Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].O>C(OCC)C>[C:16]([C:14]1[CH:13]=[CH:12][C:11]([O:20][CH3:21])=[C:10]([CH2:9][OH:8])[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1CO
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 96.4 %

Procedure:
A solution of 1.0M lithium aluminium hydride in diethyl ether (27.0 ml, 27.0 mmol) was added dropwise over 10 min to a solution of 5-tert-butyl-2-methoxybenzoic acid methyl ester (5.00 g, 22.4 mmol) in diethyl ether (90 ml) under nitrogen, maintaining temperature between 0° C. and 5° C. When addition was complete, the reaction was stirred at 20° C. for 3.5 h, then again cooled to 0° C. Addition of water (5 ml) destroyed any excess reagent and filtration of the resulting mixture through dicalite removed the unwanted inorganic residue. After drying the resulting filtrate with magnesium sulfate, evaporation under reduced pressure afforded (5-tert-butyl-2-methoxyphenyl)methanol as a pale yellow gum (4.20 g, 21.6 mmol, 96%).
Reaction SMILES: [CH2:1]([C@:3]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=2[CH2:16][O:17][CH2:18][O:19][CH3:20])[O:5][CH:4]1[CH2:6][OH:7])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:15][O:14][C:10]1[C:9]([CH2:16][O:17][CH2:18][O:19][CH3:20])=[C:8]([C@@:3]([OH:5])([CH2:1][CH3:2])[CH2:4][CH2:6][OH:7])[CH:13]=[CH:12][N:11]=1
Reactant: CC[C@]1(c2ccnc(OC)c2COCOC)OC1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@](O)(CCO)c1ccnc(OC)c1COCOC
Yield: 75.7 %

Procedure:
Following the procedure in Example 6, the reaction was carried out with 6b (0.71 g, 2.5 mmol) and LAH in dry ether (50 nmL) for 24 h to afford 7b as colorless oil (0.54 g, 76%). The crude product was sufficiently pure for the subsequent reaction. IR (CH2Cl2, NaCl,cm−1) 3391, 3056, 2984, 1593, 1446, 1382, 1265, 1037, 743, 546; 1H NMR (300 MHz, CDCl3) δ0.79 (t, J=7.3 Hz, 3H), 1.91 (q,J=7.3 Hz, 2H), 2.15 (m, 2H), 3.42 (s, 3H), 3.60 (m, 1H), 3.74 (m, 1H), 3.98 (s, 3H), 4.71 (s, 2H), 4.89 (d, J=10.7 Hz, 1H), 5.10 (d, J=10.7 Hz, 1H), 6.77 (d,J=5.5 Hz, 1H), 8.05 (d, J=5.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ7.81, 36.65, 43.80, 54.14, 55.94, 60.20, 61.13, 80.93, 96.53, 116.33, 117.94, 146.17, 156.45, 163.82; HRMS (EI) m/z calcd for C14H24NO5 (M++H) 286.1654, found 286.1658; LRMS (EI) m/z 286 (M++H, 39), 235(23), 222(86), 205(52), 194(74), 178(100), 150(49), 92(30), 77(15); [α]D23=+0.185 (c=1.08, CH2Cl2).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(O)(=O)C.O.[N+:16]([CH:19]([CH:22]=O)[CH:20]=O)([O-:18])=[O:17].[Na]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[CH:22][C:19]([N+:16]([O-:18])=[O:17])=[CH:20]2
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ncc([N+](=O)[O-])cc2c1
Temperature: 4 °C
Yield: 59.6 %

