Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:34])=[O:32]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(=O)(=O)C(F)(F)F)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added Tf2O (203 mg, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 to 1:1 hexanes:EtOAc) to yield a colorless oil (312 mg, 82% yield). 1H NMR (CDCl3, 300 MHz): δ 9.39 (brs, 2H), 7.54 (d, J=3.0 Hz, 1H), 7.26 (m, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.08 (brs, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.27 (m, 2H), 1.50 (s, 9H), 1.39 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.7, 154.9, 154.3, 133.2, 132.8, 128.1, 113.2, 112.0, 84.7, 79.3, 65.8, 46.7, 40.7, 32.4, 28.5, 28.2; 19F NMR (CDCl3, 282 MHz): δ-75.5 (s).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1.Cl>N1C=CC=CC=1.O>[C:1]([OH:7])(=[O:6])[CH:2]=[CH:3][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of malonic acid (10.4 g, 0.1 mol) and the benzaldehyde (0.05 mol) in pyridine (20 mL) was added neat piperidine (0.75 mL, 7.6 mmol). The reaction mixture was stirred at 80° C. for 17 hr, chilled, then added to 200 mL cold water. This mixture was acidified with conc. HCl (25 mL) and the white precipitate collected by filtration, washed with 5×1 0 mL water, and dried to give pure cinnamic acid in typical yields of >95%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].I[CH2:15][CH3:16].Cl>C1COCC1.O>[CH2:15]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1)[CH3:16]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc(-c2cccnc2)c1
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of 34 (36 mg, 0.25 mmol) in THF (5 mL) under argon was added sodium hydride (12 mg, 0.29 mmol) in one portion and the resultant slurry was stirred for 20 min. Iodoethane (26 μL, 0.32 mmol) was added and the resultant solution was stirred for 10 min. The reaction was stopped by the careful addition of aqueous hydrochloric acid (1 N, 2 mL), diluted with 13 mL of water and washed with ethyl acetate (3×15 ml). Dichloromethane was added (25 mL) and the aqueous was adjusted to pH 9 with NaOH(aq) (10 N). The organic fraction was collected and the aqueous fraction was extracted with dichloromethane (20 mL), the combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.27) to afford the title compound 59 (34 mg, 79% yield) as a clear oil: 1H NMR (CDCl3) δ 8.93 (m, 1H), 8.44 (m, 1H), 8.07 (m, 1H), 7.54 (br s, 1H), 7.28 (m, 2H), 4.02 (q, J=7.4 Hz, 2H), 1.49 (t, J=7.4 Hz, 3H); LRMS (ESI) m/z calcd for C10H11N3 [M+H]+ 174. found 174; HRMS (ESI) m/z calcd for C10H11N3 [M+H]+ 174.1031. found 174.1042; HPLC>97% (tR=13.28 min, 60 (A):40 (B): 0.02 (C); tR=3.67 min, 80 (A):20 (B): 0.1 (C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C@:18]3([CH3:40])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:19]3)[N:12]=2)=[O:9])=[N:6][CH:7]=1.N12CCCN=C1CCCCC2>CO>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:13]2[N:12]=[C:11]([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:16]=[CH:15][C:14]=2[F:17])([CH3:40])[N:19]=1
Reactant: C[C@@]1(c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@@]1(c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of 5-chloro-N-(5-fluoro-6-((4S,6S)-4-methyl-2-(4-nitrobenzamido)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)pyridin-2-yl)picolinamide (8b, 76 mg, 0.131 mmol) in MeOH (1.3 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich, 254 μl, 1.701 mmol). The reaction mixture was stirred at 70° C. for 1 h. The reaction was diluted with MeOH and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min. The product containing fractions were combined and neutralized with aqueous saturated sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound as a white solid (39 mg, 12% yield over two steps). MS m/z=432 [M+H]+. Calculated for C17H14ClF4N5O2: 431.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27](Cl)[C:22]=2[S:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[C:22]=2[S:21][CH:20]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c(Br)csc34)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
30 mg of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol was dissolved in 2 ml of N,N-dimethylformamide and cooled to 0° C. 9 mg of NaH was added to the mixture and stirred for 30 min. 50 mg of 7-bromo-4-chloro-thieno[3,2-d]pyrimidine was added to the mixture, heated to room temperature and stirred for 2 hr. The resulting mixture was added with aqueous ammonium chloride and extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain a bubble residue. The resulting residue was crystallized in diethylether solvent to obtain 50 mg of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]1[O:17][CH2:8]1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2CO2)c1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 3-nitrostyrene (1.0 g, 6.70 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath. 3-Chloroperoxybenzoic acid (57% pure) (2.23 g, 7.38 mmol) was added in one batch and the stirring was continued for 18 h. The reaction mixture was concentrated to a residue and diluted with CCl4 (20 mL). Precipitated m-chlorobenzoic acid was removed by filtration and the flitrate was washed with a 50:50 mixture of 5% aq. NaHCO3 and 5% aq. NaHSO3 (100 mL). The organic extract was dried over Na2SO4 and concentrated under reduced pressure to yield 0.70 g (64%) of a yellow oil. 1H NMR (CDCl3) δ2.81 (m, 1, CH), 3.20 (m, 1, CH--), 3.97 (m, 1, --CH--), 7.62 (m, 2, phenyl), 8.16 (m, 2, phenyl).