Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(C[O:15][C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[F:56][C:57]1[CH:82]=[CH:81][C:60]([CH2:61][O:62][C:63]2[CH:64]=[C:65]([CH:69]=[CH:70][C:71]=2[O:72][CH2:73][C:74]2[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=2)C(O)=O)=[CH:59][CH:58]=1>>[F:56][C:57]1[CH:82]=[CH:81][C:60]([CH2:61][O:62][C:63]2[CH:64]=[C:65]([CH:69]=[CH:70][C:71]=2[O:72][CH2:73][C:74]2[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=2)[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=2)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:59][CH:58]=1
Reactant: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(OCc2ccc(F)cc2)c1
Product: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc(OCc3ccc(F)cc3)c(OCc3ccc(F)cc3)c2)cc1O

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-3-hydroxy-4-methoxyaniline (642 mg, 0.9 mmol, example 109, step A) as described for example 109 (step B) using 3,4-di-(4-fluorobenzyloxy)benzoic acid (485 mg, 1.3 mmol) instead of N-(4-fluorobenzyl)indole-2-carboxylic acid. The crude material was purified by flash chromatography using successively 5%, 10% and 30% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as white crystals (260 mg, 34%).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:24])[CH:13]([N:21]=[N+]=[N-])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C.C(OC)(=O)C.[Re]([O-])(=O)(=O)=O.[Na+]>[CH3:10][O:11][C:12](=[O:24])[C:13]([N:21]=[C:2]=[O:1])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(Cc1ccccc1)N=[N+]=[N-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=[Re](=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)=O
Product: COC(=O)C(=Cc1ccccc1)N=C=O

Procedure:
27.3 mg (0.1 mmole) of sodium perrhenate and 1.04 grams (5.25 mmoles) of diphosgene were present at 80° C. in 1 ml of ethyl acetate saturated with hydrogen chloride. Then there were added within 20 minutes with vigorous stirring 2.05 grams (10 mmoles) of 2-azido-3-phenylpropionic acid methyl ester dissolved in 5 ml of methyl acetate. After reaction for 1 hour at 80° C., the mixture was worked up analogous to Example 1. The crude produce was distilled in a high vacuum (0.0013 mbar) at 90° to 110° C. apparatus temperature in a bulbed tube. There resulted 1.08 grams (53.2% of theory) of analytically pure 2-isocyanato-3-phenylpropenoic acid methyl ester.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
n-Butyllithium (16.5 mL of a 2.5 M hexanes solution, 41.2 mmol)was added to a 0° C. solution of diisopropylamine (5.4 mL, 41.3 mmol) in THF (40 mL). After stirring for 5 minutes, tributyltin hydride (10 g, 34.4 mmol) was added. After stirring for 15 minutes at 0° C., the reaction mixture was cooled to −78° C. and 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added dropwise. After stirring for an additional hour, the cold reaction mixture was quenched with dilute ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4), filtered and concentrated to afford a colorless liquid, 2-methylallyl tributyltin (11.6 g, 98%) which was used without purification for the next step.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11]C)=[O:6])(=O)C.C(Cl)(=O)OCO[C:40](=O)[CH2:41]CC>ClCCl>[O:33]=[S:30]1(=[O:34])[CH2:29][CH2:28][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH2:40][CH3:41])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:32][CH2:31]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Reactant: CCCC(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CCCC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 73 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (492.7 mg, 1.44 mmol) in dichloromethane (13 mL) and butyroyloxymethyl carbonochloridate (7e) gave the titled product in 73% yield (512.1 mg, 1.05 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.29 (t, 1H), 4.80 (sept, 1H), 4.05 (t, 1H), 3.79 (dd, 1H), 3.67 (ddd, 1H), 3.56 (dt, 1H), 3.13-3.19 (m, 4H), 3.09 (dt, 1H), 2.35-2.47 (m, 2H), 2.31 (t, 2H), 2.14-2.22 (m, 2H), 1.63 (q, 2H), 0.93 (t, 3H). MS-APCI (m/z+): 487 (M+H).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45](O)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:46]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]2[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:7])=[O:6])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 79.2 %

Procedure:
To a solution of N-isopropyl-1-benzenesulfonylindole-2-sulfonamide (10.0 g, 26.42 mmol), triphenylphosphine (10.4 g, 39.63 mmol), and benzhydrol (7.30 g, 39.63 mmol) in 100 ml of tetrahydrofuran was dropwise added a solution of diethyl azodicarboxylate (6.24 ml, 39.63 mmol) in 100 ml of tetrahydrofuran with stirring, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 34.5 g of a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=1/9) followed by crystallization from ethanol to give 11.4 g (yield: 79%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1CCO[Si](C)(C)C(C)(C)C
Yield: 59.6 %

