Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Pd]>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1ccccc1[N+](=O)[O-])OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(Cc1ccccc1N)OCC

Procedure:
1.13 g of (2-nitro-benzyl)-phosphonic acid diethyl ester) in ethanol are hydrogenated with Pd—C as a catalyst for 5 hours at rt and ambient pressure. The catalyst is removed by filtration and from the filtrate obtained solvent is evaporated. (2-Amino-benzyl)-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH:5]=O.Cl.NO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N:28]1C(C)=CC(C)=CC=1C.[Li+].[I-]>N1C=CC=CC=1.CCO.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:28]
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: Cc1cc(C)nc(C)c1
Agent: Cl
Agent: NO
Agent: [I-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#Cc1cc(O)cc(Br)c1
Temperature: 60 °C
Yield: 92 %

Procedure:
A solution of 3-bromo-5-methoxybenzaldehyde (4.02 g, 18.7 mmol) and hydroxylamine hydrochloride (6.50 g, 93.5 mmol) in pyridine (50 mL) and EtOH (50 mL) was heated to 65° C. for 16 h. The solvent was removed, and the remaining materials were partitioned between 1:1 EtOAc/hexanes (150 mL) and H2O (75 mL). The organic layer was washed with brine (60 mL), and the solvents were evaporated. The remaining oil was dissolved in anhydrous dioxane (50 mL), and trifluoroacetic anhydride (5.1 mL, 37.4 mmol) and pyridine (9.07 mL, 112.2 mmol) were added. The mixture was heated to 60° C. for 3 h and then cooled to RT. CHCl3 (100 mL) was added, and the organic layer was washed with H2O (2×50 mL), 5% aqueous HCl solution (30 mL), brine (30 mL), and dried with anhydrous MgSO4. The solvents were removed to provide a white solid. This solid was placed in a 150 mL flask that was flushed with nitrogen. Collidine (40 mL) and LiI (7.92 g, 59.10 mmol) were added, and the mixture was heated to 180° C. for 5 h. The reaction mixture was cooled to RT, and partitioned between H2O (400 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was acidified with 10% aqueous HCl solution, and extracted with 2:1 EtOAc/hexanes (3×125 mL). The combined organic layers were washed with H2O (100 mL), 10% aqueous HCl solution (2×50 mL), brine (75 mL), and dried with anhydrous MgSO4. The solvents were evaporated and the resulting solid was purified by flash chromatography on silica gel (10% to 40% EtOAc/hexanes) to provide 3.40 g (92%) of 3-bromo-5-hydroxybenzonitrile (116).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][C:13]#[N:14])[CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C(O)C>[Cl:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[C:13]#[N:14])[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N#CCc1cc(Cl)c2c(c1)OCO2
Agent: [Na]
Solvent: CCO
Product: N#CC(C(=O)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Yield: 112.6 %

Procedure:
Under reflux, 1.7 g of sodium (72.8 mmol) was dissolved in 50 ml of ethanol. At 50° C., a solution of 14.2 g (72.8 mmol) of 2-(7-chloro-1,3-benzodioxol-5-yl)acetonitrile and 10.3 g (72.8 mmol) of ethyl trifluoroacetate in 50 ml of ethanol was added dropwise, and the reaction mixture was then stirred under reflux for 12 hours. After cooling, the reaction mixture was concentrated on a rotary evaporator, dissolved in ethyl acetate and washed twice with 100 ml of 1N hydrochloric acid and once with water. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated to give the title compound (23.9 g; 100%) and used for the next step directly.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: COc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Yield: 46.9 %

Procedure:
The process is carried out according to the method described in step 5.1, using 5.4 g (28.64 mmol) of 2-chloro-4-methoxy-5-nitropyridine (WO 03/080610) and 4.53 g (63 mmol) of pyrrolidine. The product obtained is, in this case, purified by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate. 3 g of the expected product are thus isolated.
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CN(C=O)C.[Cu]I>[CH3:14][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[C:5]1[CH:17]=[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:24])[CH3:25])[C:2]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:3][C:4]2=1
Reactant: c1cn[nH]c1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-n3cccn3)cc21
Temperature: 170 °C
Yield: 29.2 %

