Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:25]([O:26]CC2C=CC=CC=2)[C@@H:24]([CH2:34][O:35]CC2C=CC=CC=2)[O:23][CH:10]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)C1C=CC=CC=1.[N:43]([C:46]1[N:54]=[C:53]([F:55])[N:52]=[C:51]2[C:47]=1[NH:48][CH:49]=[N:50]2)=[N+]=[N-]>C(#N)C>[C@@H:10]1([N:50]2[CH:49]=[N:48][C:47]3[C:51]2=[N:52][C:53]([F:55])=[N:54][C:46]=3[NH2:43])[O:23][C@H:24]([CH2:34][OH:35])[C@@H:25]([OH:26])[C@@H:9]1[OH:8]
Reactant: [N-]=[N+]=Nc1nc(F)nc2nc[nH]c12
Reactant: O=C(OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
A solution of 2,3,5-tri-O-benzyl-1-α-D-arabinofuranosylchloride (freshly prepared from 1.9 g of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) and 6-azido-2-fluoropurine (0.50 g) in anhydrous acetonitrile (30 mL) was stirred for 1 hour at room temperature and then 3 Å molecular sieve (1.26 g, pellets) was added. The mixture was stirred under an inert atmosphere for 3 days and then filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 2-propanol and methanol, and then sodium borohydride (0.13 g) was added. After stirring overnight at room temperature the resulting precipitate was collected by filtration. The precipitate was washed with 2-propanol followed by boiling water and then dried to obtain 0.14 g of the title compound. The organic filtrates were concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The dichloromethane solution was dried over MgSO4 and then filtered and placed on a silica gel column. Elution with 1% methanol in dichloromethane provided an additional 0.10 g of the title compound. Both samples were identical by IR and TLC to an authentic sample of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C(Cl)Cl>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[Cl:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c(N4CCNCC4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25% TFA/CH2Cl2 (10 mL) was added to tert-butyl 4-(5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (430 mg, 0.939 mmol), and the solution was stirred at room temperature. After 30 minutes, the solvent was removed under reduced pressure. The resulting residue was evaporated from toluene (3×10 mL) and dried under high vacuum for 18 hours to provide 5-chloro-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine 2,2,2-trifluoroacetate. Neat TFA (10 mL) was added to this material, and the mixture was stirred at reflux for 90 minutes. TFA was removed under reduced pressure, and the residue was evaporated from CH2Cl2 (2×10 mL). The residue was redissolved in CH2Cl2, and 2M HCl in ether (6 mL) was added. The resulting suspension was concentrated in vacuo. The residue obtained was treated with 2M HCl in diethyl ether once more (5 mL) and subjected to sonication for 2 minutes. Then the solvent was removed in vacuo, and the resulting residue was triturated with Et2O. The solid formed was filtered, washed with ether (2×5 mL) and dried under high vacuum to provide 5-chloro-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (280 mg, 0.901 mmol, 62.0% yield) as a solid. LCMS (APCI+) m/z 238.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C@H:4]1[CH2:6][NH:5]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOCC>[CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[CH2:6][N@@:5]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)C[C@H]1CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CC1CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 24.3 g of (S)-2-(2-methylpropyl)aziridine [Bull. Chem. Soc. (Japan) 35, 1004 (1962).] in 500 ml of ether is treated with 34.2 ml of triethylamine and cooled in ice. While stirring rapidly 40.4 ml (a 10% excess) of benzyl chloroformate is added dropwise over a 30 minute period. After stirring for one hour at 0°, the triethylamine, hydrochloride is filtered off and the ether removed under reduced pressure. The residue is distilled under reduced pressure. After a forerun of benzyl chloride, the product distills at 105°-122°/0.6 mm. There is obtained 51.66 g (90.5% yield) of (S)-2-(2-methylpropyl)-1-aziridinecarboxylic acid, phenylmethyl ester.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=O)(=[O:15])[CH3:14].Cl.[NH2:28][CH2:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O>[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([NH:28][CH2:29][C:30](=[O:31])[NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:34]=1)=[O:21])(=[O:15])[CH3:14]