Procedure:
p-Anisidine hydrochloride (35.0 g, 219.4 mmol) was weighed into a dry 300 mL three-necked round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel and a thermometer. Glacial acetic acid (150 mL) was added to the solid, with vigorous stirring to maintain a homogeneous suspension. To this suspension was added sodium nitromalonaldehyde monohydrate (12.0 g, 76.4 mmol) and the mixture stirred for 1.0 h at 25° C. A short-path distillation head was placed on the flask and approximately 120 mL of acetic acid/water removed under reduced pressure at 40° C. To the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL). The resulting solution was flushed with argon to :remove air and the flask immersed in an oil bath preheated to 195° C. The mixture was vigorously stirred while acetic acid was removed by distillation. When the temperature reached 184°-185° C. the mixture was stirred for a further 15 min at 185° C. and then poured (while still at ca. 180° C.) onto crushed ice (750 g). The resulting solution was allowed to stand in a refrigerator (overnight) until precipitation was complete. The dark brown solid precipitate was filtered and transferred to a round-bottomed flask (500 mL) containing 2M hydrochloric acid (250 mL). The mixture was heated at reflux for 50-60 min and the boiling; solution filtered through a preheated Buchner funnel to remove an insoluble brown gum. The hot filtrate was cooled to ca. 4° C. and extracted with chloroform (4×50 mL). The combined extracts were dried (MgSO4) and the chloroform removed on a rotatory evaporator to give the crude 3-nitro-6-methoxyquinoline 14 (9.3 g, brown solid).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16](O)=[C:17]([C:22]([O:24][CH3:25])=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.CCN(CC)CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+].[CH3:56][C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>C(Cl)Cl.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>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:60]4[CH:61]=[CH:62][C:57]([CH3:56])=[CH:58][CH:59]=4)=[C:17]([C:22]([O:24][CH3:25])=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Reactant: Cc1ccc(B(O)O)cc1
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: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
An ice cold solution of methyl 9-(4-fluorobenzyl)-4-hydroxy-2-methyl-1-oxo-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (1.1 g, 2.89 mmol) and Et3N (2.004 ml, 14.46 mmol) in DCM (30 mL) was treated with Tf2O (0.977 ml, 5.78 mmol). After 15 min, the reaction mixture was poured into sat. aq. NaHCO3 and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was dissolved in 1,4-Dioxane (9.57 ml)/Water (1.913 ml), treated with 4-methylphenyl boronic acid (0.550 g, 4.05 mmol) and Na2CO3 (0.920 g, 8.68 mmol) and then degassed with N2 for 5 min. Pd(PPh3)4 (0.334 g, 0.289 mmol) was added and the reaction mixture was warmed to 80° C. After 2 h, the reaction mixture was poured into sat. aq. NH4Cl and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. the residue was purified by ISCO (0-50% EtOAc-hexanes) to afford methyl 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (625 mg, 1.375 mmol, 47.6% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d)=7.31 (d, J=3.9 Hz, 6H), 7.22 (none, 2H), 6.96 (s, 4H), 6.15 (s, 2H), 3.70 (s, 3H), 3.59 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N:16]=O)=[C:4]([NH2:18])[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:16])=[C:4]([NH2:18])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2,6-diamino-4-benzyloxy-5-nitrosopyrimidine (0.3 g, 1.28 mmol) in water (10 ml) at 50° C. was added sodium dithionite (0.48 g, 2.76 mmol) in portions over 5 h. The reaction mixture was stirred at room temperature overnight, heated again to 50° C. and a further quantity of sodium dithionite (0.4 g) was added. After stirring for a further 12 h, the reaction mixture was cooled to room temperature, and the solution was adjusted to pH 7 with aqueous ammonia solution (0.2 ml). The resultant fine yellow solid which deposited was collected, washed with water and recrystallised from hot water (0.11 g, 35%), m.p. 130-135° C.; νmax/cm−1 3394 (NH2), 3033 (C6H5); δH (200 MHz, d6-DMSO) 5.36 (2H, s, OCH2), 5.40 (2H, s, NH2), 5.81 (2H, s, NH2), 7.39-7.56 (5H, m, C6H5).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si](C)(C)C)[C:30](=[O:42])[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)(C(C)(C)C)(C)C.F.C[C@@H]1[C@]2(OC[C@H](C)CC2)O[C@H]2C[C@@H]3[C@@](C)([C@@H]12)[C@H](O)C(=O)[C@H]1[C@H]3CC[C@@H]2[C@]1(C)CC[C@H](O)C2>C(#N)C>[CH3:20][C@@H:19]1[C@:21]2([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]2)[O:22][C@H:17]2[CH2:16][C@@H:15]3[C@@:29]([CH3:43])([C@@H:18]12)[C:30](=[O:42])[C@H:31]([OH:37])[C@H:32]1[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@:33]1([CH3:36])[CH2:34][CH2:35][C@H:9]([OH:8])[CH2:10]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: F
Solvent: CC#N
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
The title compound was synthesized from (3β,5α,11β,25R)-3-(t-butyldimethylsilyoxy)-11-(trimethylsilyoxy)spirostan-12-one was desilylated with hydrofluoric acid in acetonitrile according to the procedure described in J. Am. Chem. Soc., 1972, 94, 6190. The title compound must be carefully handled because it will rearrange to (3β,5α,12β,25R)-spirostan-3,12-diol-11-one if exposed to base.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[OH:12][CH:13]([CH3:17])[C:14](=[O:16])[CH3:15].CS([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:16][CH:14]([CH3:15])[C:13](=[O:12])[CH3:17])[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CC(=O)C(C)O
Agent: CS(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC(C)C(C)=O)n1
Reaction time: 3 h

