Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C(C)=CC=CC=1C.[F:24][C:25]([F:52])([F:51])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[C:48](O)=[N:47][CH:46]=[CH:45][N:44]=3)[C@H:37]2[CH3:50])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:48]1[C:43]([CH2:42][N:38]2[C@@H:37]([CH3:50])[C@@H:36]([C:28]3[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=[C:26]([C:25]([F:52])([F:24])[F:51])[CH:27]=3)[O:40][C:39]2=[O:41])=[N:44][CH:45]=[CH:46][N:47]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) mixture of trifluoromethanesulfonic anhydride (0.284 mL, 1.681 mmol), 2,6-lutidine (0.261 mL, 2.241 mmol) and CH2Cl2 (1 mL) was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-hydroxypyrazin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (472 mg, 1.120 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at −78° C. for 30 min then the cold bath was switched to an ice bath. Reaction mixture was stirred cold (0° C.) for additional 2 h. Crude mixture was worked up with water/CH2Cl2/Na2SO4/filtration/concentration to afford an orange oil. This was purified by preparative TLC (silica gel) developed with a EtOAc (30% v/v)/hexanes mixture to give a yellow oil as the titled compound. LCMS calc.=553.04; found=554.02 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:23][C:24](=[N:27][CH3:28])SC)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:23][C:24]([NH:27][CH3:28])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.49 g.) and N-(3.4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.20 g.) in acetonitrile (250 ml.) was heated under reflux for 48 hours. Concentration, followed by chromatographic purification on a column of alumina with sequential elution by benzene-ethylacetate (1:4) and benzene-ethanol (1:4) afforded N-(3,4-dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] guanidine as a glass (1.7 g.)
Reaction SMILES: [C:1](N1C=NC=N1)(N1C=NC=N1)=[O:2].[Br:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]1[N:21]=[C:22]([CH3:28])[N:23]([NH:25][CH:26]=[NH:27])[CH:24]=1>O1CCOCC1.CO>[Br:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]1[N:21]=[C:22]([CH3:28])[N:23]2[C:24]=1[C:1](=[O:2])[NH:27][CH:26]=[N:25]2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1NC=N
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1,1′-Carbonylbis(1H-1,2,4-triazole) (90%, 2.69 g, 14.8 mmol) and N-[4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-yl]imidoformamide (2.69 g, 9.50 mmol) were combined in 1,4-dioxane (63 mL) and the mixture was stirred for 3.5 hours at room temperature, then heated to 50° C. for 1 hour. Additional 1,1′-carbonylbis(1H-1,2,4-triazole) (90%, 1.34 g, 7.35 mmol) was added, and heating was continued for 30 minutes. After another addition of 1,1′-carbonylbis(1H-1,2,4-triazole) (90%, 269 mg, 1.48 mmol), heating at 50° C. was carried out for an additional 75 minutes. The reaction was allowed to cool to room temperature, and was then concentrated to half its original volume; the precipitate was collected and washed with ethyl acetate to afford a white solid. This was dissolved in methanol (50 mL), concentrated to dryness and triturated with water (25 mL). After collection of the solid, it was washed with 2-propanol followed by diethyl ether to provide C3 as a white solid. Yield: 1.95 g, 6.31 mmol, 66%. LCMS m/z 309.4 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.53 (s, 3H), 3.87 (s, 3H), 7.87 (s, 1H), 8.17 (s, 1H), 11.69 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][C:27]1[NH:26][CH:30]=[CH:29][N:28]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (4.18 g, 10.0 mmol) and imidazole (1.5 g, 22.0 mmol) in acetonitrile (200 ml) was stirred at 80° C. for 2 h and overnight at 25° C. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1) graduated to dichloromethane/methanol (1:9). The purified product was washed with water to give 2.0 g (49%) of the title compound. M.p. 187°-189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C[Sn](C)(C)[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=1)[C:26]#[N:27]>[Cu](I)I.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.C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])[CH:7]=1
Reactant: C[Sn](C)(C)c1cncc(C#N)c1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Cl)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 25.1 %

