Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1)=O.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[OH-].[Na+].C[N:60](C)C=O>N1C=CC=CC=1>[NH2:60][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:21][CH2:22]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,3-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (295 mg) was dissolved in N,N-dimethylformamide (4 ml). Water (0.0563 ml), [bis(trifluoroacetoxy)iodo]benzene (536 mg) and pyridine (0.303 ml) were added thereto at room temperature in this order, followed by stirring for 25 hr and 10 min. The reaction was stopped by adding a 1N aqueous solution of sodium hydroxide (9 ml), and the reaction mixture was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was washed with water (30 ml) in twice, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:3), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a pale yellow solid (168.4 mg, 61%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[SH:11].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[S:11][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cc(C)cc(S)c1F
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(C)cc(OC)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-fluoro-3-methoxy-5-methylbenzenethiol (289.4 mg) and DMF (dry) (12 mL) were added K2CO3 (255 mg) and methyl 4-chloro-3-oxobutanoate (0.217 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (330 mg).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](=[O:38])(=[O:37])[NH2:36])[CH:30]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:39]=[C:28]([C:29]4[CH:30]=[C:31]([S:35]([NH2:36])(=[O:37])=[O:38])[CH:32]=[CH:33][CH:34]=4)[N:27]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/hexane) as a yellow solid (198 mg, 74%). MS (ISN) 535.3 [(M−H)−]; mp 267° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:16]1([C:22]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:23][C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][NH:30][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[CH2:23][C:22]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)CCNC(=O)CNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 0.55 g of (3R)-3-aminomethyl-1-(tert-butoxycarbonyl)piperidine and 1.1 g of 3-(2-{(3,3,3-triphenylpropanoyl)amino}acetylamino)propionic acid in 10 ml of N,N-dimethylformamide, 0.52 g of 1-hydroxybenzotriazole monohydrate and 0.75 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide monohydrochloride were successively added at room temperature, and stirred for 2 hours at the same temperature. Then 2.0 ml of triethylamine and 10 ml of chloroform were added at room temperature, followed by an hour's stirring. The reaction liquid was distilled off under reduced pressure, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (eluting solvent: chloroform/methanol=19/1) to provide 1.41 g of the title compound.
Reaction SMILES: C(O)C.C(O)(=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]=1[C:26](=O)/[CH:27]=[C:28](\[NH:31][C:32]1[N:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=1)/SC.O.[NH2:42][NH2:43]>C(O)C.C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]=1[C:26]1[NH:43][N:42]=[C:28]([NH:31][C:32]2[N:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=2)[CH:27]=1
Reactant: COc1ccc(COc2cccc(OC)c2C(=O)/C=C(\Nc2cnc(C#N)cn2)SC)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(COc2cccc(OC)c2-c2cc(Nc3cnc(C#N)cn3)n[nH]2)cc1
Temperature: 67.5 °C
Yield: 99.1 %

Procedure:
In a 20 L container are combined ethanol (11.28 L) and acetic acid (318 mL, 5.545 mol). The reaction is vented to a bleach scrubber with a nitrogen purge. (E)-5-(3-(2-Methoxy-6-(4-methoxybenzyloxy)phenyl)-1-(methylthio)-3-oxoprop-1-enylamino)pyrazine-2-carbonitrile (940 g, 1.931 mol) and the ethanol/acetic acid solution are added to a 22 L reaction flask. To the resulting brown slurry is added hydrazine monohydrate (197 g, 3.935 mol), resulting in a slight exotherm. The resulting yellow slurry is slowly heated to 65-70° C. and monitored by HPLC. The duration of the reaction is less than one hour. The thick slurry is slowly cooled over 1-2 h to less than 30° C. The slurry is filtered and washed with cold ethanol. The material is vacuum dried at 40° C. affording (820 g, 99.1%) of the title compound. mp 215-117° C.; ES/MS m/z 429.2 [M+1]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:29][CH2:28][C@@H:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@H:20]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@H:20]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Temperature: -65 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Dimethylsulfoxide (0.145 mL, 2.049 mmol) was added to a methylene chloride (10 mL) solution of oxalyl chloride (0.768 mL, 1.537 mmol) at −20° C. under nitrogen. The reaction was then cooled to −65° C. and tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.2 g, 0.512 mmol) was added to the reaction all at once. The reaction was stirred for 2 h. Triethylamine (0.428 mL, 3.07 mmol) was added to the reaction mixture and the reaction was allowed to warm to room temperature. The reaction was diluted with methylene chloride and washed with water three times. The methylene chloride layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 45% to 65% gave the desired product (199 mg, 73%).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[O:17]=[C:18]([C@H:24]([CH3:40])[C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21].O>CCOCC.C1COCC1>[O:17]=[C:18]([C@H:24]([CH3:40])[C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:37])([Cl:38])[Cl:39])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[C@@H:20]([OH:21])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetate (0.865 mL) is added to a solution of lithium diisopropylamide (7.52 mmol) in 30 mL of ether at −78° C., and the mixture is stirred for 1 hour. A solution of bis(1,2:5,6-di-O-isopropylidene-α-L-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (8.34 mmol) in 90 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (4R,5S,6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonenal (2.57 g) in 15 mL of ether is added over 10 minutes and the reaction is continued for 2 hours before addition of 14 mL of 5 M water in THF. The mix is stirred for 1 hour, then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (7% ethyl acetate/hexanes).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[CH3:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[CH2:35][NH2:36].C1COCC1.C(Cl)(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:16])=[O:17])[CH:19]=[N:20][C:21]=1[NH:36][CH2:35][C:31]1[S:32][CH:33]=[CH:34][C:30]=1[CH3:29]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Cc1ccsc1CN
