Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([N+:22]([O-:24])=[O:23])[C:14]=1Cl>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([N+:22]([O-:24])=[O:23])[C:14]=1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([O:4][CH3:3])=[O:11]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Sodium hydride was added under ice-cooling to a DMF solution of malonic acid dimethyl ester, and then 1,2-dichloro-3,5-dinitrobenzene was added thereto and allowed to undergo the reaction at room temperature overnight. By post-treating the reaction liquid, dimethyl (2-chloro-4,6-dinitrophenyl)malonate (Dat, FN: 332) was obtained. This was dissolved in DMSO, lithium chloride and water were added, followed by stirring at 100° C. for 2 hours. By post-treating the reaction liquid, methyl (2-chloro-4,6-dinitrophenyl)acetate was obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][C:9]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)CCC.I[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38]>O1CCOCC1.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>[N+:34]([C:31]1[CH:32]=[C:33]([C:6]2[O:10][C:9]([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])=[CH:8][CH:7]=2)[CH:28]=[C:29]([N+:37]([O-:39])=[O:38])[CH:30]=1)([O-:36])=[O:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Reactant: O=[N+]([O-])c1ccc(I)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)o1
Temperature: 80 °C

Procedure:
A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 mmol) in 6 mL of dioxane was heated at 80° C. for 16 h. Evaporation of solvent and chromatography provided diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate as solid foam.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H](C2C=CC=CC=2)C)[C:5](=[O:16])[CH2:4]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2.FC(F)(F)C(O)=O>CC(N(C)C)=O.O.C(#N)C>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([C:28]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[C:20]([O:1][CH2:2][C@H:3]3[CH2:7][NH:6][C:5](=[O:16])[CH2:4]3)[N:29]=2)[CH:35]=[CH:34][C:33]=1[O:36][CH3:37]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CO)CC1=O
Reactant: COc1ccc(-c2cc3ncccc3c(Cl)n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc3ncccc3c(OC[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (R)-4-(hydroxymethyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (2.1) was placed in 2 mL dimethylacetamide and 20 mg sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg 6.37 was added and the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried to provide protected Example 78 as intermediate. The intermediate was then treated with 2 mL of trifluoroacetic acid and heated for 30 min at 160° C. in the microwave. The reaction mixture was diluted with water and acetonitrile and purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-fried.
Reaction SMILES: C([Li])(C)(C)C.C1C[O:9][CH2:8]C1.[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[CH:16]1)[CH3:12]>CN(C=O)C>[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[C:16]1[CH:8]=[O:9])[CH3:12]
Reactant: C1CCOC1
Reactant: CCOC(OCC)n1cc(C#N)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(OCC)n1c(C=O)c(C#N)c2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium (18.1 mL, 31 mmol, 1.7M in pentane) was added to a THF (100 mL) solution of 1-diethoxymethyl-1H-indole-3-carbonitrile (6.83 g, 28 mmol) at −78° C. The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and heated with DMF (20 mL). The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was treated with ether (200 mL); the organic layer was washed with water and brine, dried and evaporated to dryness. NMR (300 MHz, CDCl3, δ): 10.24 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.34 (s, 1H), 3.80 (m, 2H), 3.52 (m, 2H), 1.26 (t, J=6.4 Hz, 1H).
Reaction SMILES: C1O[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N:13]([CH3:15])[CH3:14])[CH:7]=2)([CH3:5])[O:3]C1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:15][N:13]([CH3:14])[C:8]1[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: CN(C)c1cc(C2(C)OCCO2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(N(C)C)c1
Reaction time: 1.5 h

Procedure:
A solution of the compound (2) (4.73 g, 21.2 mmol) obtained above in tetrahydrofuran (20 ml) and 1N hydrochloric acid (63.5 ml) was heated and stirred for 1.5 hours. The mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residual solid was washed with hexane and filtrated. Yield 3.46 g (91%).
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10][N:9]2C(=N[CH2:6][CH2:7][CH2:8]2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl.ClCC1C=NC=CC=1>C1C=CC=CC=1.C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH:26]([CH2:1][C:11]3[CH:10]=[N:9][CH:8]=[CH:7][CH:6]=3)[C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cl
Agent: ClCc1cccnc1
Solvent: CC#N
Solvent: c1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3cccnc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.7 %

