Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:36])[C:32]([NH:34][NH2:35])=[O:33])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32](=[O:33])[C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:36])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: NNC(=O)C(=O)N1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)C(=O)N1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 169.3 %

Procedure:
A solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 0.569 mmol) and 2-morpholino-2-oxoacetohydrazide (0.02 g, 0.175 mmol) in THF (3 mL) was cooled to −60° C. T3P (0.098 g, 0.569 mmol) (0.50 mL) was added dropwise followed by DIPEA (0.11 g, 0.854 mmol) and stirred at −60° C. for 1 h. The reaction mixture was transferred into 25 mL of iced water and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give 0.3 g of crude product, which was purified by chromatography (0-4% MeOH/CH2Cl2) to give 0.15 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-morpholino-2-oxoacetyl) acrylohydrazide (Yield 50%). NMR (400 MHz, DMSO-d6) δ 10.70-10.88 (m, 2H), 9.56 (s, 1H), 8.57 (s, 2H), 8.29 (s, 1H), 7.52-7.55 (d, J=10.4 Hz, 1H), 6.0-6.03 (d, J=10.4 Hz, 1H), 3.51-3.64 (m, 8H). LCMS m/z 507.25 [M+H]+, tR=2.012 min.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)C(C)C)(C)C.[Br:16][C:17]1[C:25]([O:26][CH3:27])=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][C:18]=1[O:28][CH3:29].S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl.C(OCC)C>[Br:16][C:17]1[C:25]([O:26][CH3:27])=[CH:24][C:20]([C:21]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:19][C:18]=1[O:28][CH3:29]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1Br
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(C2=NC(C)(C)CO2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand., 2, 34-41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) was added dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g, 102.0 mmol) was gradually added to the ice-cold solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure to yield crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-cold solution of 2-amino-2-methylpropanol (8.40 g, 94.2 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3 mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloride in methylene chloride (200 mL). After the mixture was stirred at room temperature for 10 minutes, the mixture was washed successively with water, 8.0 M hydrochloric acid, a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0 mmol) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ice water and a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized form diethyl ether-hexane to yield 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless fine needles (melting point: 172.5-174.5° C.) (20.9 g, yield: 77%).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7]CCO)[C:4]2N=C(N)N=C(O)[C:3]=2[N:2]=1>O1CCCC1>[C:6]([N:5]1[CH:4]=[CH:3][N:2]=[CH:1]1)([N:2]1[CH:3]=[CH:4][N:5]=[CH:1]1)=[O:7]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Solvent: C1CCOC1
Product: O=C(n1ccnc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
A solution of N-acetyl-S-(4-nitroxybutyroyl)cisteine (2.8 g, 9.6 mmoles) and 1,1′-carbonyldiimidazole (1.55 g, 9.6 mmoles) in tetrahydrofuran (50 ml) is prepared and left under stirring at room temperature for 1 hour. The reaction mixture is treated with acyclovir (2.16 g, 9.6 mmoles). After 6 hours of reaction at room temperature, the solution is evaporated at reduced pressure, the obtained residue treated with ethyl acetate and washed with brine. The organic phase is anhydrified with sodium sulphate and then dried under vacuum. The obtained residue is purified by chromatography on silica gel column eluting with ethyl acetate. 9-[[2-[N-acetyl-S-(4-nitroxybutyroyl)cisteinyl-]ethoxy]methyl]guanine is obtained. Yields: 9%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[NH:19][C:18]3=[S:29])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[BH4-].[Na+].[OH-].[NH4+]>ClC(Cl)Cl.C(O)=O.O.CO>[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH:7]([OH:8])[CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[NH:19][C:18]3=[S:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=S)[nH]c3ccc(O)cc3c2=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=CO
Product: O=c1c2cc(O)ccc2[nH]c(=S)n1CCN1CCC(C(O)c2ccc(F)cc2)CC1
Reaction time: 20 h
Yield: 28.5 %