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCc2sccc2C)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-methylthiophene-2-methylamine (0.016 g, 0.133 mmol), THF [2 mL]. The reaction vessel was sealed and heated to 70° C. for 18 hours, cooled to room temperature and concentrated in vacuo. Chromatography of crude material (10%–25% EtOAC/Hx) yielded the intermediate which was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound. ESI-MS (m/z): Calcd. for C18H18BrN3O2S4: 517.52 (M+H); found 516.9, 518.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 32.3 %

Procedure:
A mixture of 5.0 g (0.03 mol) of 3,5-dihydroxybenzoic acid methyl ester, 9.9 g (0.03 mol) of 1-bromooctadecane and 4.1 g (0.03 mol) of potassium carbonate in 100 ml of acetone and 5 ml of DMF was stirred at reflux for 24 hours. The solvents were removed at reduced pressure and the residue was stirred with ethyl acetate and filtered to remove inorganic salts. The filtrate was concentrated to dryness and the residue was stirred with 500 ml of methylene chloride and filtered to remove the residual 3,5-dihydroxybenzoic acid methyl ester. The filtrate was concentrated and purified by chromatography on 300 g of silica gel using 5% ethyl acetate-toluene to give 4.07 g (33% yield, mp 93°-94°) of 3-hydroxy-5-(octadecyloxy) benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@H:7]([N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[CH:4][CH:3]=1.[C:30]1([C:36]2[C:37]([C:41](O)=[O:42])=[CH:38][NH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([C@@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([C:37]3[C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:40][NH:39][CH:38]=3)=[O:42])=[CH:29][CH:28]=2)[CH2:8][OH:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)c1cccc(Cl)c1)[C@H](CO)Cc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@H](O)c1cccc(Cl)c1)[C@H](CO)Cc1ccc(NC(=O)c2c[nH]cc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a solution of tert-butyl N-[(1S)-1-(4-aminobenzyl)-2-hydoxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (120 mg) in N,N-dimethylformamide (2.0 ml) was added successively 4-phenyl-1H-pyrrole-3-carboxylic acid (64.0 mg) and 1-hydroxybenzotriazole hydrate (46.2 mg). To the mixture was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (65.6 mg) at room temperature and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml×2), a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) and brine (20 ml×1) successively. The organic solution was dried over magnesium sulfate, filtered, and evaporated to give a yellow solid. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give tert-butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phenyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate (16 mg) as a yellow foam.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH:6]([OH:12])[CH2:5]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O>[CH3:10][C:8]1([CH3:11])[CH2:9][C:4]([CH3:13])([CH3:3])[CH2:5][CH:6]([O:12][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:7]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2ccc([N+](=O)[O-])cc2)CC(C)(C)C1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
1.3 g of sodium hydride are added to a solution of 7.8 g of 3,3,5,5-tetramethylcyclohexanol in 50 ml of dimethylformamide, and the mixture is stirred at 40-50° C. for 30 min. A total of 7.0 g of 4-fluoronitrobenzene are then added a little at a time, and the mixture is subsequently heated at 100° C. for three hours and cooled to room temperature. 250 ml of ice-water are added, the mixture is stirred and the resulting solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1([NH2:39])[CH2:38][CH2:37][CH2:36]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.O>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1([NH:39][C:2]2[C:3](=[O:20])[N:4]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=3[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=2)[CH2:38][CH2:37][CH2:36]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2ccccc2OCc2ccccc2)CCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CCC3)c2=O)c1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
To 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 1.083 g) in dioxane (6 mL) was added 1-(2-(benzyloxy)phenyl)cyclobutanamine (Example 268c, 1.16 g) and N,N-diisopropylethylamine (0.76 mL) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated, dried (MgSO4), filtered and the crude product purified (SiO2 chromatography eluting with 20-50% ethyl acetate in iso-hexane) to afford the subtitle product (1.46 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:16][C:15]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[N:13]=[CH:12][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH2:37][CH:36]=2)=[CH:7][N:6]=1)=[O:10]
Reactant: Cc1c(C(=O)Nc2cnc(Br)cn2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC1(C)OB(C2=CCC(N3CCOCC3)CC2)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2cnc(C3=CCC(N4CCOCC4)CC3)cn2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A mixture of N-(5-bromopyrazin-2-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg), 4-[4-(4,4,5,5-tetramethyl[1,3,2] dioxaborolan-2-yl)cyclohex-3-en-1-yl]morpholin (185 mg), tetrakis(trophenylphosphine)palladium (0) (81 mg) and sodium carbonate (186 mg) in 1,4-dioxane (7.0 ml) was stirred at 90° C. for four hours. Then, N,N-dimethylformamide (7.0 ml) and bis(diphenylphosphine)ferrocenepalladium (II) dichloride dichloromethane adduct (57 mg) were added at room temperature and stirred at 90° C. for five hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the precipitated solid was collected by filtration. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) twice to give the titled compound (143 mg) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:34])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[S:62]1[CH:66]=[CH:65][CH:64]=[C:63]1[C:67](O)=[O:68]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:34])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:12][NH:13][C:67]([C:63]1[S:62][CH:66]=[CH:65][CH:64]=1)=[O:68]
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Reactant: O=C(O)c1cccs1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To a solution of (S)-3-Amino-2-{[3-chloro-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methylester trifluoro-acetic acid salt (0.59 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.2 mL, 1.18 mmol), DEPBT (0.35 g, 1.18 mmol), and 2-Thiophenecarboxylic acid (0.083 g, 0.65 mmol). The mixture was stirred at room temperature 15 h, treated with EtOAc (100 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-100% EtOAc in hexane) to give 0.15 g (49%) white foam. MS m/e 522.0 (M+H+).