Reactant: NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
WSC.HCl (95.9 mg, 0.5 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (59.1 mg, 0.28 mmol), 2-amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride (80.8 mg, 0.25 mmol) and 1-hydroxybenzotriazole (37.2 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2→1:1) to give the title compound (83.7 mg, 69.3%) as a white crystal.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([C:7]([NH:9][NH2:10])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.O>CCO>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[N:10][NH:9][C:7]([C:2]1[C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NNC(=O)c1ccccc1-c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a stirred solution of biphenyl-2-carboxylic acid-hydrazide (0.212 g, 1.0 mmol) in 20 mL EtOH was added 3-trifluoromethyl-benzaldehyde (0.174 g, 1.0 mmol) in 5 mL EtOH at room temperature. The mixture was refluxed for 4 h and cooled to room temperature, then was diluted by 100 mL of water. The precipitate was collected, washed with MeOH, and dried to yield the title compound (0.320 g, 87%). 1H NMR (acetone-d6): 11.60 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=12 Hz, 1H), 7.35 (d, J=12 Hz, 1H), 6.97˜7.15 (m, 10H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)=[O:26].[OH:38][CH:39]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=1)=O.CN(C1C=CC=CN=1)C>CN(C)C=O.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH:40]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][CH3:49])=[CH:46][CH:47]=2)[C:39](=[O:38])[C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[O:36])[CH2:30][CH2:29]1)=[O:26]
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)C(OC(=O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (DCC; 0.81 g, 3.92 mmol) was added in one portion to a rapidly-stirred mixture of 4-[[[(2,6-dimethylphenyl)amino]carbonyl]methyl]-1-piperazineacetic acid (1.0 g, 3.27 mmol), 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 0.88 g, 3.27 mmol) and dimethylaminopyridine (DMAP: 40 mg) in anhydrous dimethylformamide (25 mL). After 2 hours at ambient temperature, an additional equivalent of DCC and DMAP were added. The mixture was stirred further for 22 hours at room temperature before it was heated to 70° C. for 6 hours. Upon cooling, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 50% ethyl acetate in hexanes followed by ethyl acetate) afforded 0.50 g of the benzoin ester product (VI) as an off-white solid. The ester was used in subsequent reactions without additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NC1CC1
Product: Fc1cccc(CNC2CC2)c1Cl

Procedure:
Prepared from 2-chloro-3-fluorobenzoic acid (2.00 g, 11.5 mmol) and cyclopropylamine according to above-described procedures C and E, and purified over amberlyst A15 (1.86 g, 81% over 2 steps). LC-MS (2-chloro-N-cyclopropyl-3-fluorobenzamide): tR=0.76 min, ES+: 214.10; LC-MS (title compound): tR=0.60 min, ES+: 200.12.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)OCC1.[OH:13][NH:14][C:15](=N)[CH:16]([CH3:18])[CH3:17]>>[CH:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]2)[O:13][N:14]=1)([CH3:18])[CH3:17]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC2(CC1)OCCO2
Product: CC(C)c1noc(N2CCC(=O)CC2)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Intermediate 5. LC (method 6): tR=1.56 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:28][CH2:29][OH:30])[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=2)[CH2:10][CH2:9]1.[OH:31]O>C(O)(=O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N:11]3[CH2:10][CH2:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])([CH2:28][CH2:29][OH:30])[O:13][C:12]3=[O:14])[N+:16]=2[O-:31])=[CH:26][CH:25]=1