Procedure:
To a stirred solution of 2.3 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-6-hydroxy-2-thioxo-4(1H)-quinazolinone monohydrochloride in 40 parts of methanol was added a sodium hydroxide solution 1N till pH=7. 0.37 Parts of sodium borohydride were added portionwise. Upon completion, stirring was continued for 20 hours at room temperature. The reaction mixture was poured into water. The whole was acidified with formic acid till pH=2. After stirring for 30 minutes at room temperature, the mixture was treated with ammonium hydroxide (an oily precipitate was formed). Trichloromethane was added. After 1 hour, the only precipitate was dissolved. The organic layer was separated and washed with water whereupon a precipitate was formed (=precipitate I). Then the organic layer was washed again with water, dried, filtered and evaporated (=residue I). Precipitate I and residue I were purified by column chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was boiled in 20 parts of 2-propanone and 17.5 parts of 2,2'-oxybispropane. The product was filtered off and dried at 100° C., yielding 0.6 parts (28.5%) of 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,3-dihydro-6-hydroxy-2-thioxo-4(1H)-quinazolinone; mp. 218.0° C. (25). Following the same procedure and using equivalent amount of the appropriate starting materials there was also prepared:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 121.1 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.43 mmol) was dissolved in DMF (3 mL) and triethylamine (150 μL, 1.07 mmol, 2.5 eq.) added, followed by 1-chloromethyl-4-methoxybenzene (58 mg, 0.43 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 244 mg of the title compound 20 as a yellow oil: 1H NMR (CDCl3): δ 8.15-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.85-7.80 (m, 1H), 7.67-7.62 (m, 1H), 7.23-7.15 (m, 2H), 6.87-6.82 (m, 2H), 3.91-3.76 (m, 4H), 3.42 (s, 2H), 2.93-2.88 (m, 2H), 2.03-1.87 (m, 5H), 1.52-1.43 (m, 2H), 1.01-0.94 (m, 2H), 0.81-0.73 (m, 2H). LC: 100%. MS (EI): m/z 469 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]([CH2:19][C:20](=[O:21])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(CNc1ccc(Cl)cc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CN(C(=O)Cc1ccccc1)c1ccc(Cl)cc1)c1ccccc1
Reaction time: 2 h

Procedure:
After dissolving compound 12 (2.27 g, 14.7 mmol) in THF, compound 11 (1.5 g, 6.1 mmol) was added thereto. After the agitation for 2 hours at room temperature, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4 and distillation under the reduced pressure was carried out. After the removal of a junk by column chromatography (EA/HX= 1/9), the next reaction was followed as a crude condition.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:31])[CH2:29][CH3:30])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1C
Temperature: 25 °C

Procedure:
To a solution of trans-N-benzyloxycarbonyl-3-methyl-4-phenylaminopiperidine (1.5 g, 4.6 mmol), 4-dimethylaminopyridine (375 mg, 3.1 mmol), and acetonitrile (10 ml) is added propionyl chloride (3.6 ml, 41 mmol). The solution is stirred and refluxed for 30 minutes, cooled to room temperature, and diluted with a saturated solution of sodium carbonate (30 ml). The resultant mixture is extracted with ethyl acetate (2×30 ml) and the organic phases combined, dried over magnesium sulfate, and concentrated to an oily residue which is chromatographed on silica gel (1/1 EtOAc/Hex) to give trans-N-benzyloxycarbonyl-3-methyl-4-[(1-oxopropyl)-phenylamino]piperidine as an oil: 1.6 g, 91%.
Reaction SMILES: [C:1](=[O:14])([O:12][CH3:13])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH3:11].OS(O)(=O)=O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:1](=[O:14])([O:12][CH3:13])[O:2][C:3]1[CH:8]=[C:7]([N+:20]([O-:22])=[O:21])[C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH3:11]
Reactant: CCc1cc(F)ccc1OC(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1cc(F)c([N+](=O)[O-])cc1OC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
2-Ethyl-4-fluorophenyl methyl carbonate (2.4 g, 12.11 mmol) was added dropwise to H2SO4 (7.2 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0° C. and KNO3 (1.469 g, 14.53 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexane) provided 2-ethyl-4-fluoro-5-nitrophenyl methyl carbonate (1.7 g, 58% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.20 (d, J=6.8 Hz, 1H), 7.64 (d, J=12.1 Hz, 2H), 3.88 (s, 3H), 2.62 (q, J=7.5 Hz, 1H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[S:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.[OH-].[Na+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:8][C:5]1[CH:4]=[C:3]([S:9][CH3:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: CSc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 80.1 %

