Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:48])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:21]([NH:36][C:37](=[O:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:20]=3[N+:45]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:45][C:20]1[C:21]([NH:36][C:37](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:24][C:19]=1[C:18]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:48]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(OCCCCc3ccccc3)c(NC(=O)c3ccccc3)c2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)c2ccc(OCCCCc3ccccc3)c(NC(=O)c3ccccc3)c2N)nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-(2-nitro-4-phenylbutoxybenzoylaminobenzoyl)-1,2,3-triazole-5-carboxylate (b-1) (529.5mg, 0.78 mmol) prepared in the step (b) was dissolved in ethanol (8 ml) and ethyl acetate (2 ml), 10% palladium on carbon (53 mg) was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for two days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resultant precipitate was collected by filtration to give ethyl 4-(2-amino-4-phenylbutoxybenzoylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (c-1) as a yellow oil (484.4 mg, 96%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([CH3:14])[O:11][CH2:12][CH3:13].C(O)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:14])([CH3:9])[O:11][CH2:12][CH3:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](C)C
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCO[Si](C)(C)CCc1ccccc1
Temperature: 41 °C
Yield: 74.5 %

Procedure:
312 mg Of styrene and 312 mg of dimethylethoxysilane were placed in a glass reaction tube and 0.006 ml of acetic acid was added. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 41° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 80% and phenethyldimethylethoxysilane was produced at a yield of 74.5%. The yield of (α-methylbenzyl) dimethylethoxysilane was 5.5%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40].[NH2:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[CH:33]=[CH:34][C:35]=3[CH3:36])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-phenylethyl)benzamide (156 mg, 0.28 mmol) in dichloromethane (11 mL) was added 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (75 μL, 0.42 mmol) and triethylamine (78.7 μL, 0.56 mmol). The reaction mixture was stirred at room temperature for 16 hours then applied to the flash chromatograph to afford the titled compound 147 mg (79%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1

Procedure:
According to the method of V. P. Chernetskii, A. I. Kiprianov, Zh. Obsch. Khim, 1956, 26, 3465, a mixture of 2-fluoronitrobenzene (14.0 g, 100 mmol), p-iodo aniline (10.95 g, 50 mmol) and triethylamine (13.9 ml, 100 mmol) was heated under reflux for 42 hours. The mixture was cooled, diluted with ethyl acetate (300 ml) washed consecutively with water (100 ml), 2N sodium hydroxide (100 ml) and brine (100 ml). The organic layer was dried (MgSO4), concentrated under reduced pressure and the residue was recrystallised from ethyl acetate to give N-(4-iodophenyl)-2-nitroaniline, 10.03 g, as bright orange needles, m.p. 171°-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate with ruthenium dioxide to give 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone of melting point 147.5°-148.5° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.CI.Cl>C1COCC1>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2ccccc2-c2ccccc21
Temperature: -70 °C
Yield: 67.6 %

