Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1
Reactant: C#CCCc1nc2cc(C#N)ccc2o1
Reactant: Ic1ccccn1
Product: N#Cc1ccc2oc(CCC#Cc3ccccn3)nc2c1
Yield: 37.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (89 mg, 0.43 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-5-carbonitrile (100 mg, 0.51 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.16 mmol, 37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile as a brown solid.
Reaction SMILES: OC=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].[N:19]1C=CC=C[C:20]=1NC(=O)CC1ON=C(C)C=1.[H-].[Na+].C(OCC)=O>C1COCC1.[OH-].[Na+]>[N:19]1[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:20]=1
Reactant: Cc1cc(CC(=O)Nc2ccccn2)on1
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC=O
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)Nc2cccnc2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General method for the synthesis of α-hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide: A solution of N-pyridyl-3-methyl-5-isoxazoleacetamide (1.1 g, 5 mmol) in THF (20 mL) was slowly added to a suspension of NaH (60% in oil; 0.5 g, 12.5 mmol) in 10 mL of THF. The reaction mixture was stirred at rt for 30 mins. and then ethyl formate (2 mL, 25 mmol) was added. After stirring at rt overnight, the reaction was conc. in vacuo and the residue was dissolved in 100 mL of a 1N aqueous NaOH solution and extracted with 25 mL of EtOAc. The aqueous layer was separated and brought to pH 5-6 with the addition of an aqueous 6N HCl solution. The resulting light yellow precipitate was collected and washed with cold water, affording the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=3)=[O:20])=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)O)c(F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cccc(C(F)(F)F)c2)c(F)c1
Yield: 11.6 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol), 3-(trifluoromethyl)aniline (44.3 mg, 0.275 mmol), HATU (125 mg, 0.330 mmol) and DIEA (0.048 mL, 0.275 mmol) in DMF (10 mL) was stirred at rt for 5 h. After LCMS analysis showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give crude product which was purified by preparative HPLC to give pure product 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide (14.56 mg, 0.032 mmol, 12% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.03 (br. s., 1H), 7.77 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.46-7.36 (m, 2H), 7.31-7.24 (m, 2H), 6.28 (s, 1H), 4.24-4.19 (m, 2H), 3.84 (s, 2H), 1.41 (t, J=6.8 Hz, 3H); ES-LCMS: m/z 435.1 (M+H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)(O)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)([NH:45][CH:42]4[CH2:44][CH2:43]4)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(NC1CC1)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
For the formation of the correspondent chloride, the same procedure was used as that in example 2, except that 4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one (55 mg, 0.112 mmol) was used in the place of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one. The obtained chloride was dissolved in DMF (8 ml). To this solution were added potassium carbonate (K2CO3) and cyclopropylamine (0.049 ml, 0.786 mmol). The reaction mixture was stirred at ambient temperature for 15 hours after which time it was partitioned between CHCl3 and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound as a white solid (19 mg, 0.036 mmol, 32% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(I)cc(C=O)cc1OC
Yield: 48.8 %

Procedure:
The compound was prepared according to general procedure E with 5-iodovanillin (1.8 mmol) in dry acetone (25 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h15. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 673 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 320 mg of purified compound were obtained (49% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.28 (t, J=7.2 Hz, 3H), 3.97 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.55 (s, 1H), 7.95 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.2, 57.4, 62.1, 70.5, 92.4, 113.9, 135.1, 135.5, 153.1, 169.4, 191.1. MS (ESI): m/z 364.9 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([O:27]CC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-].Cl>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([OH:27])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in H2O (5 mL) and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100° C. for 24 hours before it was cooled to room temperature. The mixture was acidified with 1N HCl and it was extracted with three 20 mL portions of dichloromethane. The organic extracts were dried over Na2SO4 and evaporated to yield 5-(1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 364.1. found 365.1 (M+1)+; retention time 2.70 minutes.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]12[NH:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([NH:31][C:32]1[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]3)[CH2:24]2>ClCCl>[CH2:1]([N:30]1[CH:27]2[CH2:28][CH2:29][CH:23]1[CH2:24][CH:25]([NH:31][C:32]1[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]3)[CH2:26]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2C3CCC2CC(Nc2ccc4[nH]ncc4c2)C3)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 52 %