Procedure:
50 g of 4-chloro-3-methylmercaptophenol, 62 g of 3,4-dichlorobenzotrifluoride and 12 g of sodium hydroxide are stirred in 150 ml of dimethyl sulphoxide for 6 hours at 142° C. The reaction mixture is then poured onto ice and extracted with toluene. Distillation of the organic phase yields 81 g of 3-(2'-chloro-4-trifluoromethylphenoxy)-6-chlorothioanisole with a boiling point of 158° C./0.4 mbar.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:44]=[CH:43][C:42]([CH2:41][N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:48][CH:47]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
In a dry round bottom flask, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (89.4 mg, 0.2 mmol), 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride (66.7 mg, 0.24 mmol) were dissolved in dry N,N-dimethylformamide (3.0 mL). Then added diisopropylethylamine (107 μL, 0.6 mmol) and finally HATU (114 mg, 0.3 mmol) to the reaction, continued at room temperature for 2 hours. After completion, purified the product using reverse phase HPLC using water-acetonitrile solvent system. Pure fractions were mixed and evaporated to a minimal amount then basified with sat.NaHCO3 solution and extracted into EtOAc ((2×100 mL), combined organic layer was washed with sat. brine solution, dried over Na2SO4 and evaporated to get the pure product 72 mg (57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.80 (m, 6 H) 1.97 (br. s., 2 H) 2.15 (s, 3 H) 2.34 (br. s., 8 H) 3.42 (s, 2 H) 3.93 (s, 3 H) 4.07 (t, J=12 Hz, 2 H) 4.80 (t, J=8.21 Hz, 1 H) 7.26 (d, J=8.59 Hz, 2 H) 7.51-7.67 (m, 2 H) 7.70 (m, J=8.59 Hz, 2 H) 8.05 (s, 1 H) 8.29 (s, 1 H) 8.37 (d, J=8.34 Hz, 1 H) 10.09 (s, 1 H). [M+H] calc'd for C33H40F2N8O3, 635; found 635.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:15]([C:18](=[O:29])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[O:16][CH3:17])[C:9]=1[F:30])(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[C:9]([F:30])=[C:10]([CH:15]([O:16][CH3:17])[C:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:29])[C:11]([F:14])=[CH:12][CH:13]=1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(NC(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To a stirred solution of (RS)-{3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2,4-difluoro-phenyl}-carbamic acid tert-butyl ester (514 mg) at rt in dioxane (10 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (6 ml). Stirring at rt was then continued for 3 h. The light yellow solution was concentrated. The solid residue was suspended in EtOAc and washed with 1 N NaOH. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 2:3) to give (RS)-2-(3-amino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (215 mg) as an off-white solid. MS 332.3 ([M+H]+)
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]1)=[O:16])[CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:32]([C@@H:31]1[CH2:35][CH2:36][CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33])=[O:16])[CH3:13])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](NC(=O)[C@@H]1CCCC[NH2+]1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.27 g (37.54 mmol) of the hydrochloride from example 21A and 10.50 g (48.81 mmol) of N-Boc-L-proline are dissolved in methylene chloride (30 ml) and cooled to 0° C. Subsequently, the solution is treated with 18.56 g (48.81 mmol) of HATU and 5.82 g (45.05 mmol) of ethyldiisopropylamine and stirred at 0° C. for 30 min. After further addition of 11.64 g (90.10 mmol) of ethyldiisopropylamine, the mixture is stirred at room temperature for 72 h and then evaporated. The residue is taken up using ethyl acetate and the solution is washed with aq. citric acid and aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by means of silica gel chromatography using cyclohexane/ethyl acetate 5/1. 18.25 g (99% of th.) of product are obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([OH:13])(=[O:12])[CH3:11].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([OH:56])[CH2:26][N:27]([CH2:43][C@H:44]([OH:55])[C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([NH:52][CH:53]=[O:54])[CH:46]=2)[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[CH:34][CH:33]=2)=[CH:21][C:20]=1[NH:57][CH:58]=[O:59].I.[NH2:61][C:62]1[C:63]([C:70]([NH:72][C:73](=[NH:76])SC)=[O:71])=[N:64][C:65]([Cl:69])=[C:66]([NH2:68])[N:67]=1>C(O)C>[C:10]([OH:13])(=[O:12])[CH3:11].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:55][C@H:44]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([NH:52][CH:53]=[O:54])[CH:46]=1)[CH2:43][N:27]([CH2:26][C@@H:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[C:20]([NH:57][CH:58]=[O:59])[CH:21]=1)[OH:56])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:73]([NH:72][C:70]([C:63]2[C:62]([NH2:61])=[N:67][C:66]([NH2:68])=[C:65]([Cl:69])[N:64]=2)=[O:71])=[NH:76])=[CH:36][CH:37]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.92 mmol) was added to a solution of {4-[4-(4-{bis-[2-(4-hydroxy-3-formylaminophenyl)-2-(R)-hydroxyethyl]amino}-butyl)phenyl]butyl}amine diacetic acid salt (13) (129 mg, 019 mmol) in absolute ethanol (4 mL). The mixture was stirred at 70° C. (oil bath) for 10 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (79 mg, 0.20 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and cooled to rt. The solvent was removed by rotary evaporation. The residue was purified by Biotage silica gel column chromatography (A=dichloromethane, B=10% concentrated aqueous ammonium hydroxide in methanol, gradient B/A 1% to 25%) to give the desired adduct 14 as a greenish yellow solid (44 mg, 26%): 1H NMR (500 MHz, DMSO-d6) δ 1.50 (m, 8H), 1.98 (s, 6H), 2.58 (m, 4H), 3.20 (m, 8H), 4.45 (m, 2H), 6.60 (br, 2H), 6.80 (m, 4H), 7.08 (m, 4H), 8.00 (s, 2H), 8.28 (s, 2H), 9.56 (br, 2H); m/z (ESI) 791 [C38H47ClN10O7+H]+; [α]D25 −4.0° (c 0.35, MeOH); mp 128-130° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N+]#N)=[CH:9][CH:8]=1.NC1C=CC(C)=CC=1.N([O-])=O.[Na+].[CH2:27]([C:30]#[N:31])[CH:28]=[CH2:29]>[H+].[B-](F)(F)(F)F.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:7]1([CH3:6])[CH:12]=[CH:11][C:10]([CH:29]=[CH:28][CH2:27][C:30]#[N:31])=[CH:9][CH:8]=1
Reactant: C=CCC#N
Reactant: Cc1ccc([N+]#N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: Cc1ccc(N)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CCC#N)cc1
Temperature: 46 °C
Yield: 53 %