Procedure:
187 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 175 mg of 5-(trimethylstannyl)nicotinonitrile, 25 mg of copper iodide and 75 mg of tetrakis(triphenylphosphine)palladium were added in turn to 3 ml of degassed toluene, and the mixture was stirred at 110° C. for 17 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 58 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin 4-yl}nicotinonitrile as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20]OS(C)(=O)=O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[OH:33][CH2:34][C:35]1[O:39][C:38]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:37][CH:36]=1>CO>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:38]4[O:39][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccc(CO)o4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give, after chromatography on silica gel eluting with methanol, the title compound: Rf=0.41 (silica gel, methanol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:37].Cl>CN(C)C=O>[CH3:37][N:20]([C:19]1[C:14]2[S:13][CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[C:15]=2[N:16]=[CH:17][N:18]=1)[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)csc23)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)csc12)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
54 mg (0.11 mmol) of tert-butyl 4-(7-(4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate obtained in Example 109 was dissolved in 2 ml of N,N-dimethylformamide, and 3.4 mg (0.143 mmol) of NaH was added thereto. After 0.5 hr, 10 μl (0.143 mmol) of iodomethane was dropwise added to the mixture at room temperature, heated to 50° C. and stirred for 3 hr. The resulting mixture was neutralized with 1 N aqueous hydrochloride, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure to obtain 40 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cncc(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Product: Cc1cncc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)c1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 3-Bromo-5-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:34])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:34])[C:20]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.8 %

Procedure:
To a suspension of tert-butyl 1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylate 28 (69.7 g, 147.2 mmol) in DCM (348.5 mL) and triethylsilane (18.83 g, 25.87 mL, 161.9 mmol) was added TFA (151.1 g, 102.1 mL, 1.325 mol) (mixture sets solid on initial addition of TFA then goes into solution after complete addition). Resulting orange solution was stirred at room temperature overnight. Additional TFA (16.78 g, 11.34 mL, 147.2 mmol) was added and the mixture stirred at room temperature for 2 h. Mixture then heated at 40° C. for 20 mins to force reaction to completion. Mixture was concentrated in vacuo, chloroform (300 mL) was added and mixture again concentrated in vacuo to leave an orange solid suspension. Mixture triturated in DCM (approx. 200 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid. Filtrate was concentrated in vacuo, residue re-slurried in DCM (approx 50 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid which was combined with first crop of solid. Solid dried under vacuum overnight to leave desired product 29 as a yellow solid (82.8 g, 96%). 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.59 (s, 1H), 9.50 (dd, 1H), 8.84 (dd, 1H), 8.33 (d, 1H), 3.13-3.10 (m, 4H), 2.57-2.47 (masked signal, 1H) and 2.08-1.93 (m, 4H). MS (ES+) 418.1.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=[CH:3]1.[CH:11]([N:14]=[C:15]=[S:16])([CH3:13])[CH3:12].Cl>C(#N)C.C(O)C>[ClH:1].[CH:11]([NH:14][C:15]([N:7]1[CH2:8][CH2:9][C:10]2[NH:2][CH:3]=[N:4][C:5]=2[CH2:6]1)=[S:16])([CH3:13])[CH3:12]
Reactant: CC(C)N=C=S
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CC(C)NC(=S)N1CCc2[nH]cnc2C1
Yield: 76.5 %

Procedure:
A solution of 2 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in 20 ml of acetonitrile and 5 ml of ethanol is refluxed 8 h. Evaporation of the solvent leaves a residue that is treated with one equivalent of ethanolic hydrogen chloride. Evaporation of the solvent leaves a residue which is crystallized from acetone to give 2.5 g of 5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 170°.
Reaction SMILES: [H-].[Na+].[CH2:3]1[S:11](=[O:13])(=[O:12])[O:10][CH2:9][CH2:8][O:7][S:4]1(=[O:6])=[O:5].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24](Cl)=[O:25]>C(COC)OC>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([CH:3]1[S:4](=[O:5])(=[O:6])[O:7][CH2:8][CH2:9][O:10][S:11]1(=[O:13])=[O:12])=[O:25]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(c1ccc2ccccc2c1)C1S(=O)(=O)OCCOS1(=O)=O
Reaction time: 0.75 h
Yield: 84.5 %