Procedure:
Benzaldehyde (37 μl, 0.364 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol) were added to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (73 mg, 0.301 mmol) obtained in Example 525 in dichloromethane (1 ml), and the resulting mixture was stirred at room temperature for 25 hours. The reaction was terminated by the addition of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was washed with cold methanol and collected by filtration to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (52 mg, 52%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)#[N:2].ClCC(OC(=O)CCl)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>ClC(Cl)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[C:28]([O:33][CH3:34])[CH:29]=1)=[O:15])#[N:2]
Reactant: N#CCCCCCCCCCCC(=O)O
Reactant: COc1ccccc1OC
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)CCCCCCCCCCC#N)cc1OC
Temperature: 75 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
In 50 ml of dichloroethane were dissolved 10.5 g (0.05 mole) of 11-cyanoundecanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 75° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 14.2 g of 4-(11-cyanoundecanoyl)-1,2-dimethoxybenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>CCO>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: CC(=O)c1ccc(CCCBr)cc1
Solvent: CCO
Product: CC(=O)c1ccc(CCCOc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)cc1
Yield: 76.6 %

Procedure:
Alkylation of 4-benzyloxy-7-hydroxycoumarin (2.68; 0.01 mole) with 1-(4-acetylphenyl)-3-bromopropane (2.41 g; 0.01 mole) as described in Example 45 gave 3.28 g (77%) of title compound of m.p. (EtOH) 117° νmax (mull) 1725, 1682, 1620 cm-1 ; τ(DMSO) 7.92 (2H, m); 7.48 (3H, s); 7.18 (2H, m); ; 5.94 (2H, t, J 6.4 Hz); 6.69 (2H, s); 6.16 (1H, s); 3.17-2.00 (12H, m). (Found; C, 75.14; H, 5.52; C21H24O5 requires; C, 75.68; H, 5.65%)
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(F)nc1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To an N,N-dimethylformamide (50.0 mL) solution of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 30 minutes at room temperature. 2-Fluoro-5-methylpyridine (1.80 g, 16.2 mmol) was then added at 0° C., and stirred for 5 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.67 g, 59.3%).
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O)#[N:2].[BH4-].[Na+].ClCCl.C([OH:24])C>O>[OH:24][C:3]1([C:1]#[N:2])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[CH2:4]1
Reactant: CCO
Reactant: COc1cc2c(cc1OC)C(=O)C(C#N)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(O)(C#N)C2

Procedure:
2-Cyano-5,6-dimethoxy-indan-1-one (18.2 g) was suspended in ethanol (360 ml) under an atmosphere of nitrogen and treated with a solution of sodium borohydride (6.57 g) in water (25 ml) and ethanol (36 ml). After 11/2 hours dichloromethane (200 ml) was added. After a further 30 minutes the excess sodium borohydride was destroyed by the dropwise addition of acetic acid (2 ml) in dichloromethane (10 ml). The inorganic salts were filtered off and the filtrate was concentrated under reduced pressure then extracted into ethyl acetate (3×200 ml). The organic extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to give 2-hydroxy-5,6-dimethoxyindane-2-carbonitrile as a yellow solid (17.1 g).
Reaction SMILES: C[Al](C)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[C:21]([NH2:22])=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:18]=1)=O)C>C(Cl)(Cl)Cl>[N:6]1([NH:5][C:15]([C:17]2[C:21]([NH2:22])=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[N:18]=2)=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: NN1CCOCC1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Product: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M solution in toluene, 625 microliters, 1.25 mmol) is added to a solution of 4-aminomorpholine (121 microliters, 1.25 mmol) in CHCl3 (3 ml) at room temperature. The reaction mixture was stirred for 1 h, then 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-2A-1a, 188 mg, 0.5 mmol) was added in one portion. The reaction mixture was stirred at 45° C. for 4 h, cooled to room temperature, and quenched with 1 M HCl (1 ml) (CAREFUL: gas evolution). The pH of the solution was adjusted to ˜13 using 25% KOH, at which point all solids went into solution. The aqueous solution was extracted with EtOAc (2×) and the combined organic solution was washed with saturated aqueous brine, dried, and concentrated under vacuum to give the product I-10A-1a as an amorphous solid (208 mg): MS 432.0 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.44-7.32 (m, 4H), 7.28-7.23 (m, 2H), 7.13-7.09 (m, 2H), 3.86 (m, 4H), 2.95 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(NC(C)=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example 33(a)] in acetic anhydride (8 mL) and acetic acid (4 mL), at −5° C., was treated dropwise with a mixture of acetic acid (1.75 mL) and concentrated nitric acid (1.22 mL). The mixture was warmed to 0° C., then stirred at 0° C. for 2 hours and then poured onto water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residual oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2:5) to give 4-ethyl-2-nitro-N-acetyl-aniline (1.4 g) as an orange solid. LC-MS (METHOD B): RT=2.95 minutes; 209.2 (M+H)+. (b) 4-Ethyl-5-methyl-2-nitro-N-acetyl-aniline
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:13])[CH:6]=1.[CH3:14][N:15]1[CH2:24][C:23](=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1>CCOCC>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:23]2([OH:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][N:15]([CH3:14])[CH2:24]2)=[C:7]([F:13])[CH:6]=1
Reactant: CN1CC(=O)c2ccccc2C1
Reactant: Fc1cc(Cl)ccc1CBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CN1Cc2ccccc2C(O)(Cc2ccc(Cl)cc2F)C1
Yield: 82.2 %

