Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][Br:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(Cl)ccc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(CBr)cc2cc(Cl)ccc21
Temperature: 80 °C

Procedure:
A solution containing 5-chloro-2-methyl-indole-1-carboxylic acid tert-butyl ester (3.0 g, 11.3 mmol), NBS (1.33 g, 11.3 mmol), and benzoyl peroxide (0.4 g, 1.13 mmol) in CCl4 (100 mL) is heated at 80° C. for 3 hours. An additional portion of NBS (0.65 g, 5.65 mmol), and benzoyl peroxide (0.2 g, 0.56 mmol) is then added and the reaction mixture is heated for an additional 3 hours. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to a brown oil which is triturated with hexane to remove residual succinimide, filtered, and concentrated. The resultant oil (4.5 g, >100%) is used directly in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ1.72 (s, 9H), 4.88 (s, 2H), 6.63 (s, 1H), 7.27 (dd, J=9.0, 2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H) ppm; MS (EI): m/z 343 (M+).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25]O)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][F:27])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CF)CC1
Yield: 24.3 %

Procedure:
A mixture of (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (41 mg), perfluoro-1-butanesulfonyl fluoride (62 mg), triethylamine (62 mg) and triethylamine.trishydrofluoride salt (33 mg) in tetrahydrofuran (1 mL) was stirred 24 h at room temperature. The mixture was then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl:acetate (3:1 to 1:1 v/v) as eluant to afford the title compound (10 mg, 24%) as a colorless solid. MS (EI): 403.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:5][CH:4]1[C:6]([OH:8])=O.Cl.[NH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH:3]1[CH2:5][CH:4]1[C:6]([NH:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1)=[O:8]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: COC1CC1C(=O)O
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: COC1CC1C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 35.6 %

Procedure:
In the same manner as in Example 278 and using 2-methoxycyclopropanecarboxylic acid (86 mg, 0.74 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (280 mg, 0.74 mmol), N,N-diisopropylethylamine (190 mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (83 mg, 35%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:7]1[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:9][O:10][C:21]1([CH3:23])[CH3:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of (RS)-[2-hydroxy-1-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (7.97 g) in dichloromethane (400 ml) were added sequentially 2,2-dimethoxypropane (36 ml) and p-toluenesulphonic acid monohydrate (0.75 g) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with 0.5 N aq NaOH, the phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to afford (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.05 g, 89%) as a yellow solid. MS (EI): 403 (M+), 388 ([M-CH3]+), 332 ([M-CH3—C4H8]+), 288 ([M-CH3—C4H8—CO2]+), 57 ([C4H9]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Solvent: O
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl) thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 8.54 (d, 1H, J=0.9 Hz), 7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H , J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2.½ H2O: C, 58.0; H, 4.24; N, 9.05. Found: C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][CH3:8])[S:4][C:3]=1[C:9](OCC)=O.[CH:14]([NH2:16])=O.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[C:3]2[S:4][C:5]([S:7][CH3:8])=[CH:6][C:2]=2[N:1]=[CH:14][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1sc(SC)cc1N
Reactant: NC=O
Product: CSc1cc2ncnc(Cl)c2s1

Procedure:
As shown in scheme I, cyclisation of ethyl 3-amino-5-(methylthio)-thiophene-2-carboxylate using formamide and further treatment with phosphorous oxychloride gave 4-chloro-6-(methylthio)thieno[3,2-d]pyrimidine in good yield. Treatment of this 4-chlorocompound with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH gave 3-(6-(methylthio)thieno[3,2-d]pyrimidin-4-ylamino)-5-tert-butylselenophene-2-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][NH:39]3)=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:43][CH2:44][CH2:45][OH:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:44][CH2:45][OH:46])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)NCCC3)C1
Reactant: OCCCBr
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1

Procedure:
In analogy to the procedure described in example 4(a), the (3R,4R)-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was alkylated with 1-bromo-3-hydroxy-propane to yield the (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 637 (M+H)+.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])[C@@H:12]2[C@@H:15](OS(C)(=O)=O)[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])/[C:12]/2=[CH:15]\[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C1\C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C/NC(C)=O)C[C@H]12
Yield: 47.7 %