Procedure:
A solution of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a (1.08 g, 3.8 mmol) in anhydrous DMF (10 mL) was treated with 60% dispersion of NaH in mineral oil (0.17 g, 4.3 mmol) while stirring under nitrogen. After effervescence the reaction was stirred for an additional 30 min. At this time the reaction was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (15-1) (0.908 g, 3.8 mmol) and continued to stir under nitrogen for 10 hours. After reaction water (50 mL) was added slowly and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate to afford 161a (1 g, 35%), which was used directly without further purification. LCMS: (M+H)+ 443.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]#[C:6][CH3:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:28]([S:35]/[C:36](/I)=[CH:37]\[CH:38]=[C:39](/[S:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)\[C:40]#[C:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N(CC)CC>O.C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:47]([S:46]/[C:39](=[CH:38]\[CH:37]=[C:36](/[S:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[C:3]#[C:4][C:5]#[C:6][CH3:7])/[C:40]#[C:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: C[Si](C)(C)C#C/C(=C/C=C(/I)SCc1ccccc1)SCc1ccccc1
Reactant: CC#CC#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCNCC
Product: CC#CC#C/C(=C/C=C(/C#C[Si](C)(C)C)SCc1ccccc1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a DMF (5 mL) solution of 1-trimethylsilyl-1,3-pentadiyne (0.4 g, 2.94 mmol) under argon was added TBAF (0.8 g, 3 mmol) and several drops of water. The dark brown solution was stirred for 2 h at room temperature, then diluted with benzene (3 mL). The benzene layer was washed with saturated brine (5×5 mL). After drying (MgSO4) and filtering, the solution was transferred to a flask containing 8 (500 mg, 0.96 mmol), (Ph3P)2PdCl2 (34 mg, 0.048 mmol), CuI (9 mg, 0.048 mmol) and Et2NH (1 mL). The mixture was stirred under argon at room temperature for 40 h, and then concentrated in vacuo. Ether (100 mL) and water (25 mL) were added, the layers were separated, the ether layer was washed with brine (3×20 mL), dried (MgSO4), concentrated in vacuo and the residue purified by flash column chromatography (1:6 CH2Cl2 :hexanes) giving 9 as a yellow oil (0.25 g, 57% yield): 1H NMR δ 7.15-7.3 (m, 10 H), 6.99 (d, J=11.7 Hz, 1 H), 6.90 (d, J=11.7 Hz, 1 H), 4.09 (s, 2 H), 4.06 (s, 2 H), 1.98 (s, 3 H), 0.20 (s, 9 H); 13C NMR δ 120-138 (several), 102.32 102.09, 84.37, 80.86, 72.45, 64.35, 37.36, 37.27, 4.82, -0.200.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 37.3 %

Procedure:
Following the procedure in Example 283b, and starting with 293c (150 mg, 0.53 mmol, 1.0 eq.) and {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (629 mg, 1.59 mmol, 3.0 eq.) afforded 293d as a yellow solid (110 mg, 37%). MS-ESI: [M+H]+ 557.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:38]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.1 g. (6 mmoles) of 4,5-bis-(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 1.3 g. (12 mmoles) of potassium tert-butoxide in 60 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 1.7 g. of benzoyl chloride in 15 ml. of toluene was then added and the reaction mixture stirred overnight at room temperature. The mixture was diluted with methylene chloride, which was washed with 10% aqueous sodium bicarbonate solution, dried and evaporated. The residue was purified by chromatography on Fisher 100-200 mesh silica gel (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to afford 1.8 g. of colorless crystals, m.p. 105.5°-106° C.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[N:21]O)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH4+].[Cl-]>CCO.[Zn]>[S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=NO)cccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Yield: 99.9 %

Procedure:
To a solution of 44 (620 mg, 2 mmol) in EtOH (15 mL) was added zinc powder (320 mg, 5.0 mmol) and NH4Cl (0.53 g, 10 mmol). The reaction mixture was heated at reflux overnight, filtered and the filtrate was concentrated to dryness. The residue was diluted with DCM (100 mL) and water (20 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford 600 mg (100%) of (1-tosyl-1H-indol-4-yl)methanamine (46) as yellow syrup: MS (ESI) m/z=284.1 [M−15]+.
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:34]([O:36]CC[Si](C)(C)C)=[O:35])[CH2:13][C:14]1[CH:33]=[CH:32][CH:31]=[CH:30][C:15]=1[CH2:16][NH:17][CH:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:34]([CH:12]([N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1])[CH2:13][C:14]1[CH:33]=[CH:32][CH:31]=[CH:30][C:15]=1[CH2:16][NH:17][CH:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])([OH:36])=[O:35]
Reactant: CC(C)CC(NCc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)CC(NCc1ccccc1CC(C(=O)O)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 102.2 %

