Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].[Br-]>ClCCl>[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3([Br:1])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: Br
Reactant: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C3CCCCC3)cc2)cc1
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C3(Br)CCCCC3)cc2)cc1
Reaction time: 3 h

Procedure:
A drop of 48% HBr was added to a solution of 2.7 g (6.29 mmol) of 2-bromo-1-[4-(4-cyclohexancarbonyl-phenoxy)-phenyl]-2-methyl-propan-1-one dissolved in 60 ml of dichloromethane; 0.322 ml (6.29 mmol) of bromide dissolved in 5 ml of dichloromethane were added drop wise, in 15′. After 3 h, the organic phase was washed with water and with a sodium metabisulphite solution, separated, dried on sodium sulphate and evaporated in vacuum obtaining 3.2 g of product as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21]([CH3:23])C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([F:26])[C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.Cl.[F:28][CH2:29]CN.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH:8]=[C:7]([F:24])[C:6]([F:25])=[C:5]([F:26])[C:4]3=[N:3][C:2]=2[N:21]([CH2:23][CH2:29][F:28])[CH:20]=1)=[O:16])[CH3:19]
Reactant: NCCF
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cn(CCF)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Yield: 75.4 %

Procedure:
3-Ethoxycarbonyl-1-(2-fluoroethyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under conditions similar to Example 3, but starting with ethyl 2-(2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl)(dimethylamino)acrylate (3.9 g), 2-fluoroethylamine hydrochloride (3 g) and triethylamine (4.2 cc) in ethanol (100 cc). After the addition of DBU (1.8 cc), the solution is heated for 2 hours to 80° C. After the same treatment of the reaction mixture as in Example 24, 3-ethoxycarbonyl-7,8,9-trifluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g) is obtained in the form of a yellow solid, m.p. 302°-304° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:27][N:26]=3)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[O:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:24][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:13]=2)=[CH:19][CH:18]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: C1COCCN1
Reactant: CC(C)C(C)(c1ccc(-c2cc(CBr)no2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(C)(c1ccc(-c2cc(CN3CCOCC3)no2)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 50 °C

Procedure:
Morpholine (17.5 μL, 0.200 mmol) was added to a stirred solution of 1e (49.0 mg, 0.100 mmol) and cesium carbonate (130 mg, 0.400 mmol) in DMF (1.00 mL) at rt. The resulting mixture was heated to 50° C. for approximately 1 h, cooled to rt, and then filtered through a short column of CELITE® eluting with EtOAc. The filtrate was concentrated in vacuo and the crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 1f. m/z (ES) 499 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([O:15][CH2:16][C:17](=[O:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(COCc1ccccc1)COCc1ccccc1
Yield: 75.6 %

Procedure:
A mixture of sulfur trioxide/pyridine complex (2.33 g, 4 equivalents) in DMSO (3 ml) and triethylamine (2.05 ml, 4 equivalents) was stirred to give a pale yellow solution. To this was added a solution of 1,3-dibenzyloxy-2-propanol (1 g) in DMSO (1 ml) over 2 minutes. (The reaction mixture was kept in a water bath). The temperature of the reaction mixture reached 30° C. After 10 minutes the water bath was removed and the reaction mixture was stirred at room temperature (ca 20-25° C.) for 3 hours. The reaction mixture was diluted with ethyl acetate (15 ml) and water (15 ml), stirred and the organic extract was separated. The organic extract was washed with 5% w/v sodium chloride (2×10 ml) and water (10 ml). The separated organic extract was concentrated in vacuo to give an oil which solidified to provide 0.75 g of 1,3-dibenzyloxy-2-propanone in 75.8% yield. An NMR spectrum of product was concordant with a reference sample.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3].O.[C:34]([O:38][CH2:39][CH:40]=[CH2:41])(=[O:37])[CH:35]=[O:36].O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[N:19]([C:35](=[O:36])[C:34]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)/C(C)=C/[C@@H]1CCCN1C(=O)OCC=C