Procedure:
4.38 g (25 mmol) of 2-chloro-4,6-dimethoxypyrimidine, 2.31 g (26.2 mmol) of 3-hydroxy-2-oxobutane and 0.66 g (6.3 mmol) of sodium methanesulfinate were heated in the presence of 5.17 g (37.5 mmol) of potassium carbonate in 25 ml of N,N-dimethylformamide to 120° C. with stirring. After 3 hours, the solvent was removed in a rotary evaporator at 70° C./20 mbar. The residue was purified by chromatography on a silica gel column (eluent hexane/ethyl acetate 4:1). The title product was obtained from the product fraction in the form of a pale yellowish oil in a yield of 4.58 g (80.4 percent of theory) (GC content 99 percent). Other data concerning the title compound was:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[C:5]([CH3:10])[O:4][N:3]=1.[BrH:11].BrBr.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:11][CH2:8][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:10])=[O:9]
Reactant: Br
Reactant: CC(=O)c1c(C)noc1C
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
400 mg (2.87 mmol) of 1-(3,5-dimethylisoxazol-4-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 1.42 mL (8.62 mmol) of hydrobromic acid and 163 μl (3.16 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. The solution is diluted with water, basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 540 mg of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N+:7]2[O-:20]
Reactant: Brc1cccc2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1cccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 5-bromoquinoline (2.5 g, 12.02 mmol) in DCM (50 mL) was added m-CPBA (3.50 g, 15.62 mmol) in three portions at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 h. After this time, 1N NaOH (40 ml) was added to the reaction, and the resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (2.7 g, 99% yield) as light yellow solid. LCMS, [M+H]+=223.9. 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=8.8 Hz, 1H), 8.65 (d, J=6.0 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 7.44 (dd, J=8.2, 6.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:29])[CH3:28]
Reactant: COc1ccnc(C(=O)Nc2cccc(OCc3ccccc3)c2)c1O
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(C(=O)Nc2cccc(OCc3ccccc3)c2)c1OC(C)=O
Reaction time: 3 h
Yield: 67 %

Procedure:
3-Hydroxy-4-methoxy-3′-benzyloxypicolinanilide (20 mg) was dissolved in 1 ml of acetic anhydride, and a reaction was allowed to proceed at 80° C. for 3 hr. The reaction solution was concentrated under the reduced pressure. The concentrate was extracted with chloroform, followed by washing with a saturated sodium hydrogencarbonate solution and then with saturated brine. The washed extract was then dried over anhydrous sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give 15 mg (yield 67%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1)=[O:4].[OH:13][NH2:14].C(N(CC)CC)C.Cl.ON>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=[NH:12])[NH:14][OH:13])[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1CCC(C#N)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(C(=N)NO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A mixture of 4-cyano-cyclohexanecarboxylic acid methyl ester (1070 mg, 6.40 mmol), N-hydroxyamine as a free base solution was prepared by the addition of triethylamine (9.8 mL, 64 mmol) to a solution of N-hydroxyamine HCl salt (4.4 g, 64 mmol) in DMSO (40 mL), stirred at room temperature for 5 min, filtered, and rinsed with THF. The reaction was heated in a sealed vial in an oil bath at 80° C. overnight. The reaction was diluted with ethyl acetate (200 mL) washed with aqueous saturated ammonium chloride (200 mL) and brine (200 mL). The water layer was extracted with ethyl acetate (200 mL) and the resulting second organic layer was washed with brine (200 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to give 4-(N-hydroxycarbamimidoyl)-cyclohexanecarboxylic acid methyl ester (770 mg, 60%) as a white solid. LCMS calcd for C9H16N2O3 (m/e) 200, obsd 201 (M+H).
Reaction SMILES: CO[C:3](=[O:34])[CH:4]([C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[CH:4]1[C:3](=[O:34])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[CH:11][C:6]=2[CH2:5]1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 145 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2,6-dichloro-phenyl)-propionic acid methyl ester (0.18 g, 0.36 mmol) (from Example 2b supra) in glacial acetic acid (2 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 135° C. overnight and 145° C. for another 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6-(2,6-dichloro-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a gray solid. (Yield 61.2 mg, 36.3%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[Cl:14][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[C:10]([Cl:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: COc1cc(Cl)c(C(=O)CBr)c(Cl)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cc(Cl)c(-c2csc(N)n2)c(Cl)c1
Yield: 50.4 %