Procedure:
Dissolve 2-{2-[2-(1,3-dioxo-1,3,dihydro-isoindol-2-yl)-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl]-benzylamino}-4-methyl-valeric acid, tert-butyl ester (221 mg, 0.372 mmol) in tetrahydrofuran (5 mL) and treat with tetrabutylammonium fluoride (0.43 mL of a 1.0M solution in tetrahydrofuran, 0.43 mmol). Stir for 1.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (75 mL). Wash with 1N hydrochloric acid (25 mL) and brine (25 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give the title compound as a white solid (188 mg).
Reaction SMILES: [Cl-].CO[NH3+].[CH3:5][O:6][N:7](C)[C:8]([C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[S:13][CH:14]=1)=O.O.[CH2:30](O)[CH3:31]>>[CH:30]1([CH2:31][C:8]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:13][CH:14]=2)=[N:7][O:6][CH3:5])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1
Reactant: CCO
Reactant: CON(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CO[NH3+]
Agent: [Cl-]
Solvent: O
Product: CON=C(CC1CCCCC1)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
At room temperature, methoxyammonium chloride (171 mg) was added to a solution of tert-butyl 4-{4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (403 mg) in ethanol (2 ml). The reaction mixture was stirred at 50° C. for 24 hours, and water was then added. The aqueous phase was separated off and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-[4-(2-cyclohexyl-N-methoxyethanimidoyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (361 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:47].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[F:47])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(F)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a slurry of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (82 mg, 0.132 mmol, 1 equiv) in acetonitrile (2.6 mL) was added Selectfluor (56 mg, 0.159 mmol, 1.2 equiv). After stirring 18 h, reaction is an orange slurry. LCMS indicated ˜50% conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a yellow solid (22 mg, 26% yield). 1H NMR (500 MHz, CDCl3) δ 7.20-7.16 (m, 1H), 7.15-7.10 (m, 1H), 7.04-6.99 (m, 1H), 6.99-6.94 (m, 1H), 6.87-6.81 (m, 1H), 4.95 (s, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.35 (br. s., 2H), 4.19-4.11 (m, 2H), 2.80 (s, 3H), 2.78-2.73 (m, 2H), 2.27 (s, 3H), 2.18 (br. s., 2H), 1.81 (s, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) d−119.41 (s, 1F), −139.50 (s, 1F), −175.35 (s, 1F); LCMS (ESI, M+1): 639.5.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5]C.C1(C#C)C=CC=CC=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#N>C(#N)C1C=CC=CC=1>[C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccco1
Reactant: C#CCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCC#Cc1ccco1
Reaction time: 4 h
Yield: 69 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 4 h at 65° C. showed the presence of 1.38 mmol (69% yield) of 2-(1-hexynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [CH2:1]([N:3]([CH3:7])[C:4]([NH2:6])=[O:5])[CH3:2].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([N:3]([CH3:7])[C:4]([NH:6][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])=[O:5])[CH3:2]
Reactant: CCN(C)C(N)=O
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: CCN(C)C(=O)NC(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 65.1 %

Procedure:
In 50 ml of anhydrous dioxane, 7.7 g (0.075 mole) of 1-ethyl-1-methyl-urea was dissolved, into this solution 8.9 g (0.075 mole) of phenylisocyanate was added dropwise under stirring condition. The reaction was continued at a room temperature for 15 hours, then the precipitate thus formed was obtained by filtration and recrystallized from ethanol to obtain 10.8 g (yield 65%) of 1-ethyl-1-methyl-5-phenylbiuret having a melting point of 157°-159° C.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[C:24]([O:26]CC)=[O:25])[CH2:10][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:7].[OH-].[Na+]>C(O)C>[F:44][C:41]([F:42])([F:43])[C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:46])[F:45])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[C:24]([OH:26])=[O:25])[CH2:10][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: CCOC(=O)[C@@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine (0.42 g) in ethanol (30 ml) was added 1N sodium hydroxide solution (30 ml) and the whole was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residual aqueous solution was neutralized with conc. hydrochloric acid. The solution was extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.26 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.ClCCl>O>[CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 88.6 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (2 g) prepared in the Examples 1-3, triethylamine (1.1 g), p-toluenesulfonylchloride (1.9 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 1 hour. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionic acid methylester (3.0 g, yield 91%).