Procedure:
To the solution of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.096 mmol) and 1H-pyrazole (7.88 mg, 0.116 mmol) in 1,4-dioxane (2 mL) and DMF (0.5 mL), was added copper(I) iodide (18.37 mg, 0.096 mmol), N1,N2-dimethylethane-1,2-diamine (17.00 mg, 0.193 mmol) and potassium phosphate (61.4 mg, 0.289 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated to 170° C. for 1 h in a microwave. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth (Celite®) and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC (eluent 2% MeOH:DCM) to afford (S)-tert-butyl 1-(4,6-dimethyl-5-oxo-9-(1H-pyrazol-1-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (40 mg, 0.028 mmol, 29% yield) as a brown solid. LC/MS (ESI) m/e 406.5 [(M+H)+, calcd for C23H28N5O2 406.2] LC/MS retention time (method E): tR=0.71 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N:12]([O-])=O.[Na+]>Cl.O.C([O-])(=O)C.[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:11])[CH:10]=[N:12][NH:1]2)=[CH:4][CH:5]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(C)cc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(=O)cn[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-4-methylphenylethanone (5.0 g, 33.6 mmol) in concentrated HCl (100 mL) is treated, in portions, with a solution of sodium nitrite (5.7 g, 82.6 mmol) in water (˜10 mL). The resulting solution is stirred at 60° C. for 2 hr, cooled to ambient temperature and diluted with a saturated solution of sodium acetate (˜200 mL). Solid sodium acetate is added portionwise until the solution tested basic to pH paper. Upon stirring, the title compound precipitated as a white solid which is collected and air dried (2.3 g, 14.3 mmol). MS m/z: [M+H]+=161; 1H NMR (CDCl3, 300 MHz) δ8.1 (d, 1H), 7.85 (s, 1H), 7.45 (s, 1H) 7.3 (d, 1H), 2.55 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([CH2:23]O)[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([CH2:23][Cl:3])[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnn(Cc2ccccc2)c1-c1ccccc1
Solvent: Cc1ccccc1
Product: ClCc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Thionyl chloride (4.35 g) was added to a solution of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)methanol (8.06 g) in toluene (100 ml) dropwise at 0° C., and the mixture was stirred at room temperature for one hour and then refluxed for ten minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g, yield: 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:34][C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40](Cl)=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](/[CH:15]=[CH:14]/[C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH:12]=[CH:11][C:10]=2[NH:13][C:40]([C:36]2[S:37][CH:38]=[CH:39][C:35]=2[CH3:34])=[O:41])=[N:17]1
Reactant: CCN(CC)CCOc1ccc(N)c(/C=C/c2n[nH]c3ccccc23)c1
Reactant: Cc1ccsc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)c2sccc2C)c(/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Crude (E)-N-(2-{3-[2-(1H-indazol-3-yl)vinyl]-4-nitrophenyloxy}ethyl)diethylamine (2.0 g, 5.2 mmol) obtained in Step 1 was dissolved in ethanol (20 mL) and the solution was treated by tin (1.9 g, 16 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature in a similar manner to Example 2, to obtain (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine. In a similar manner to Example 29, (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine (0.49 g, 1.4 mmol) was dissolved in THF (15 mL) and the solution was added with triethylamine (0.58 ml, 4.2 mmol) and 3-methylthiophenecarbonyl chloride (0.23 g, 1.4 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was triturated in ethyl acetate to obtain Compound 237 (0.42 g, 63%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4].[Se](=O)=[O:20]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=[O:20])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4]
Reactant: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reactant: O=[Se]=O
Solvent: O
Product: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reaction time: 8 h
Yield: 18 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and argon-filled balloon, 7-chloroacetamido-2-methylquinoline-5,8-dione (28) (prepared as described in Example 28) (0.529 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and allowed to go to completion (29.5 hours). The selenium was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4° C. overnight. Solid precipitate from the chilled mixture was filtered yielding 0.0985 g. of crude product (yield of 18%). This was purified by recrystallization from ethyl acetate/dichloromethane. The original remaining filtrate was diluted with 50 ml of dichloromethane and washed with 3% sodium bicarbonate solution (2×50 ml.). The aqueous layer was then extracted with dichloromethane (2×20 ml.) The organic layers were dried with magnesium sulfate and rotoevaporated to give a dark orange solid. The product was dried under vacuum overnight and 0.2941 g. of product was obtained (yield of 52%, total 70%). This product could be further purified by flash chromatography and recrystallization from ethyl acetate/dichloromethane: mp 190°-192° C.; 1H NMR (CDCl3) δ 4.26 (2H, s, C-7NHCOCH2Cl), 8.04 (1H, s, C-6H), 8.33 (1H, d, J=8.1 Hz, C-3H), 8.62 (1H, d, J=8.1 Hz, C-4H), 9.54 (1H, br. s, C-7NH), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3310, 3089, 2950, 2852, 1731, 1720, 1678, 1644, 1521, 1118 cm-1 ; EIMS, m/e (relative intensity) 278/280 (M+, 2.7/1, 95), 243 (33), 229 (33), 215 (55), 202 (base), 175 (61), 146 (17); HRMS, m/e for C14H9ClN2 O3 calculated 278.009435, found 278.008764; analysis for C14 H9ClN2O3 calculated C, 51.72; H, 2.53; Cl, 12.72; N, 10.05; Found C, 51.81; H, 2.9; Cl, 12.79; N, 9.86.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:12]1[CH2:16][CH:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:15]1[O:14][C:13](=[O:26])[N:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(F)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CO)N1CC(COc2cccc(F)c2)OC1=O
Yield: 96.5 %

