Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11]N=C[CH:8]=2)[O:5][CH:6]=1.BrC1OC([Si](C)(C)C)=C(Br)C=1.[N:24]1C=CC=C(B(O)O)[CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[N:24][CH:25]=[CH:11][CH:12]=2)[O:5][CH:6]=1
Reactant: Brc1coc(-c2ccncc2)c1
Reactant: OB(O)c1cccnc1
Agent: C[Si](C)(C)c1oc(Br)cc1Br
Product: Brc1coc(-c2cccnc2)c1

Procedure:
The sub-title compound was prepared by a method analogous to that described for the preparation of 4-bromo-2-(4-pyridyl)-furan from 2,4-dibromo-5-(trimethylsilyl)furan and pyridine-3-boronic acid. The sub-title compound (725 mg) was obtained as a beige solid, m/z 224,226 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl.[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36](O)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.[N-]=[N+]=[N-]>CN(C)C=O>[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36]([NH:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: NC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](N)C1CCCCC1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 82.4 %

Procedure:
Stir overnight H-(L)-Chg-(L)-Pal-NH2.2HCl (1.13 g, 3 mmol), Ac-(L)Phe(4-CN)-OH (0.84 g, 3.6 mmol), diisopropylethylamine (10 mmol). and diphenylphoshoryl azide (803 μl 3.6 mmol) dimethyl formamide (30 mL) overnight. Evaporate dimethyl formamide, precipitate by ether, filter and wash by ether to give Ac-(L)-Phe(4-CN)-(L)-Chg-(L)-Pal-NH2 (1.282 g, 82%). ##STR21##
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[S:7][C:6]1=[O:16].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[S:7][C:6]1=[O:16])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc2c(c1)sc(=O)n2CCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCn1c(=O)sc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carbaldehyde (Intermediate 71, 158 mg, 0.67 mmol) in CH2Cl2 (5 mL) was added Et3N (0.11 mL, 0.80 mmol) and the mixture was cooled to 0° C. To this solution, methanesulfonyl chloride was added dropwise (57 μL, 0.74 mmol) and the mixture was maintained at 0° C. for 90 min. CH2Cl2 and 4% aqueous sodium bicarbonate solution (10 mL) were added to the reaction mixture and stirred for 10 min. The two layers were separated and the organic phase was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the title compound as a colourless oil (243 mg, 99% yield) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[CH:5]2.F[B-](F)(F)F.[CH3:20][O+](C)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:20])[C:6]([C:13]#[N:14])=[CH:5]2
Reactant: C[O+](C)C
Reactant: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1nc2ccc(Br)cc2cc1C#N