Procedure:
To a solution of (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g) in toluene (150 ml) was added allyl glyoxylate monohydrate (3.68 g). The resulting mixture was heated to reflux with azeotropic removal of water for hours. Evaporation of the solvent gave a residue of allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]glyoxylate, which was dissolved in xylene. After evaporation of the solvent in vacuo, the residue was dissolved in dichloromethane (150 ml). To this solution were added successively 2,6-lutidine (2.75 ml) and thionyl chloride (1.95 ml) at -20° C. After stirring at -20° C. for 15 minutes, the reaction mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) at 5° C. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in degassed N,N-dimethylformamide (80 ml), and to the solution were added 2,6-lutidine (2.75 ml) and triphenylphosphine (1.29 g). After standing for 6 hours at ambient temperature, the reaction mixture was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The separated organic layer was washed in turn with water, cold 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-4:6 V/V) to give allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl- 2-oxo-3-20 butenyl]3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (9.78 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
In a round-bottomed flask, 4.0 g of 1H-indazole-3-carboxylic acid, 2.6 g of N,O-dimethylhydroxylamine hydrochloride, 9.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 8.4 ml of pyridine are placed in 120 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in water. The yellow precipitate obtained is washed with water and then dried under reduced pressure. 3.5 g of compound are obtained.
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.O.C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([N:5]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:19])=[CH:16][CH:15]=1)[O:6][Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 186.3 %

Procedure:
To a solution of 1.0 g (3.09 mmol) of compound 2 in CH2Cl2 (5 mL) were added 0.733 g (3.71 mmol) of 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride, 0.189 g (1.545 mmol) of 4-dimethylaminopyridine, and 0.438 g (4.63 mmol) of 2-aminopyridine. After stirring for 12 hours at room temperature, H2O and ethyl acetate were added. The organic layer was separated, washed with sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=10:1) to give 2.3 g of compound 5 in 75% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Br:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:9][C:5]1[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH:11]=[CH2:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Br)c1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Br)cc1OC

Procedure:
3-methoxybromobenzene (0.5 mL), acryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (8.0 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:33])[C:27]([NH:29][C:30](=[O:32])[CH3:31])=[CH2:28].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:25][C:26](=[O:33])/[C:27](/[NH:29][C:30](=[O:32])[CH3:31])=[CH:28]\[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Temperature: 100 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.4 mmol), 2-acetylaminoacrylic acid methyl ester (16.6 mg, 0.54 mmol), triethylamine (0.75 mL, 5.4 mmol) and Pd(OAc)2 (15 mg) in MeCN (5 mL) in a pressure vessel is heated at 100° C. for 18 h. The mixture is filtered and the solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)CC)C.CN1CCCC1=O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: O=C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCNC(=O)C3)cc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (55.0 mg, 0.166 mmol), piperazin-2-one (0.110 g, 1.10 mmol) and triethylamine (0.275 mL, 1.97 mmol) in N-methylpyrrolidinone (3.00 mL, 31.1 mmol) was heated at 150° C. for 2d. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water and brine. The organic layer was dried Na2SO4, concentrated to give 325, analyzed by rHPLC. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.63-4.30 (m, 4H), 4.06 (d, J=8.0 Hz, 2H), 3.81-3.63 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([N:20]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.O.NN>CCO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:20])[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2
Reactant: CC(c1cc2c(Cl)cccc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1cc2c(Cl)cccc2nc1-c1ccccn1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
2-(1-(5-Chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (220 mg, 532 μmol) was added to EtOH. To the resulting slurry was added hydrazine hydrate (133 μl, 2658 μmol) and the mixture was heated in an oil bath at 80° C. for 3 h. The reaction mixture was cooled to room temperature, filtered, and rinsed with EtOH (˜10 mL). The filtrate was acidified with 1.0 N HCl (˜5 mL) and concentrated on the rotavap to remove ethanol. A minor amount of solid precipitated and was removed by filtration. The filtrate was neutralized with solid sodium carbonate and extracted (2×) with DCM:IPA (4:1). The organic extracts were dried with sodium sulfate, filtered and concentrated to obtain 103 mg (68%) of a solid/film. LC-MS (+esi, M+H+=284.0). 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.42 (d, J=6.65 Hz, 3H) 4.71 (q, J=6.65 Hz, 1 H) 7.38-7.42 (m, 1 H) 7.60-7.68 (m, 2 H) 7.88-7.97 (m, 2 H) 8.02 (dq, J=7.78, 0.80 Hz, 1 H) 8.68-8.71 (m, 1 H) 8.82 (t, J=0.78 Hz, 1 H). LC-MS (+esi, M+H+=284.0).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@H:13]([O:18][S:34]([CH3:33])(=[O:36])=[O:35])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
206 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyrate was dissolved in 1,000 ml of methylene chloride and cooled to -10° C. After adding 79 g of triethylamine, 82.5 g of methanesulfonyl chloride was slowly added thereto under cooling at the same temperature. The obtained mixture was stirred at 15° to 0° C. for 1 hour and then 500 ml of water was added thereto to effect liquid/liquid separation. The organic layer was separated and washed successively with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. Thus 253 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-methanesulfonyloxy-4-phenylbutyrate was obtained as a pale yellow, oily substance.
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][CH3:3].CNC.C(=O)CC.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH:16]=O>>[CH3:19][O:18][CH:15]([O:14][CH3:13])[CH:16]=[C:2]([CH3:3])[CH:1]=[O:4]
Reactant: CCC(=O)O
Reactant: COC(C=O)OC
Agent: CNC
Solvent: CCC=O
Product: COC(C=C(C)C=O)OC
Temperature: 40 °C