Procedure:
A mixture of fluorene (78.3 g) and THF (700 mL) was cooled down to −70° C., and n-BuLi (300 mL, corresponding to 0.48 mol) was dropwise added thereto while maintaining −60° C. or lower. Then, methyl iodide (66.8 g) was added, and the temperature was allowed to slowly go back to a room temperature. The mixture was cooled again down to 0° C. to add 3M-hydrochloric acid (300 mL), and the reaction mixture was extracted with toluene. The organic layer obtained was washed well in order with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the residue was purified by means of column chromatography (silica gel, eluting solvent: toluene/heptane [40/60]) and recrystallization (ethanol) to obtain 9-methylfluorene (57.4 g) of pale yellow crystal. Melting point: 47.3-48.8° C.
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[C:73]([CH2:78][O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH:72]=1)[OH:70].[CH3:87][O:88][C:89]1[CH:90]=[C:91]([NH:95][C:96]2[C:105]3[C:100](=[C:101]([CH3:130])[CH:102]=[C:103]([S:106]([C:109]4[CH:114]=[CH:113][CH:112]=[C:111]([C:115](=[O:129])[NH:116][C:117]5[CH:122]=[CH:121][C:120]([CH2:123][CH2:124][CH2:125][CH2:126][CH:127]=O)=[CH:119][CH:118]=5)[CH:110]=4)(=[O:108])=[O:107])[CH:104]=3)[N:99]=[CH:98][C:97]=2[C:131]([NH2:133])=[O:132])[CH:92]=[CH:93][CH:94]=1>>[Si:80]([O:79][CH2:78][C:73]1[CH:72]=[C:71]([C@@H:69]([OH:70])[CH2:68][NH:67][CH2:127][CH2:126][CH2:125][CH2:124][CH2:123][C:120]2[CH:121]=[CH:122][C:117]([NH:116][C:115]([C:111]3[CH:110]=[C:109]([S:106]([C:103]4[CH:104]=[C:105]5[C:100](=[C:101]([CH3:130])[CH:102]=4)[N:99]=[CH:98][C:97]([C:131]([NH2:133])=[O:132])=[C:96]5[NH:95][C:91]4[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH3:87])[CH:90]=4)(=[O:107])=[O:108])[CH:114]=[CH:113][CH:112]=3)=[O:129])=[CH:118][CH:119]=2)[CH:76]=[CH:75][C:74]=1[OH:77])([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:81])[CH3:82]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN)ccc1O
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCC=O)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCCNC[C@H](O)c6ccc(O)c(CO[Si](C)(C)C(C)(C)C)c6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using Intermediate 9 in place of Intermediate 2 and Intermediate 120 in place of Intermediate 112. ES/MS calcd. for C51H62N5O8SSi+ 932.40. Found m/z=932.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 90.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e obtained from step 4 of Example 3 as starting materials to obtain (Z)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-o ne 55 (77 mg, yield 90.8%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:36])[N:21]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:32](=[O:33])[CH:31]=[CH:30][C:29]3=[O:34])=[CH:24][CH:23]=2)[C:20](=[O:35])[CH:19]=[CH:18]1>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:30]2[CH2:31][C:32](=[O:33])[N:28]([C:25]3[CH:26]=[CH:27][C:22]([N:21]4[C:20](=[O:35])[CH2:19][CH:18]([S:11][C:9]5[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=5)[C:17]4=[O:36])=[CH:23][CH:24]=3)[C:29]2=[O:34])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)N1c1ccc(N2C(=O)C=CC2=O)cc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(c3ccc(N4C(=O)CC(Sc5cc(C(C)(C)C)c(O)c(C(C)(C)C)c5)C4=O)cc3)C2=O)cc(C(C)(C)C)c1O
Yield: 75.6 %

Procedure:
The procedure of Example 1 is repeated using 17.8 grams of 2,6-di-tert-butyl-4-mercaptophenol, 10 grams of 1,4-bis(maleimido)benzene, and 0.75 grams of triethylamine. The residue is recrystallized from acetone to give 21 grams of an off-white solid, m.p. 274°-278° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:18]([O-])([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19].CCN(CC)CC>C1(C)C=CC=CC=1.[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:18](=[O:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:3][CH:4]=1
Reactant: CCOP(=O)([O-])OCC
Reactant: COc1ccc(C(N)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a mixture of (4-bromophenyl)(4-methoxyphenyl)methanamine, 1-1-c, (2 g, 6.8 mmol), diethyl phosphate (1.1 g, 8.2 mmol) and Et3N (1.3 g, 10.2 mmol) in toluene (25 ml) was added Pd(PPh3)4 (1.5 g, 20%). The mixture was allowed to stir for two days at 100° C. The mixture was then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified over silica gel (5% MeOH/DCM) to obtain as an oil, 1-1-d, (1.00 g). 1HNMR (300 MHZ, DMSO-d): 1.29 (m, 6H), 3.77 (s, 3H), 4.10 (m, 4H), 5.19 (s, 1H), 6.82 (d, 2H), 7.26 (d, 2H), 7.48 (d, 2H), 7.74 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10](O)[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:44]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([F:44])[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: F[C@@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
After dissolving (R)-1-benzyloxy-3-trityloxypropan-2-ol (CAS 83526-68-5) (10.45 g) in toluene (50 ml), nonafluoro-1-butanesulfonyl fluoride (7.95 ml) was added and the mixture was cooled on ice. Next, 1,8-diazabicyclo[5.4.0]undeca-7-ene (6.63 ml) was added dropwise while stirring. The mixture was stirred for 30 minutes on ice, and then for 3 hours and 30 minutes at room temperature. The reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (7.52 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15]
Reactant: OCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 3,3,3-trifluoropropan-1-ol (61.8 ml) and pyridine (224 ml). Cool to between 0° C. and 10° C. and add portion-wise p-toluenesulfonylchloride (147 g). Allow to warm to ambient temperature and stir overnight. Add HCl 0.5N (1.6 L), extract with ethyl acetate, combine the organic layers, dry over MgSO4, filter, and evaporate to give the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].[CH3:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[C:7]([CH2:8][OH:10])[CH:11]=[CH:12][CH:13]=2)(=[O:3])=[O:4])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC1CCNCC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)c2cccc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11 g (50 mmol) of 3-chlorosulphonylbenzoic acid in suspension in dichloromethane (300 ml) is treated with 12.4 g (125 mmol) of 4-methylpiperidine and the reaction mixture is maintained under stirring at ambient temperature overnight. The resulting solution is washed successively with a 10% aqueous solution of citric acid and a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure in order to produce a colourless viscous residue. The latter is taken up in methanol and, whilst maintaining the temperature between 0° C. and 10° C., is titrated by trimethylsilyldiazomethane until a characteristic yellow coloration persists. The excess reagent is destroyed with a few drops of formic acid, and the reaction medium is concentrated under reduced pressure. The traces of acid and methanol are eliminated by two azeotropic evaporations under reduced pressure with toluene. The residue, taken up in tetrahydrofuran (300 ml), is treated with lithium borohydride (2N in THF, 30 ml). The reaction medium is taken to reflux for 2 hours then cooled down and hydrolyzed with a saturated solution of ammonium chloride. The resulting mixture is extracted with ethyl acetate then the organic phase is washed with a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure. The residue is purified on a silica column (eluent: 5% acetone in dichloromethane) in order to produce the expected benzyl alcohol in the form of a white solid.
Reaction SMILES: C(O[CH2:10][C@@H:11]([O:30]S(C)(=O)=O)[C@@H:12]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O.O>[F:20][C:18]1[CH:19]=[C:14]([CH2:13][C@H:12]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:11]2[CH2:10][O:30]2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H](COC(=O)c1ccccc1)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1