Procedure:
To a suspension of magnesium shavings (15.7 g) and a few crystals of iodine in anhydrous ether (200 ml) is slowly dropped 4-chloro-2-fluorobenzylbromide (146.0 g) in anhydrous ether (200 ml) at such a rate so as to maintain the ether reflux. After the addition is complete, the reaction mixture is heated under reflux for two hours. A solution of 2-methyl-2,3-dihydro-4(1H)-isoquinolone (70.2 g) in anhydrous ether (200 ml) is slowly added dropwise. After the addition is complete, the reaction mixture is heated under reflux for three hours. The reaction mixture, after cooling, is stirred in 1.5 l. saturated ammonium chloride and extracted with ether. The combined ether extracts are washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield a solid, which upon trituration with petroleum ether, yields the product (109.5 g, 82%), mp 113°-116°. An analytical sample is recrystallized from anhydrous ether to yield needles, mp 116°-117°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[CH3:31][S:32]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)(=[O:34])=[O:33]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.1 g) in dichloromethane (1 liter) under ice cooling are added triethylamine (52 ml) and then methanesulfonyl chloride (21.6 ml), and the mixture is stirred for 25 minutes. The reaction mixture is acidified with diluted hydrochloric acid and stirred. The organic layer is taken, washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2: 90.0 g) as an organge oil. This product can be used in the next step without further purification. IR ν (CHCl3) cm-1 : 1741, 1703, 1602. 1HNMR δ (CDCl3) ppm: 2.22 to 2.82(2H, m), 3.07(3H, s), 3.67, 3.78(3H, 2s), 3.75 to 4.03(2H, m), 4.55(1H, t, J=7.8 Hz), 5.08 to 5.39(3H, m), 7.43 to 7.58(2H, m), 8.23(2H, d, J= 8.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To 4,6-dichloropyrimidine (0.533 g, 35.8 mmol) in MeOH (15 ml) was added tert-butyl N-(2-aminoethyl)carbamate and the reaction stirred at room temperature for 6.5 hours. Reaction concentrated in vacuo, solids triturated with EtOAc/petrol. Filtrate which contains the desired product was concentrated and EtOAc and sat. NaHCO3 added.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]2[OH:16])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NS(=O)(=O)c2cccc(Cl)c2)[C@@H]1O

Procedure:
Following the procedure in Example 105, using (3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile and 3-chloro-benzenesulfonyl chloride as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C.O>[O:28]1[CH2:29][CH2:30][N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:18])[CH2:26][CH2:27]1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a stirred suspension of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (10 ml) was added morpholine (0.814 ml, 9.30 mmol) via a syringe. The resulting suspension was then stirred overnight at 75° C. in a sealed tube. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5% (2M NH3 in methanol) in dichloromethane, giving the desired 1-(3-morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (560 mg, 1.754 mmol, 94% yield). 1H NMR (DMSO-d6) δ 8.14-8.10 (m, 2H), 7.40 (d, J=9 Hz, 1H), 3.95 (t, J=7.4 Hz, 2H), 3.58-3.54 (m, 4H), 3.03-2.97 (m, 2H), 2.64-2.59 (m, 2H), 2.33-2.28 (m, 6H), 1.74-1.64 (m, 2H).