Procedure:
A suspension of 6-bromo-3-cyano-2-[1H]-quinolone (14.6 g) in dichloromethane (150 cm3) was stirred under nitrogen with trimethyloxonium tetrafluoroborate (10.35 g) for 2 days. A solution of 2M sodium hydroxide (100 cm3) was added and the aqueous phase was extracted with dichloromethane (3×200 cm3). The dried (MgSO4) extracts were concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with hexane:ethyl acetate, 4:1, to give a solid which was recrystallised from ethyl acetate to afford 6-bromo-3-cyano-2-methoxyquinoline, m.p. 169°-172°, (1.96 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([Br:19])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[Br:19][C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Br)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 126B (760 mg, 2.1 mmol), 4-fluorobenzenesulfonyl chloride (600 mg, 3.1 mmol), dichloromethane (10 mL), and pyridine (0.69 mL, 8.5 mmol) was stirred for 18 hours, diluted with dichloromethane (100 mL), washed with 0.5M HCl (2×100 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) eluted with 50-75% dichloromethane/hexanes to provide the desired product. MS (ESI(+) lm/e 478, 480 (M+H)+, 495, 497 (M+NH4)+, 500, 502 (M+Na)+; (ESI(−)) m/e 476, 478 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.73 (m, 2H), 7.62 (d, 1H), 7.40 (m, 7H), 6.85 (d, 1H), 5.25 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[O:24])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:27]([O-:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[OH:24])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP([O-])OCC
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOP(=O)(OCC)C(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5.0 ml dichloromethane solution of 500 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 0.23 ml of diethyl phosphite and 0.22 ml of 1,8-diazabicyclo[5.4.0]-7-undecene at −40° C., followed by overnight stirring at room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with chloroform and then washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 400 mg of diethyl [[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)methyl]phosphonate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.CC1(C)C(C)(C)OB([C:29]2[CH:33]=[CH:32][NH:31][N:30]=2)O1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:29]4[CH:33]=[CH:32][NH:31][N:30]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Product: NC(=O)c1nc2n(c1-c1cc[nH]n1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.2 g) was reacted with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole similar to as described in Example 4 and triturated from water followed by methanol to give 107 mg of 10-bromo-9-fluoro-3-(1H-pyrazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 3.3 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-pyrazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][CH2:11][C@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:11][O:10][N+:8]([O-:22])=[O:9]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (6.42 mL, 58.9 mmol) was added dropwise to a stirred solution of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (12 g, 53.5 mmol) and triethylamine (8.95 mL, 64.2 mmol) in DCM (268 mL) at 0° C. After 2 h, the solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5-40% EtOAc/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.40 (q, J=6.0 Hz, 1H), 5.28 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.74 (dd, J=13.0, 3.0 Hz, 1H), 4.47 (dd, J=13.0, 6.5 Hz, 1H), 4.25-4.16 (m, 2H), 1.82 (d, J=6.0 Hz, 3H), 1.82-1.71 (m, 4H), 1.63-1.46 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)oc1=O
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a sealed vial is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 0.215 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (57 mg, 0.258 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and 2M aq. Na2CO3 (0.45 ml, 0.9 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-4% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford the title compound (24 mg, 25%) as a off-white solid. LCMS (ESMS): m/z 442.43 (M++1).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[C:7]([N:12]2[C:16]([C:17]3[O:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=[C:27]([CH3:28])[C:19]=4[N:18]=3)=[CH:15][C:14]([C:32]([F:35])([F:34])[F:33])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1>O1CCOCC1>[Cl:5][C:6]1[C:7]([N:12]2[C:16]([C:17]([NH:18][C:19]3[C:20]([C:21]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[CH:26][C:27]=3[CH3:28])=[O:22])=[CH:15][C:14]([C:32]([F:35])([F:34])[F:33])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 8 h
Yield: 14.3 %

Procedure:
Isopropyl amine (0.35 mL, 4.11 mmol) was added to a solution of 619 mg (1.37 mmol) of the product of Step B in dioxane (8 mL) at 25° C. After being stirred overnight, the resulting heterogenous mixture was concentrated and the residue was triturated with methanol (10 mL). Filtration gave 100 mg of the title product. The filtrate was concentrated and the resulting residue was triturated with diethyl ether. Filtration of the resulting solid provided an additional 320 mg of the title product, m.p. 170-172° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:13]2[C:14]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:6][CH2:7]3)[N:12]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: O=C1CCC(=O)N1
Reactant: CCCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound A8) and succinimide as starting compounds.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH:12]([CH:16]([S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:51][NH2:52]>C(Cl)Cl>[OH:51][NH:52][C:13](=[O:14])[CH:12]([CH2:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:16]([S:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)O)cc1OC
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)NO)cc1OC
Reaction time: 0.5 h
Yield: 189.5 %