Procedure:
To a suspension of 3 g NaH in 50 mL of glyme was added 1.0 g of ethylene methanedisulfonate. To this solution was added 1.1 g of 2-naphthoyl chloride and the H2 evolved was measured. The theoretical amount of H2 evolved in about 45 min. The solvent was then removed from the solution on a rotary evaporator. The residue was taken up in 50 mL of water and washed with CH2Cl2. The water solution was acidified and an oil separated which was then extracted with CH2Cl2 which was dried over MgSO4, and evaporated to leave 1.65 g (93%) of crude product. Subsequent crystallization from CH2Cl2-cyclohexane gave 1.49 g (84%) ethylene 2-naphthoylmethanedisulfonate, m.p. 150-158° C. (95-4).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:15]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)(C)(C)C.C(=O)[C:26]1[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:28].Cl>O1CCCC1>[C:21]([O:20][C:18]([O:17][C:15]1[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=1[CH:27]=[O:28])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
350 mg (2.8 mmol) of N,N-dimethylaminopyridine and 8.1 ml (46.9 mmol) of N,N-diisopropylethylamine are added to a solution containing 20.9 g (95.7 mmol) of di(tert-butyl)dicarbonate in 150 ml of tetrahydrofuran under a stream of nitrogen. 10 ml (93.8 mmol) of salicylaldehyde are added dropwise. After stirring at ambient temperature for 2 hours, the medium is treated with a 1N aqueous hydrochloric acid solution and then extracted with a heptane/ethyl acetate 1/1 mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. 21.5 g of 2-(tert-butoxycarbonyloxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(-n2ccc(Oc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 60 °C
Yield: 14 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.58 mmol) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.19 g, 0.64 mmol) in anhydrous acetonitrile (10 mL) was added cesium fluoride (0.22 g, 1.46 mmol). The reaction mixture was heated at 60° C. for 16 hours, followed by the addition of ethyl acetate (30 mL). The mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) and further purified by recrystallization in ether to afford the title compound as a colorless solid in 14% yield (0.032 g): mp 67-70° C. (ether); 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=8.1 Hz, 1H), 7.45-7.25 (m, 8H), 7.11-7.08 (m, 2H), 6.35 (dd, J=8.1, 2.7 Hz, 1H), 6.05 (t, J=5.6 Hz, 1H), 5.81 (d, J=2.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.1, 161.8, 153.3, 152.8, 152.1, 137.7, 132.2, 130.3, 128.8, 127.9, 127.7, 126.4, 122.5, 121.1, 103.4, 100.2, 44.1, 17.3; MS (ES+) m/z 418.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (52.8 mg, 45%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.[Cl-].[Na+]>[C:14]1([CH2:13][NH:20][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Indole-5-carboxylic acid (3.0 g) in anhydrous terahydrofuran (THF) (25 ml) was treated with 1,1-carbonyldiimidazole (CDI) (3.35 g) with stirring at room temperature for 1 h. A further amount (1.0 g) of CDI was added and, after stirring for a further 1H, benzylamine (4.0 g) was introduced. Stirring was continued for 24 h. The solution was diluted with water (50 ml), saturated with sodium chloride, and the THF layer separated off. The organic solution was washed with 1N hydrochloride acid (3×50 ml), brine (2×50 ml), dried (MgSO4) and evaporated under reduced pressure to given an oil (6.0 g) which was chromatographed on silica (Merck 7734, 200 g) eluting with methylene chloride and then methylene chloride/methanol (50:1) to give a foam (4.0 g). Crystallization from ethyl acetate/petroleum/ether (b.p. 60°-80°) gave the title compound as a solid (2.05 g) m.p. 155°-160°.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][C@H:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([SH:8]2[CH2:9][C@@H:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: c1ccc(C2N[C@H](c3ccccc3)CS2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)[SH]2C[C@@H](c3ccccc3)NC2c2ccccc2)c1
Yield: 45.5 %

Procedure:
By proceeding in a fashion similar to that described in Example 41 §A, but starting from 1.2 g of (2RS,4R)-2,4-diphenylthiazolidine, 1.04 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 1.03 g of N,N'-dicyclohexylcarbodiimide in 15 cm3 of acetonitrile, and after treatment, 0.98 g of (2RS,4R)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-2,4-diphenylthiazolidine is obtained in the form of a meringue-like product.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1
Yield: 106.6 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4 using 3-cyclopentyl-4-methoxy-benzoic acid (10.00 g, 45.4 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.4 mmol), N,N-DMF (5 drops), tin(IV) chloride (5.8 mL, 49.7 mmol) and 2-benzyl-4,5-dimethylfuran (10.1 g, 54.3 mmol) in CH2Cl2. The final organic extracts were concentrated to give 18.8 g of the title compound, synthetically pure. 1H NMR: consistent.