Procedure:
Propionic acid (24.7 mL) was added carefully to an aqueous solution of dimethylamine (40%, 41.6 mL), stirring and cooling (ice-water bath) to ensure the temperature of the mixture did not exceed 10° C. A pale yellow solution formed and the cooling bath was replaced with a heating mantle. From this point on, the temperature was controlled by a digital controller; a temperature probe was placed in the flask and the mantle was connected to the controller. The mixture was warmed to 40° C., the solution became colorless and dimethoxyacetaldehyde (aq. 60%, 100 mL) was added. The mixture was heated to 60° C. and propionaldehyde (42.26 g) was added dropwise at such a rate that the temperature did not exceed 68° C. (ca. 30 min). During the addition the color of the mixture changed, first from yellow to orange, and then to brown. The mixture was vigorously stirred and the temperature was maintained at 70° C. for 24 hours. The reaction mixture was allowed to cool down to a room temperature and then was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate (3 g) and the solvents were evaporated on a rotary evaporator at the room temperature. 117 g of a dark reddish-brown material was obtained. The crude product was distilled under reduced pressure (<0.5 mm Hg) using a modified version of a falling film apparatus at 78° C. (the b.p. of ethyl acetate, which was used as the heating medium). The clear distillate (of formula II, R1 and R2 are methyl; 101 g) was collected in a trap cooled in a dry ice bath.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]#[N:19])=[CH:9][CH:8]=1>CS(C)=O.O>[OH:3][N:2]=[C:18]([NH2:19])[CH2:17][C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([Br:6])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: N#CCc1cccc2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: NC(Cc1cccc2ccc(Br)cc12)=NO
Temperature: 60 °C
Yield: 80.8 %

Procedure:
Hydroxylamine hydrochloride (1.14 g, 16.5 mmol) was dissolved in aqueous sodium hydroxide (1N, 16.5 mL, 16.5 mmol) and the solution diluted with DMSO (50 mL). 7-Bromo-2-naphthalenylacetonitrile (1.35 g, 5.5 mmol) was added in one portion and the resulting mixture heated to 60° C. After a total of 18 hours, the mixture was cooled to room temperature and diluted with water (100 mL) to give a precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give a tan solid (1.24 g, 81%) which was of sufficient purity for use in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O.[ClH:51]>CN(C=O)C.CCOCC>[OH2:10].[ClH:51].[ClH:51].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:45][CH2:46]3)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:45][CH2:46]3)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:51].[ClH:51]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(F)c(F)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CO1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(CCN2CCC(N3CCCCC3)CC2)(c2ccc(F)c(F)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
A mixture of 0.86 g of the compound obtained in step C of EXAMPLE 26 and 0.7 g of 4-(piperid-1-yl)-piperidine in 3 ml of DMF is heated at 70° C. for 4 hours 30 minutes. After cooling to RT, the reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with 1 N NaOH solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent. The product obtained is taken up with a saturated solution of hydrochloric acid in ether and the precipitate formed is wrung to give 0.49 g of the expected product. M.p.=260° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7](Cl)=[N:6][C:5]=2[NH:4][CH:3]=1.I[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>O.C1COCC1.CS(C)=O>[Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[N:6][C:5]=2[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: Clc1ncc2c(Br)c[nH]c2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CI)CC1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCCCNc1ncc2c(Br)cn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C

Procedure:
A 10 mL microwave tube was charged with 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.23 g, 1.0 mmol), tert-butyl trans-4-(iodomethyl)cyclohexylcarbamate (0.51 g, 1.5 mmol), K2CO3 (0.28 g, 2.0 mmol), DMSO (1.5 mL) and THF (3 mL). The mixture was heated at 150° C. for 100 min in microwave. After the reaction mixture was cooled to ambient temperature, n-butylamine (0.18 g, 2.5 mmol) was added. The mixture was heated at 150° C. for 90 min in microwave. After cooling to ambient temperature, the reaction was poured into water and extracted with EtOAc (3×). The combined organic layer was dried (Na2SO4) and concentrated. The crude mixture was purified by Isco to provide tert-butyl trans-4-((5-bromo-2-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)cyclohexylcarbamate (0.35 g, 73%) as a white solid. MS m/z 480.2 [M+H]+.