Procedure:
6.17 g (0.03 mol) of 4-methyl-benzenediazonium tetrafluoroborate (mp 105-110° C.; prepared by nitrosation of p-toluidine with sodium nitrite in aqueous fluoboric acid according to A. Roe, Org. Reactions vol V, 1949,193) are suspended in 60 ml of ethanol. Allyl cyanide (4.0 g; 0.06 mol) and palladium acetate (67 mg; 0.3 mmol) are added, and the light orange suspension is heated gently to 46° C., at which temperature a gentle evolution of nitrogen is visible. The mixture is stirred at the same temperature until the nitrogen evolution ceases (ca 3 h), resulting in a dark brown clear solution. The reaction mixture is poured into 300 ml of cold water and extracted with 2×100 ml of hexane:ethyl acetate 85:15 (v:v). The organic phases are washed with saturated aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. The light green solution is concentrated to ca 20 ml by rotary evaporation, and allowed to crystallize in the refrigerator. Filtration yields 2.5 g (53%) of 4-p-tolyl-but-3-enenitrile as very thin, colorless leaflets, mp 60-61° C., consisting of the pure (E) isomer, as determined by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[CH3:11][CH2:12]O.OS(O)(=O)=O>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: CCO
Reactant: Cc1cc(CC(=O)O)on1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)no1
Reaction time: 48 h
Yield: 97.3 %

Procedure:
To a solution of 2-(3-methylisoxazol-5-yl)acetic acid (7.28 g, 51.6 mmol) in EtOH (200 mL, 3425 mmol) was added concentrated H2SO4 (0.30 mL, 5.63 mmol) at room temperature. After 48 h, the reaction mixture was concentrated in vacuo to give a dark brown oil. The crude ester was filtered over a plug of silica (50 g) and the product was eluted with 40% Et2O:60% Hexanes (400 mL). The filtrate was subsequently concentrated to give the product ethyl 2-(3-methylisoxazol-5-yl)acetate (8.50 g, 50.2 mmol, 97% yield) as a clear oil. LC/MS m/z 170 [M+H]+.