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:23][CH2:24][CH3:25])([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]1)=[O:5])[CH3:2].[Br-:26].[Li+]>CN(C=O)C>[Br:26][CH2:11][C@@H:8]1[O:7][C@@H:6]([P:4]([O:23][CH2:24][CH3:25])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9]1
Reactant: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirring solution of (±)-2-diethoxyphosphinoyl-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 60) (12.0 g, 30.61 mmol) in dry DMF (60 mL) was added anhydrous lithium bromide (13.3 g, 153.05 mmol). The solution was then stirred at 80° C. for 4 h. The mixture was cooled and concentrated to dryness under reduced pressure. The residue was then dissolved in methylene chloride and the solution was washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and concentrated. The cis-trans mixture was separated by flash chromatography eluting with 10→20% acetone in hexanes.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].Cl.O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29]([C:30]3[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:37])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CON(C)C(=O)c1cccnc1C
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of N-methoxy-2,N-dimethyl-nicotinamide (135 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via automated flash chromatography to afford the desired sulfonamide: 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1 H), 8.58 (d, 1 H), 8.22 (d, 2H), 7.81 (d, 2H), 7.53-7.46 (m, 3H), 7.20-7.14 (m, 1 H), 2.30 (s, 3 H), 1.31 (s, 9H); MS (ES) M+H expect 444.1, found 444.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([N@@:14]2[CH2:16][CH:15]2[CH3:17])=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]([N@@:14]2[CH2:16][CH:15]2[CH3:17])=[O:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N2CC2C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)N2CC2C)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (R)-(3-methoxy-4-nitrophenyl)(2-methylaziridin-1-yl)methanone (1 equiv) in MeOH (0.22 M) was added 10% palladium on carbon (18 weight %). The reaction was stirred at room temperature for 1 h under hydrogen. The mixture was filtered through a pad of celite and concentrated to give the desired product (94% yield) as a white solid. MS (ESI) m/z 207.1 [M+H]+.
Reaction SMILES: CC12C3(C)[N:6]4[CH2:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][N:13]1[CH2:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16][N:3]2[CH2:4][CH2:5]4.Cl>CO>[NH:6]1[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16][NH:3][CH2:4][CH2:5]1
Reactant: COC(=O)C1CN2CCN3CCCN4CCN(C1)C2(C)C34C
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCCNCCCNCCNC1
Temperature: 0 °C

Procedure:
A solution of 5.00 g (16.2 mmol) of compound 3 prepared in the preceding stage in 50 ml of absolute methanol is brought to reflux. 30 ml of a 35% aqueous hydrochloric acid solution are added in small amounts. Reflux is maintained for 48 hours. The mixture is cooled to 0° C. and the precipitate formed is filtered off and then washed with ice-cold methanol. The filtrate is evaporated and then the residue is taken up in the minimum amount of methanol. The precipitate formed is filtered off and washed with ice-cold methanol. Compound 5·4HCl is isolated in the form of a white powder (4.55 g, Yield =76%). Overall yield starting from the tetraamine: 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33](=[O:35])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]3[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=3[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Reactant: CCCCCCCNCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
N-[2-(4-Chlorophenyl)ethyl]-N-heptylamine (0.093 g, 0.366 mmol) was dissolved in DMF (5 ml). (4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.112 g of methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (yield 62.7%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[CH3:18][N:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)CCCC2=O

Procedure:
