Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[CH:43]=1)#[N:17]>CO>[O:40]1[CH:41]=[CH:42][CH:1]=[C:38]1[CH2:37][N:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:23]1[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]([CH3:28])([CH3:27])[C@@H:24]1[OH:29]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](N(Cc2ccco2)c2ccccc2)[C@H]1O

Procedure:
The title compound was prepared from (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) and the title A compound by the same procedure as described for the title compound of Example 1. The product was obtained as a colorless solid (1.07 g, 72%), mp 134°-135° C. [α]D =+92.20° (c=0.78, MeOH). Analysis calculated for C23H22N2O3 · 0.02 H2O: C, 73.70; H, 5.93; N, 7.47. Found: C, 73.65; H, 5.63; N, 7.52.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc2cc(OCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanol and methanesulfonic acid chloride were converted to yield Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester as colorless solid, MS: 430 (MH+).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]1[CH2:42][CH:41]([OH:43])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][N:46]=3)[CH:39]=2)[O:34]1>[Zn]>[NH2:51][C:48]1[CH:49]=[CH:50][C:45]([O:44][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[O:34][CH:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[CH2:42][CH:41]3[OH:43])=[N:46][CH:47]=1
Reactant: COc1ccccc1C1CC(O)c2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2O1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: COc1ccccc1C1CC(O)c2cc(Oc3ccc(N)cn3)ccc2O1

Procedure:
6-(5-Aminopyridin-2-yloxy)-2-(2-methoxyphenyl)chroman-4-ol was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 79 mg 2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 97(c)) and 262 mg of Zn. 1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, 1H, J 2.9 Hz), 7.47 (dd, 1H, J 7.5, 1.6 Hz), 7.33 (dt, 1H, J 8.5, 7.4, 1.6 Hz), 7.06 (d, 1H, J 2.8 Hz), 7.03-7.05 (m, 2H), 7.01 (d, 1H, J 7.4 Hz), 6.79 (dd, 1H, J 8.6, 2.8 Hz), 6.75 (d, 1H, J 8.7 Hz), 6.71 (d, 1H, J 8.6 Hz), 5.52 (d, 1H, J 6.5 Hz), 5.44 (d, 1H, J 10.5 Hz), 5.01 (s, 2H), 4.86-4.92 (m, 1H), 3.83 (s, 3H), 2.27-2.32 (m, 1H), 1.80-1.88 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].[NH2:33]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:33][N:15]1[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18](=[O:19])[N:13]([C:5]2[C:6]3[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]1=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC1(C)Cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)c2O1
Yield: 88.7 %

Procedure:
A solution of 1.0 gram (0.003 mole) of 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-6-trifluoromethyluracil (prepared in a manner analogous to that of Example 1, Step G, except that methyl iodide and potassium carbonate were not used) in 30 mL of tetrahydrofuran was stirred, and 0.5 gram (0.003 mole) of potassium carbonate, then 0.7 gram (0.003 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene were added. Upon completion of the addition, the reaction mixture was stirred for one hour and then diluted with water and extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated, yielding 1.0 gram of 1-amino-3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran- 7-yl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:11]([O-:13])=[O:12])=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Reaction time: 0.33 h

Procedure:
4 g (20 mmol) of the product obtained in Stage A are dissolved in 16 ml of concentrated sulfuric acid with stirring and cooling in ice. The solution is brought to 55° C. and 1.3 ml of concentrated nitric acid are added dropwise, care being taken to maintain the temperature between 55° and 60° C. The stirring is continued for 20 minutes and the mixture is then poured onto crushed ice. The product is precipitated by addition of 40% sodium hydroxide. It is filtered off, washed with water and then dried. 3.7 g of product are thus collected. The product is recrystallized from 95° C. ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)N[C@@H]1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCC[C@@H](NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 30.2 %