Procedure:
Mesylate 30 was dissolved in methanol/water at 0° and a solution of sodium hydroxide in water was added. After all of the starting material was consumed, the reaction was extracted and the residue purified using silica gel chromatography to obtain epoxide 31 as a white solid, m.p.=99°.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=O)=CC=1)([O-])=O.[CH3:43][O:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH3:43][O:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[O:31][C:32]=4[C:33]([F:35])([F:34])[F:36])=[O:27])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[O:10])[CH2:51][CH2:52]1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a mixture of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester (150 mg, 0.26 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) at room temperature was added piperidin-4-yl-acetic acid methyl ester (0.04 g, 0.25 mmol) followed by N,N-diisopropylethylamine (0.14 mL, 0.8 mmol). The mixture was stirred in a 90° C. oil bath overnight. The mixture was blown to dryness and the crude was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution with 0%-60% ethyl acetate in hexane) to give [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid methyl ester (70 mg). LCMS calcd for C31H33F3N4O5 (m/e) 598, obsd 599 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:17][NH:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Temperature: 20 °C
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (9.45 g, 50 mmol), 1-cyclopropylmethanamine (5.0 g, 70 mmol), and potassium carbonate (10 g) was stirred for 12 h in acetonitrile (50 mL) at 55° C. The mixture was cooled to 20° C., filtered, and the filter-cake was washed with acetonitrile (3×25 mL). The filtrate was concentrated under vacuum to obtain 11.9 g (99%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.6, 2.4 Hz, 1H), 4.62 (bs, 1H), 3.02 (d, J=7.1 Hz, 2H), 1.09 (m, 1H), 0.61 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14](O)=[O:15].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14]([Cl:24])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid (270 mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.16 mL, 1.88 mmol), followed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction mixture was stirred at room temperature for 2 hours. After the mixture was concentrated in vacuo, the residue was diluted with dichloromethane and concentrated in vacuo again to afford 280 mg of the product (yield was 90%), which was used for next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[Cl:1]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]nc(Cl)c2c1

Procedure:
1.00 g (5.06 mmol) of 3-chloro-5-nitro-1H-indazole was suspended in 50 ml of ethanol, and 5.71 g (25.3 mmol) of tin(II) chloride dihydrate were added. The mixture was left to stir at reflux overnight, saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed under reduced pressure. The mixture was triturated with tert-butyl methyl ether and the solid was filtered off with suction. Yield: 544 mg (purity 90%, 58% of theory)