Procedure:
p-Nitrobenzyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e2) (100 mg) and powdered anhydrous potassium carbonate (62 mg) were stirred in dimethylformamide (2 ml) at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the product was then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2×20 ml) and brine (20 ml), then dried (MgSO4) and evaporated in vacuo. The residue was rapidly chromatographed on silica gel using ethyl acetate as eluant to afford p-nitrobenzyl (5R,6Z)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e3) (39 mg) as a foam; νmax (CH2Cl2) 1770, 1705 and 1625 cm-1 ; δ(CDCl3) 2.05 (6H, br, s+ d, CH3CO and CH3CH), 3.04 (2H, m, centre of AA'X, 4-CH2) 4.61 (1H, br t, J 8.5 Hz, 5-CH), 5.18 and 5.46 (each 1H, d, J 14 Hz, CH2Ar), 5.82 (1H, d, J 13.5 Hz, =CH.S), 5.90 (1H, m, CH3CH), 7.15 (1H, dd, J 10.5 and 13.5 Hz, NHCH=), 7.58 and 8.13 (each 2H, d, J, 9 Hz, ArCH2), and about 8.05 (1H, br d, NH).
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([C:15](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)[CH3:13]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[N:6]2[CH:5]=[N:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[NH:1][C:12]=1[CH3:13])=[O:17])[CH3:20]
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(C(=O)OCC)ncn2C1c1cccc([N+](=O)[O-])c1
Yield: 48.4 %

Procedure:
A solution of 2 g of 5-amino-4-ethoxycarbonylimidazole and 3.4 g of ethyl α-acetyl-3-nitrocinnamate in 50 ml of ethanol is refluxed under heating for 7 hours under a nitrogen atmosphere. The ethanol is removed under reduced pressure, the resulting oil is purified by column chromatography on silica gel with a mixture of chloroform and methanol as eluent. Recrystallization from a mixture of isopropyl alcohol and isopropyl ether gives 2.5 g of 3,8-diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine, melting at 160°-162° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=1.[O-:11]S([O-])(=O)=O.[Na+].[Na+].C>CCOC(C)=O.CCO.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:9]([NH2:10])=[O:11])[S:7][CH:8]=1
Reactant: N#Cc1cc(Cl)cs1
Reactant: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1cc(Cl)cs1
Temperature: 28 °C
Reaction time: 1.25 h
Yield: 31 %

Procedure:
Equip a 12-L reaction flask with a cooling bath, air stirrer, and thermometer probe and charge with KOH (288.6 g, 5.143 moles) and water (6.04 L) to form a solution that exotherms to about 31° C. Allow the solution to cool to about 28° C., and charge the mixture with 4-chloro-2-thiophene carbonitrile (671.3 g, 4.675 moles) (a small amount of solids are undissolved). Add EtOH (675 mL), at which time a gradual exotherm occurs and continues over 1-1.5 h to about 38° C. Stir the reaction at ambient temperature overnight. Filter the reaction mixture under vacuum, wash with water, and dry to give crude product. Dissolve the solids in EtOAc (10.0 L), treat with Na2SO4 and activated charcoal for 1-2 h, then filter and wash with EtOAc. Concentrate the filtrate on a rotary evaporator at 45° C. until solids begin to precipitate out. Release the vacuum and increase the temperature to 60-65° C. to redissolve the solids. With stirring at 60° C., add heptane (3.5 L) slowly to precipitate solids. Stir for 15-20 min at 60° C., then cool the mixture to 30-40° C. and filter. Wash the solids with heptane (2×0.75 L), and dry to give the title compound as a white solid (235.4 g, 31%). Obtain a second crop (67.8 g, 9%) from the filtrate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CCOC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=4[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=3)=[O:9])[CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26, 50 mg, 0.159 mmol) and 4-chlorophenylacetic acid (27.2 mg, 0.159 mmol) in pyridine (1 mL) was added HATU (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% MeOH in DCM to afford the title compound (28 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([O:22][C:4]([CH3:8])([CH3:5])[CH3:3])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reaction time: 3 h
Yield: 143.9 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1 g, 1.992 mmol) in CH2Cl2 (30 mL) and t-butyl acetate (21.00 mL) at rt was added 70% perchloric acid (0.513 mL, 5.97 mmol). After 3 h, the reaction mixture was diluted with CH2Cl2 (100 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (800 mg, 1.433 mmol, 72.0% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.20 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 5.59 (s, 1H), 3.76 (s, 3H), 2.70 (s, 3H), 1.32 (s, 9H). LCMS (M+H)=560.15.
Reaction SMILES: Cl.C1(NCC2CCCCC2N)CC1.[CH:14]1([N:17]2[CH2:26][CH:25]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:19]3[C:27](=[O:56])[C:28]4[N:29]([CH:31]=[C:32]([C:44]([NH:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=5[F:55])=[O:45])[C:33](=[O:43])[C:34]=4[O:35]CC4C=CC=CC=4)[CH2:30][CH:18]23)[CH2:16][CH2:15]1>>[CH:14]1([N:17]2[CH2:26][CH:25]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:19]3[C:27](=[O:56])[C:28]4[N:29]([CH:31]=[C:32]([C:44]([NH:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=5[F:55])=[O:45])[C:33](=[O:43])[C:34]=4[OH:35])[CH2:30][CH:18]23)[CH2:16][CH2:15]1
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2
Agent: Cl
Agent: NC1CCCCC1CNC1CC1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2