Procedure:
Using (R)—N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (336 mg, 1.00 mmol) and 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol), the same procedure was followed as in Example 2 to give 142 mg (30%) of the desired compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Yield: 101.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg) and 3-(methylsulfonyl)phenylboronic acid (122 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.58 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the reaction mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with 50-100% ethyl acetate/isohexane as eluent to yield the sub-titled compound (320 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[C:40]2[CH:39]([CH2:41][O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH:47]=O)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:37]1[C:38]2[CH:39]([CH2:41][O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH2:47][N:21]([CH:18]([C:9]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:13](=[O:14])[C:12]4=[CH:15][CH:16]=[CH:17][N:11]4[N:10]=3)[CH2:19][CH3:20])[CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:40]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=CCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
A mixture of 3-benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 150 mg, 0.41 mmol), (3-oxo-propyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (Org. Lett. 2002, 4, 3001–3003, 184 mg, 0.62 mmol), acetic acetic (1.5 eq), 4 Å molecular sieves (100 mg), and 1,2-dichloroethane (10 mL) was stirred at room temperature for 30 min, then treated with sodium triacetoxyborohydride (130 mg, 0.62 mmol). After 3 h, the mixture was filtered and the filtrate washed with saturated sodium bicarbonate and water, dried (MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/hexanes to give the title compound as a white solid (115 mg, 44%): MS (ESI+) 644.44 (M++H).
Reaction SMILES: [Na].[CH:2]1([CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=O)[CH2:4][CH2:3]1.[NH2:16][C:17]([NH2:19])=[S:18].Cl>CCO>[CH:2]1([CH2:5][O:6][CH2:7][C:8]2[NH:19][C:17](=[S:18])[NH:16][C:10](=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)COCC1CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1cc(COCC2CC2)[nH]c(=S)[nH]1
Temperature: 25 °C

Procedure:
Sodium (4.0 g, 172 mmol) was added to EtOH (80 mL) and stirred until all dissolved at 60° C. The solution was cooled down to rt and a solution of ethyl 4-(cyclopropylmethoxy)-3-oxobutanoate (15.7 g, 78.4 mmol) in EtOH (80 mL) was added, followed by thiourea (7.2 g, 94 mmol). The mixture was stirred under reflux conditions for 24 h. Hydrochloric acid (aq, 1 M) was added until pH˜4 and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient of EtOAc and DCM to give the title compound as a solid, 15.7 g (95%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[CH2:10]([CH:13]([C:16]#[N:17])[C:14]#[N:15])[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:13]([CH2:8][N:6]1[CH:7]=[C:3]([Cl:2])[CH:4]=[N:5]1)([C:16]#[N:17])[C:14]#[N:15])[CH:11]=[CH2:12]
Reactant: ClCn1cc(Cl)cn1
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cc(Cl)cn1
Yield: 72.5 %

Procedure:
1.43 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.01 g of allyl malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.22 g of allyl [(4-chloro-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (20), hereinafter) shown by below formula.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[N:30]([CH2:31][C:32](O)=[O:33])[C:29](=[O:35])[N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=4)[C:27]=3[CH3:46])=[CH:24][CH:23]=[N:22]2)=[CH:17][CH:16]=1)#[N:14].CN>C1COCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[N:30]([CH2:31][C:32]([NH:3][CH3:1])=[O:33])[C:29](=[O:35])[N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=4)[C:27]=3[CH3:46])=[CH:24][CH:23]=[N:22]2)=[CH:19][CH:20]=1)#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 1.25 h
Yield: 52.4 %

Procedure:
1,1′-carbonyl diimidazole (45 mg, 0.278 mmol) was added to a solution of {5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-1-yl}acetic acid (Example 22) (65 mg, 0.139 mmol) in THF (2.0 mL). The mixture was stirred for 1.25 h then a 2M methylamine in THF (0.278 mL, 0.556 mmol) was added. The mixture was stirred for 45 min then a second aliquot of 2M methylamine in THF (0.278 mL, 0.556 mmol) was added. The mixture was stirred for a further 40 minutes then partitioned between EtOAc and water. The phases were partitioned. The organic phase was dried over Na2SO4 and evaporated. The product was purified by chromatography on a 12 g silica gel column, eluting with 5% methanol in DCM. The material thus obtained was freeze dried from acetonitrile-water to afford the title compound (35 mg) a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:31][CH2:32][CH3:33])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)OCc1ccccc1)c1cccn([C@@H](CC)C(=O)OC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1283.5 %

Procedure:
To a solution of (S)-2-(3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (100 mg, 0.26 mmol) in anhydrous DMF (3 mL) was added NaH (60% dispersion, 10 mg, 0.26 mmol) and the reaction was stirred at ambient temperature for 30 minutes. Propyliodide (30 μL, 0.31 mmol) was added dropwise and the reaction stirred at ambient temperature overnight. The mixture was concentrated in vacuo to a solid and partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (30% EtOAc/hexane) to afford the title compound as a pale green solid (1.43 g, 40%): 1H NMR (400 MHz, CDCl3) δ 0.85-0.95 (6H, m), 1.35 (9H, s), 1.55-1.65 (2H, m), 1.85-1.95 (1H, m), 2.20-2.27 (1H, m), 3.6-3.7 (2H, m), 5.15-5.2 (2H, m), 5.5-5.6 (1H, m), 6.25 (1H, t), 7.25-7.45 (7H, m); M+H 429.4.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CNc1ccc2c(c1)OCO2