Reactant: OO
Reactant: O=C1OC(CCO)(c2ccccc2F)CCN1c1cccc(-c2ccc(F)cc2)n1
Solvent: CC(=O)O
Product: O=C1OC(CCO)(c2ccccc2F)CCN1c1cccc(-c2ccc(F)cc2)[n+]1[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (680 mg, 1.66 mmol) was added to acetic acid (20 mL), 30% aq hydrogen peroxide (50 mL) was added at rt and the reaction mixture was stirred for about 5 h at 80° C. The mixture was extracted with CH2Cl2 and the organic phase washed with Na2SO3 solution, then dried over Na2SO4. Removal of the solvent gave the crude product, which was purified by HPLC and give 2-(4-fluorophenyl)-6-(6-(2-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)pyridine 1-oxide (80 mg, 11%). LC-MS Method 2, tR=1.704 min, m/z=427.1. 1H NMR (CD3OD) 2.33-2.50 (m, 2H), 2.60-2.77 (m, 2H), 3.08-3.20 (m, 1H), 3.32-3.40 (m, 1H), 3.40-3.52 (m, 1H), 3.70-3.85 (m, 1H), 7.08-7.37 (m, 5H), 7.40-7.69 (m, 4H), 7.70-7.86 (m, 2H). 1H NMR (400 MHz, CDCl3): δ=2.5 (s, 2H), 2.6 (m, 2H), 3.05 (m, 1H), 3.3 (m, 1H), 3.35-3.6 (m, 1H), 3.75 (m, 1H), 7.0-7.8 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9](Cl)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].O.[S-2:23].[Na+].[Na+]>O>[CH2:13]([NH:12][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([SH:23])[N:8]=[C:7]([CH3:21])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
31.5 g. of 4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 Mol.) are dissolved in 100 ml. of alcohol. 14.8 g. of sodium sulfide monohydrate and about 2 ml. of water are added and the mixture is stirred for one hour without cooling. The precipitated 4-butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is filtered off, yield 27.5 g. (88%), m.p. 140°-142° (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C.O>[CH2:19]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:18]=[CH2:17]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1C=O
Temperature: 50 °C

Procedure:
To a mixture of 5-chlorosalicylaldehyde (8.20 g, 52.37 mmol, 1.00 eq.) and potassium carbonate anhydrous (8.69 g, 62.85 mmol, 1.20 eq.) in DMF (100 mL), allyl bromide (4.7 mL, 54.99 mmol, 1.05 eq.) was added. The mixture was heated at 50° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (150 mL). The mixture was extracted with DCM (2×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give 2-allyloxy-5-chloro-benzaldehyde. The product was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[OH:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]3[C:39](=[O:41])[NH:38][CH:37]=[CH:36][C:35]=3[N:34]=[C:33](SC)[C:32]=2[C:44]#[N:45])=[CH:27][CH:26]=1.O>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:33]3[C:32]([C:44]#[N:45])=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][OH:21])=[CH:26][CH:27]=4)[C:40]4[C:39](=[O:41])[NH:38][CH:37]=[CH:36][C:35]=4[N:34]=3)[N:18]=2)=[CH:12][CH:13]=1
Reactant: CSc1nc2cc[nH]c(=O)c2c(-c2ccc(OCCO)cc2)c1C#N
Reactant: OCc1csc(-c2ccc(Cl)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2csc(-c3ccc(Cl)cc3)n2)nc2cc[nH]c(=O)c2c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
64 mg (0.57 mmol) of potassium tert-butoxide were suspended in 3.5 ml of DMF, 96 mg (0.42 mmol) of [2-(4-chlorophenyl)-1,3-thiazol-4-yl]methanol [Simiti, I. et al. Arch. Pharm. 1972, 305, 509-515] and then 100 mg (0.28 mmol) of the compound from Example 21A were added and the mixture was stirred at 60° C. for 16 h. Another 64 mg (0.57 mmol) of potassium tert-butoxide were added, and the reaction was stirred once more at 80° C. overnight. Water was added, and the reaction solution was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator, The crude product was and purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][N:20]=1)CCC>CN(C=O)C.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>[Br:7][C:6]1[C:2]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1scc(Br)c1-c1ncco1
Temperature: 90 °C
Yield: 66.9 %