Procedure:
In a manner similar to that described in example Z-35, from 16a (45 mg, 0.0957 mmol) and racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine hydrochloride (102 mg, 0.425 mmol) was prepared racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12[(phenylmethyl)oxy]1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2″,4,5]pyrazino[1,2a]quinazoline-10-carboxamide as a white solid after silica gel chromatography (1-12% methanol/dichloromethane gradient elution). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (56 mg, 0.0949 mmol) the title compound was prepared as a white solid (41 mg, 81%). 1H NMR (CDCl3) 12.10 (br s, <1H), 10.45 (m, 1H), 8.27 (s, 1H), 7.33 (m, 1H), 6.88 (m, 2H), 477 (m, 1H), 4.61-4.49 (m, 4H), 4.33 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H), 2.17 (m, 1H), 1.86-0.86 (m, 10H), 0.658 (m, 1H), 0.499-0.32 (m, 2H); ES+ MS: 499 (M+1),
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[F:13][C:14]1[C:15]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:16][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:18][CH:19]=1>C(Cl)Cl.CN(C=O)C>[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:17]3[N:16]=[C:15]([N:36]4[CH2:37][CH2:38][N:39]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:40][CH2:41]4)[C:14]([F:13])=[CH:19][N:18]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: N#CCC(=O)O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCN(C(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.83 h
Yield: 63.9 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 50 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(5-fluoro-4-(piperazin-1-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (23 mg, 0.057 mmol) and TEA (0.400 mL, 2.87 mmol) in DMF (1 mL) was added drop wise. The mixture was then stirred at room temperature for 90 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (17 mg). MS 467.5 (M+H); UV 201.0, 269.4 nm
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:27][NH2:28])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:16])[NH:27][NH2:28])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reaction time: 2 h
Yield: 118.9 %

Procedure:
A mixture of Example 1a (1 g, 3.51 mmol) and tert-butylcarbazate (465 mg, 3.51 mmol) in DCM (10 mL) was stirred at rt for 2 h. Trifluoroacetic acid (2 mL) was added and mixture was stirred for 2 h. The solvent was removed and the residue was dissolved in EtOAc (15 mL), washed with saturated sodium bicarbonate solution, dried (anh. MgSO4), filtered and evaporated to give the title compound (1.32 g) as a brown solid. (M+H)+=317.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]C1C=CC([N+]([O-])=O)=CC=1)=O.Cl.[NH2:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>CN(C)C=O>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:26]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)C(=O)N[C@@H](CO)C(=O)O

Procedure:
1.5 ml of triethylamine are added to a solution of 4.2 g of 4-nitrophenyl 2-(2,6-dichlorophenyl-amino)-phenyl-acetate and 3.6 g of the hydrochloride of the methyl ester of L-leucyl-L-serine in 30 ml of dimethylformamide and the mixture is allowed to react for one hour at room temperature. It is then acidified to pH 5 with 1 N hydrochloric acid and partitioned between chloroform and water. After washing with water, the organic phase is dried and evaporated. The residue is ground with diethyl ether. After recrystallising from a mixture of ethyl acetate and petroleum ether, the methyl ester of N-{[2-(2,6-dichlorophenyl-amino)-phenyl]-acetyl}-L-leucyl-L-serine is obtained as colourless crystals; melting point 216°-218°: [α]D =-30° (c=0.635 in chloroform).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9]CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:4]1.[H][H]>[Pd].CO>[NH2:9][C@H:8]1[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[CH2:4][C@H:3]1[O:2][CH3:1]
Reactant: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1N
Yield: 71.4 %

Procedure:
A mixture of 53 parts of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1-piperidinyl]-1-oxobutyl]pyrrolidine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 28.3 parts (71.4%) of cis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine as a residue (int. 43).