Procedure:
To a solution of 2-bromo-1-(2,6-dichloro-4-methoxyphenyl)ethanone (10-3, 1.3 g) and thiourea (0.42 g, 5.5 mmol) in 95% EtOH (15.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-ylamine (10-4, 0.60 g, 2.2 mmol) as yellow solids in 47% yield: 1H NMR (500 MHz, CDCl3) δ 7.08 (d, J=1.8 Hz, 1 H), 6.83 (d, J=1.8 Hz, 1 H), 6.49 (s, 1 H), 4.88 (brs, 2 H), 3.77 (s, 3 H); ESI-MS m/z 275.1 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:17][CH2:16][N:15]3[C@@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)C=CC=CC=1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH2:11]1[C@H:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[CH2:14][CH2:13][O:12]1
Reactant: c1ccc(CN2CCN3CCOC[C@H]3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C1CN2CCOC[C@H]2CN1
Yield: 103.1 %

Procedure:
To a solution of (9aR)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (1.8055 g, 7.77 mmol) in MeOH (80 mL) was added 1 N aq. HCl (15.5 mL, 15.5 mmol) and 10% Pd/C (50% water, 360 mg). The mixture was hydrogenated under balloon pressure overnight, and was then filtered through a 0.2 μm PTFE membrane. The solution was concentrated in vacuo and the residue was azeotroped with MeOH (3×50 mL) to provide crude (9aR)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.7185 g, >100% crude yield) as an orange solid. LCMS: (M+H)+: 142.9.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:24]([CH2:25][C:26](OC)=[O:27])=[N:23][N:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:21](=[O:36])[C:16]=3[N:17]([CH3:20])[C:18]=2[CH:19]=1.O>C1(C)C=CC=CC=1.ClCCl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:24]([CH2:25][C:26]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:27])=[N:23][N:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:21](=[O:36])[C:16]=3[N:17]([CH3:20])[C:18]=2[CH:19]=1
Reactant: COC(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Reactant: CCNCC
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
0.41 ml (4 mmol) of diethylamine is added at 0° C. under argon to a solution of 2 ml (4 mmol) of trimethylaluminium (2M in toluene) in 30 ml of toluene, the reaction mixture is stirred for 20 min at room temperature, 0.095 g (0.25 mmol) of methyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetate is added and the reaction mixture is stirred for 4 h at reflux. The mixture is cooled to 4° C., 3 ml of water and dichloromethane are added, the solution is filtered and the filtrate is concentrated under reduced pressure. Water, 1M hydrochloric acid and 150 ml of dichloromethane are added to the residue, the organic phase is separated, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. After recrystallization from diethyl ether, 0.10 g (0.24 mmol) of compound is isolated in the form of a white solid with a fluffy appearance.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[C:28]([NH:29][C:30](=[O:41])[C:31]([CH3:40])([CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)=[C:27]2[C:22]([C:23](=[O:42])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1.[OH-].[Na+]>C(#N)C.O>[CH3:17][O:18][C:19]1[C:28]([NH:29][C:30](=[O:41])[C:31]([CH3:40])([CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[C:27]2[C:22]([C:23](=[O:42])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1NC(=O)C(C)(C)CCCCCCBr)OCCC2=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(c1NC(=O)C(C)(C)CCCCCCOc1ccc([N+](=O)[O-])cc1)OCCC2=O

Procedure:
49 mg of p-nitrophenol and 49 mg of potassium carbonate were added to a solution of 150 mg of N-(7-methoxy-4-chromanon-8-yl)-2,2-dimethyl-8-bromooctaneamide (252) in acetonitrile (5 ml), and the mixture was heated under reflux for 15 hr. 10 ml of water was added to the reaction mixture, and the mixture was made alkaline with 2N aqueous NaOH solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation to give N-(7-methoxy-4-chromanon-8-yl)-2,2-dimethyl-8-p-nitrophenoxyoctaneamide. This product was dissolved in 10 ml of ethyl acetate, 50 mg of Pd-C (10%) was added thereto, and the mixture was stirred under hydrogen. The Pd catalyst was removed by filtration, and the solvent was removed to give N-(7-methoxy-4-chromanon-8-yl)-2,2-dimethyl-8-p-aminophenoxyoctaneamide. This product was dissolved in 10 ml of ethanol, 50 mg of PtO2 and 500 mg of 37% aqueous formaldehyde solution were added thereto, and the mixture was stirred under hydrogen at room temperature for 15 hr. The catalyst was removed by filtration, the filtrate was concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to give 34 mg of the intended title compound. Ethanol in which a HCl gas had been dissolved was added thereto, and the solvent was removed by distillation to give a hydrochloride.