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (0.166 mg, 0.581 mmol), Pd(PPh3)4 (67 mg, 0.0581 mmol) and 2-(tributylstannyl)oxazole (250 mg, 0.698 mmol) in DMF (1.1 mL) was evacuated and purged with nitrogen three times. The reaction mixture was heated to 90° C. for 18 h and the resulting solution was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 20/1 to 1/1, v/v) to give 2-(4-bromo-2-nitrothiophen-3-yl)oxazole (107 mg, 67%). Retention time (min)=1.948, method [1], MS(ESI) 274.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([C:17]([F:18])([F:20])[F:19])[CH2:15][O:16][C:29]3=[O:31])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC(Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-3,3,3-trifluoropropan-1-ol (0.61 g, 1.6 mmol), prepared in the previous step, was dissolved in 48 mL methylene chloride. Triethylamine (2.2 mL, 16 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.20 g, 4.15 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 10% acetone/hexane) afforded the title compound (0.47 g, 75%) as a white solid, mp 154-156° C. HRMS: calcd for C13H8BrF3N2O2S+H, 392.95202; found (ESI, [M+H]+), 392.9518. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1I)[CH3:2].[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C(N(CC)CC)C>C1COCC1.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>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][Si:12]([CH3:16])([CH3:15])[CH3:11])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1nc(N)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(N)ccc1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 18 g (72.6 mmol) 6-ethyl-5-iodo-pyridin-2-ylamine and 14.4 mL (102 mmol) 1-trimethylsilyl-ethyne using 1.38 g (7.3 mmol) CuI, 5.1 g (7.3 mmol) PdCl2(PPh3)2 and 101 mL (726 mmol) triethylamine in 100 mL dry THF. For the work-up the solvent is removed under reduced pressure, the crude product is taken up in ethyl acetate and the organic phase is extracted with water. The product is purified twice by chromatography on silica gel using a cyclohexane/ethyl acetate gradient. Yield: 12.73 g (80%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH:20](Cl)[CH2:21][CH3:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:5]([N:8]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1OCC1CCCC1
Reactant: CCC(Cl)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnc(N2CCCC2)c(OCC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of 0.544 g (0.0020 mol) 5-bromo-3-cyclopentylmethoxy-pyrazin-2-ylamine in 10 mL dimethylformamide was added 0.349 g (0.0080 mol) sodium hydride 55% in oil and the mixture was stirred at room temperature for 20 min. To the resulting suspension was added 0.345 mL (0.0030 mol) 1-bromo-2-chlorobutane and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was washed with water and 10% aqueous sodium bicarbonate, dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to yield 0.579 g (0.0018 mol) of the title compound as yellowish crystals melting at 54-55° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:50]([C:51]#[N:52])=[C:49]([S:53][CH2:54][C:55]3[N:56]=[C:57]([C:60]4[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=4)[O:58][CH:59]=3)[N:48]=[C:47]([NH2:67])[C:46]=2[C:68]#[N:69])=[CH:41][CH:40]=1)[CH2:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][NH:24][C:25](=[O:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>ClCCl>[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73].[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73].[NH2:27][CH2:26][C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:50]([C:51]#[N:52])=[C:49]([S:53][CH2:54][C:55]3[N:56]=[C:57]([C:60]4[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=4)[O:58][CH:59]=3)[N:48]=[C:47]([NH2:67])[C:46]=2[C:68]#[N:69])=[CH:41][CH:40]=1)=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCNC(=O)CN)OC(=O)CCNC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 79 mg (0.080 mmol) of the compound from example 32A was introduced in 0.5 ml of dichloromethane, admixed with 0.061 ml (0.798 mmol) of trifluoroacetic acid and stirred at RT. After 3 hours, again, the same amount of trifluoroacetic acid was added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 54 mg (65% of theory) of the target compound.