Procedure:
3,4-Methylenedioxyaniline (30.7 g) was dissolved in 300 ml of dry tetrahydrofuran, followed by the addition of 10.7 g of sodium hydride (in oil, 60%) and 22.7 ml of methyl bromoacetate under ice cooling. Under an argon stream, the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with ether. The organic layer so obtained was washed with water, shaken together with a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby reddish brown crystals were obtained. The crude crystals were decolored and then recrystallized from methanol, whereby 28.0 g of methyl 2-[N-(3,4-methylenedioxyphenyl)amino]acetate were obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CCO>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][NH2:22])=[O:18])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Yield: 51.7 %

Procedure:
Synthesized according to General Procedure C: 51c (2.87 g, 10.4 mmol, 1.0 equiv.), anhydrous hydrazine (1.31 mL, 41.6 mmol, 4.0 equiv.), EtOH (20 mL, 0.5 M). 46c (1.41 g, 51.5%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.39-7.34 (m, 5H), 3.84 (br s, 2H), 3.77 (br s, 2H), 3.43 (br s, 2H), 3.08 (s, 2H), 2.56 (br s, 2H), 2.44 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ 170.5, 169.9, 135.5, 130.0, 128.7, 127.1, 60.6, 53.9 (br), 53.4 (br), 47.7 (br), 42.2 (br). HRMS (ESI): 263.1513 (M+1); calcd. for C13H19N4O2: 263.1508.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[F:10][C:7]1[CH:8]=[N:9][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C1CCNC1
Reactant: N#Cc1cc(F)cnc1Cl
Product: N#Cc1cc(F)cnc1N1CCCC1
Yield: 90 %

Procedure:
Prepared in 90% yield from the product of Example 169A and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 192.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.90-1.96 (m, 4H), 3.61-3.65 (m, 4H), 8.05 (dd, J=8.5, 3.0 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]=[O:22]>C1COCC1.CCCCCC>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]([OH:22])[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH3:2])=[CH:5][CH:6]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: BrCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(C(O)c2cc(Br)ccc2OC)cc1
Reaction time: 2 h

Procedure:
To a stirred −78° solution of p-bromoethylbenzene (2.03 g, 11 mmol) in 10 mL of dry THF under Ar was added 5 mL of 2.5 M n-BuLi (12 mmol) in hexane over 10 min. The temperature was allowed to rise to −10° over 2 hr whereupon the reaction was cooled to −78° before adding solid 5-bromo-2-methoxybenzaldehyde (2.15 g, 10 mmol). After stirring overnight at 20°, the reaction was quenched with saturated aq. NH4Cl and diluted 5 fold with H2O prior to 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over Na2SO4. After concentration using a rotary evaporator, the residue was chromatographed on silica gel using 10% EtOAc/hexane to elute 1.44 g of 5-bromo-2-methoxy-4′-ethylbenzhydrol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(OCC)(=O)C>C(Cl)Cl>[CH2:10]([O:9][C:7]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methylethanolamine (149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chloroformate (70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide the desired compound. 1H NMR (CDCl3,TMS) δ 7.36 (m, 5H), 5.14 (s,2H), 3.78 (m, 2H), 3.47 (m, 2H), 3.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CO>CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (125 mg, 0.3 mmol) and PtO2 in EtOAc (15 mL) was stirred at rt under 1 atm of H2 gas for 2 h. Toluene (4 mL) and MeOH (5 mL) were added to the reaction mixture, stirred for 20 minutes, filtered the catalyst, and the filtrate solution was concentrated in vacuo to obtain the product (117 mg, 100%) as a white solid. 1H NMR (DMF-d7) δ 8.52 (d, 1H, J=5.0 Hz), 7.68-6.67 (m, 12H), 6.48 (d, 1H, J=5.0 Hz), 5.38 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 1-methylimidazole
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:13]=[C:14]([C:28]2([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:15]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:22]([CH2:23][O:24][NH2:25])=[CH:21][CH:20]=2)[CH:17]=1>>[F:11][C:12]1[CH:13]=[C:14]([C:28]2([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:15]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:22]([CH2:23][O:24][N:25]=[CH:9][C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)[CH:17]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(CON)cc3)c2)CCOCC1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: COC1(c2cc(F)cc(Sc3ccc(CON=Cc4ccc([N+](=O)[O-])o4)cc3)c2)CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 6, 5-nitrofuran-2-carboxaldehyde was reacted with O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}hydroxylamine to give 5-nitrofuran-2-carboxaldehyde O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as a gum in 58% yield.