylamine. To the mixture was added dropwise, on an ice-bath, 12.65 g of methanesulfonyl chloride. The mixture was stirred for one hour under the same conditions, followed by concentration under reduced pressure. To the concentrate was added methanol. The resulting crystalline precipitate was collected by filtration, which was dissolved in 100 ml of methanol. To the solution was added, while stirring at room temperature, 100 g of water containing 12 g of sodium hydroxide. Methanol was distilled off under reduced pressure. To the residue was added 700 ml of water. To the mixture was added, while stirring at room temperature, 80 ml of 4N HCl. The resulting crystalline precipitate was collected by filtration to give 13.12 g of the title compound as a colorless crystalline product.