Procedure:
To a solution containing (-)-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanoic acid (285 mg, 0.53 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen atmosphere is added anhydrous DMF (41 μL, 0.53 mmol) followed by oxalyl chloride (2 M in CH2Cl2, 0.66 mL, 1.31 mmol). The yellow solution is stirred for 30 minutes then O-(trimethylsilyl)hydroxylamine (0.32 mL, 2.65 mmol) is added dropwise. The resulting white precipitate is stirred for 10 minutes then partitioned between 1 N HCl (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×20 mL) and the combined organic extracts are washed with water (30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a pale yellow oil. The crude product is combined with the product of a reaction performed on identical scale and chromatographed on silica gel (CH2Cl2 →CH2Cl2 :MeOH, 19:1) to afford (-)-N-hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanamide (560 mg, 95%) as a cream-colored foam. TLC analysis [pet-ether/EtOAc, 1:2, Rf (carboxylic acid)=0.45, Rf (hydroxamate)=0.40]. [α]23D -28° (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40-1.80 (m, 6H), 2.10 (m, 1H), 2.22 (m, 1H), 2.60 (m, 2H), 2.68 (m, 1H), 3.05 (broad s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 6.76 (d, J=8.7 Hz, 1H), 6.98 (m, 2H), 7.12 (m, 3H), 7.28 (m, 2H), 7.52 (m, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.84 (d, J=7.4 Hz, 2H), 8.85 (broad s, 1H) ppm. Mass spectrum (FAB) m/z 557 (M)+.
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=NC=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([CH:29]([CH3:31])[CH2:30][CH3:2])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CCC(C)[C@@H](CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
Intermediate I was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.88-0.95 (m, 6H) 1.11-1.20 (m, 1H) 1.34 (s, 9H) 1.44-1.54 (m, 1H) 1.64-1.72 (m, 1H) 3.17-3.27 (m, 1H) 3.33-3.43 (m, 1H) 4.11-4.21 (m, 1H) 4.81 (s, 1H) 5.92 (d, J=8.20 Hz, 1H) 8.05 (s, 1H). LCMS (ESI) 407.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCN
Product: CCNC(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride is reacted with ethyl amine using General Method E1 or E2, to produce the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.[CH2:17](Br)[CH3:18]>CN(C)C=O>[Br:3][C:4]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CCBr
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of NaH (60%, 0.15 g, 3.75 mmol) in anhydrous dimethylformamide (10 mL) was added 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.68 g, 2.50 mmol) at room temperature and the reaction was stirred at 50° C. for 0.5 h. The reaction mixture was cooled down to room temperature and ethyl bromide (0.22 mL, 0.32 g, 2.93 mmol) was added and stirred at 50° C. for 1.5 h. After completion, the mixture was poured onto ice water (10 g), and the white precipitate was filtered off to give 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.57 g, 1.90 mmol, 76%). ESMS m/z 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[CH3:32][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: Cc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 73.6 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and meta-tolyl isocyanate (0.0095 mL, 0.076 mmol) were reacted to give the title compound as a pale tan solid (21.6 mg, 73%). 1H NMR (DMSO-d6) δ: 10.68 (br. s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 7.98 (dd, J=7.9, 1.2 Hz, 1H), 7.41-7.45 (m, 3H), 7.29 (s, 1H), 7.21-7.25 (m, 3H), 7.13-7.16 (m, 1H), 7.05-7.08 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.78 (d, J=7.3 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.51-3.59 (m, 2H), 2.93-2.99 (m, 1H), 2.27 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:27])([CH3:26])[C:23]#[C:24][CH3:25])[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C.[ClH:36].CO>CCOC(C)=O>[ClH:36].[ClH:36].[CH3:27][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:28][CH3:29])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:26])[C:23]#[C:24][CH3:25]
Reactant: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of Compound 56 (73 mg, 0.15 mmol) in AcOEt (6 ml) was added an excess amount of 10% HCl-MeOH (3 ml), and stirred for 18 h. After the solvent was evaporated in vacuo, the residual solid was recrystallized from MeOH-ether to give Compound 57 (48 mg, 78%) as a white solid.
Reaction SMILES: [S:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)([CH3:4])(=[O:3])=[O:2].[ClH:26].CCCCCC>C(OCC)(=O)C>[ClH:26].[CH3:4][S:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCOS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)OCCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.06 g of tert-butyl N-(12-mesyloxydodecyl)carbamate in 60 ml of ethyl acetate was added 10 ml of hydrochloric acid under ice-cooling and the mixture was stirred at room temperature for one hour. The reaction solution was cooled with ice, hexane was added, the crystal thus precipitated out was recovered by filtration and dried under reduced pressure to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([O:18][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 58 (55 mg) in anhydrous tetrahydrofuran (3 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (10 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat ethyl bromoacetate (0.026 mL) in one charge the reaction was then allowed to warm to ambient temperature under an atmosphere of nitrogen over 30 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL). The extract was dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to provide the title compound (14 mg). LC/MS MH+ 391, Rt 1.84 min (5 min run).