Procedure:
A procedure similar to that described in Preparation (b) was repeated, except that 0.93 g of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(3-fluorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 72), 9 ml of anhydrous tetrahydrofuran and 7.2 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) were used, to give 0.63 g of the title compound having an Rf value of 0.18 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[NH4+].[OH-].C(Cl)Cl>CO>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[NH:8][CH2:7][CH2:6][CH:5]4[OH:12])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: OC1CCNc2ncc(Br)cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Yield: 22 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (89 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (125 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-10% (5% NH4OH in methanol)/methylene chloride as the eluting solvent gave the title compound as brown solids (22% yield). M.p. 124-128° C., LCMS: m/z=326 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.08 (s, 1H), 2.62 (t, J=5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m, 2H), 3.63 (t, J=5.0 Hz, 4H), 4.85 (t, J=4.0 Hz, 1H), 6.68 (s, 1H), 6.71 (s, 1H), 7.59 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=2)[CH2:7][CH:8]=[CH:9][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(C=O)s2)CC=CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1(c2ccc(CO)s2)CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step 2, above (3) (0.93 mmol), in 3 ml methanol at 0° C. was added sodium borohydride (2.0 mmol). The reaction was slowly allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was quenched with saturated ammonium chloride and extracted (2×10 ml EtOAc). The organic extracts were combined and washed with saturated sodium bicarbonate and brine, dried with MgSO4, filtered and concentrated to yield the title compound (4).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@H:6]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C@@:6]3([CH3:24])[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@@]2(C)CO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (124 mg, crude) was added iodomethane (0.25 mL, 4 mmol) and DMSO (2 mL). The mixture was cooled to 0° C. and then −78° C. and sodium 2-methylpropan-2-olate (0.154 g, 1.6 mmol) was added, followed by more DMSO (0.7 mL). The cooling bath was removed and the mixture was stirred at room temperature for 14 hours and then diluted with EtOAc and water, extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] found 323.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19]C)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:11]([N:8]1[CH2:9][CH2:10][C:6]([CH2:18][OH:19])([CH2:4][O:3][CH3:1])[CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(COC)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1(CO)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A solution of 1-benzyl-3-methoxymethylpyrrolidine-3-carboxylic acid ethyl ester (Example A18a, 2.30 g, 8.3 mmol) in anhydrous tetrahydrofuran (10 mL) is added dropwise to an ice-cold suspension of lithium aluminum hydride (0.821 g, 22 mmol) in tetrahydrofuran (50 mL). The resulting mixture is stirred at room temperature for 18 hours, cooled and quenched by the sequential dropwise addition of 1N sodium hydroxide and water. The solids are removed by filtration, re-suspended in hot tetrahydrofuran and filtered. The combined filtrates are concentrated in vacuo and the residue is partitioned between dichloromethane and water. The organic extracts are dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (1.71 g). 1H NMR (200 MHz, CDCl3): δ 7.41-7.17 (m, 5H), 3.84-3.43 (m, 4H), 3.34 (s, 2H), 3.32 (s, 3H), 2.85-2.60 (m, 2H), 2.54-2.14 (m, 31), 1.98-1.50 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][C:8](=[O:20])[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH2:21]([N:7]1[C:8](=[O:20])[CH2:9][C@@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 8.4 g (22.2 mmol) of methyl-trans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate in 200 mL of 3:1 tetrahydrofuran/methanol was added 50 mL (50 mmol) of a 1N aqueous lithium hydroxide solution and the resulting mixture was stirred at 60° C. for 2 h. The solution was concentrated and acidified with 100 mL of 1N aqueous hydrochloric acid. The resulting mixture was then extracted with three 250-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid and saturated aqueous brine (200 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title acid as a colorless foamy solid that was used without further purification. LC/MS 364.3 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:14]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: c1ccc(C[C@H]2CN(Cc3ccccc3)CCN2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C[C@H]2CNCCN2)cc1
Yield: 47.3 %

Procedure:
A mixture of 0.32 gm (1.2 mMol) 1-benzyl-3(S)-benzylpiperazine and 0.06 gm 20% palladium(II) hydroxide on carbon in 50 mL methanol was hydrogenated at room temperature over night at an initial hydrogen pressure of 50 p.s.i. The reaction mixture was filtered, the solid washed with methanol, and the filtrate concentrated under reduced pressure to provide 0.10 gm (50%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(=O)([O-])[O-].[K+].[K+].[C:25]([O:28][CH2:29][CH3:30])(=O)[CH3:26]>CN(C)C=O>[O:28]1[C:25]2[CH2:26][CH2:9][N:8]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:7][C:6]=2[CH:30]=[CH:29]1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2occc2C1)CCC3

Procedure:
5-Benzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine (410 mg, 1.9 mmol) was dissolved in ethanol (4 ml), and the solution was mixed with 10% palladium on activated carbon (80 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The reaction solution was filtered to remove 10% palladium on activated carbon, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4,5,6,7-tetrahydro-furo[3,2-c]pyridine. This compound and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (590 mg, 1.9 mmol) and potassium carbonate (400 mg, 2.9 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (4 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 94 mg (0.27 mmol, 14% in yield) of the title compound.