6-Acetamido-1-tetralone (10.0 g, 49.2 mmol) was dissolved in tetrahydrofuran (100 ml). Sodium hydride (oil, 3.0 g) was added to the solution, which was refluxed with heating under nitrogen atmosphere for 2 hours. After cooling, methyl iodide (30 ml) was added to the reaction mixture, which was refluxed with heating under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue, and extraction was conducted. The ethyl acetate layer was concentrated, and the residue was purified by alumina column chromatography (development solvent; ethyl acetate: n-hexane=33:67˜50:50). The product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate diisopropyl ether, to give the titled compound (4.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[S:23][C:24]([CH:27]=O)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[S:23][C:24]([CH2:27][N:49]6[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)s5)cc4c3C2)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)s5)cc4c3C2)nc1
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
To a 0° C. solution of methyl-2-{8-[5-(formyl)-thien-2-yl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.09 g, 0.21 mmol) in DCM (50 mL) was added Na(OAc)3BH (0.114 g, 0.53 mmol) and stirred for 10 min. To the reaction mixture was added N-methylpiperazine (0.107 g, 1.07 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was partitioned between DCM (100 mL) and water (15 mL) and the organic layer was separated, washed with water (2×10 mL), dried over sodium sulphate filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-thien-2-yl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.08 g).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:10]=1[NH2:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:11][C:10]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[CH3:8])=[O:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(NC(=O)C(C)(C)Br)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-bromo-2-methylpropanoyl bromide (4.50 g, 19.57 mmol) was added to a mixture of 2,4,6-trimethylaniline (2.41 g, 17.78 mmol), triethylamine (3.60 g, 35.56 mmol), and CH2Cl2 (20 ml) at 0° C. under Ar atmosphere. The cooling bath was removed after the addition was completed, and the reaction mixture was stirred at room temperature for 1.5 hour, after which time the mixture was diluted with CH2Cl2 (20 ml) and added aqueous solution of NH4Cl. After the aqueous phase was separated, the organic layer was washed with brine and dried over anhydrous MgSO4. Filtration and concentration of the filtrate gave 2-bromo-N-mesityl-2-methylpropanamide as a pale yellow solid (5.05 g, 17.78 mmol, 100%). A solution of this amide (284 mg, 1.00 mmol) in dry THF (5 ml) was added to a mixture of sodium hydride (60% in mineral oil, 80 mg, 2.00 mmol), aniline (112 mg, 1.20 mmol) and THF (5 ml), and the resulting mixture was stirred for overnight at room temperature. The mixture was then added an aqueous solution of NH4Cl (15 ml), extracted with ethyl acetate (20 ml×2), and the combined organic layer was washed with brine then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum, and the residue was purified by column chromatography on silica (eluent: Hexane/Ethyl acetate=5/1˜4/1) to give the amide as a white solid (255 mg, 0.86 mmol, Y=86%). 1H NMR (300 MHz, CDCl3): δ 8.35 (s, 1H), 7.25-7.17 (m, 2H), 6.84-6.71 (m, 5H), 3.98 (s, 1H), 2.23 (s, 3H), 2.11 (s, 6H), 1.63 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 173.8, 144.5, 136.4, 134.8, 131.0, 129.0, 119.2, 116.2, 58.4, 26.2, 20.8, 18.6. IR: 3341 (m), 3310 (s), 2987 (w), 1666 (s), 1607 (m), 1488 (s), 1376 (m), 1318 (m), 1264 (m), 1210 (m), 1162 (m), 850 (m), 749 (s), 696 (m) cm−1. HRMS Calc'd for C19H24N2O: 297.1967. Meas: 297.1956.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C#CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.7 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propynyl)-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propynyl)-3-D-galactopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][Br:20])[CH:23]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: BrCc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CBr)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2 g, 6.06 mmol) was suspended in 1,4-dioxane (250 mL). α,α′-Dibromo-m-xylene (8 g, 30.3 mmol) was added followed by sodium hydride (0.3 g, 7.5 mmol, 60% in mineral oil). The reaction was heated to 60° C. and stirred for 16 hours. The reaction was filtered through Celite® and the filtrate was concentrated to an oil that was partitioned between water and dichloromethane and extracted with dichloromethane (4×250 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (1.2 g, 38%). 1H NMR (400 MHz, CDCl3) δ 7.57 (app q, J=7.6 Hz, 1H); 7.28-7.25 (m, 2H); 7.17 (s, 1H); 7.08 (m, 1H); 6.94 (app dt, J=1.2, 9.6 Hz, 1H), 6.87-6.82 (m, 1H); 5.99 (s, 1H), 5.34 (s, 2H), 5.20 (s, 2H); 4.43 (s, 2H); 2.29 (s, 3H). ES HRMS m/z 511.9672 (M+H C21H17Br2F2NO2 requires 511.9667).