Procedure:
DBU (55 ul, 0.367 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (58.6 mg, 0.167 mmol) in benzene (16.0 ml) and acetonitrile (3 ml), under an atmosphere of argon. 3-(chloromethyl)pyridine hydrochloride (27.4 mg, 0.167 mmol) was then added. The reaction mixture was stirred at room temperature for 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (8.60 mg). 1H NMR (CDCl3): δ 1.40-1.80 (bm, 8H), 1.90 (m, 2H), 2.30 (m, 1H), 2.51 (m, 3H), 2.74 (d, J=17.27 Hz, 1H), 3.74 (m, 3H), 3.85 (s, 3H), 6.73 (d, J=8.32 Hz, 1H), 6.89 (m, 1H), 7.02 (s, 1H), 7.30 (m, 1H), 7.92 (m, 1H), 8.26 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 97 mg (0.21 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 3 mL diethylamine in 7 mL THF. Yield: 50 mg of a yellow powder. LC-MSD, m/z for C25H23BrN4O2 [M+H]+=491.0, 493.0; HPLC retention time: 2.9 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:15]1[O:19][C:18]2[CH:20]=[C:21](O)[CH:22]=[CH:23][C:17]=2[O:16]1>>[O:16]1[C:17]2[CH:23]=[CH:22][C:21]([O:1][CH2:2][CH:3]3[CH:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:7][CH2:6][NH:5][CH2:4]3)=[CH:20][C:18]=2[O:19][CH2:15]1
Reactant: OCC1CNCCC1c1ccccc1
Reactant: Oc1ccc2c(c1)OCO2
Product: c1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1

Procedure:
reaction of 3-hydroxymethyl-4-phenyl-piperidine of formula (V) coming from step b) with sesamol (VI) to obtain the formula (I) 3-[(1,3-benzodioxol-5-yloxi)methyl-]4-phenyl-piperidine:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:37]([F:38])=[CH:36][C:35]([CH2:39][O:40][CH3:41])=[CH:34][C:33]=4[F:42])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[CH:43]([OH:46])[CH2:44][CH2:45][C:17]=23)[CH2:11][C@H:10]1[NH:47]C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.Cl.O1CCOCC1>>[NH2:47][C@H:10]1[C@H:9]([OH:8])[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:37]([F:38])=[CH:36][C:35]([CH2:39][O:40][CH3:41])=[CH:34][C:33]=4[F:42])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[CH:43]([OH:46])[CH2:44][CH2:45][C:17]=23)[CH2:11]1
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)[C@H](O)[C@@H](C)C3)CCC4O)ccc2F)c(F)c1

Procedure:
The alcohol intermediate prepared as described above was treated with 4.0 M HCl in dioxane (10 mL, 40 mmol) at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two diastereoisomers of the title compound as white powders.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([NH:23][CH3:24])[CH:14]=1>>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:18])[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[C:15]([NH:23][CH3:24])[CH:14]=1
Reactant: CNc1cc(F)ccc1C(=O)OC
Reactant: CNS(C)(=O)=O
Agent: [Li]CCCC
Product: CNc1cc(F)ccc1C(=O)CS(=O)(=O)NC

Procedure:
In a similar manner to that described in Example 12(a), N-methylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with methyl 4-fluoro-2-methylaminobenzoate to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(N-methylsulphamoyl)ethanone, m.p. 140°-142°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[NH2:12])[C:6]=2[CH:14]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[N:12]=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)[C:6]=2[CH:14]=1
Reactant: CN(N)C1=NOCc2ccc(Cl)cc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CN(N=Cc1ccc([N+](=O)[O-])cc1)C1=NOCc2ccc(Cl)cc21
Reaction time: 2 h
Yield: 74 %

Procedure:
An amount of 1.4 g. of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine is dissolved in 70 ml. of ethanol by heating at 50° C, then 1.12 g. of p-nitro-benzaldehyde are added. The solution is stirred, then allowed to stand for 2 hours. The formed crystals are collected by filtering and recrystallized from 500 ml. of benzene. An amount of 1.7 g. (74%) of 6-chloro-4-[1-methyl-2-(4-nitro-benzylidene)-hydrazino]-1H-2,3-benzoxazine are obtained; m.p. 251° C with decomposition.
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.[NH3:22]>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)nc(N)nc21

Procedure:
A mixture of the product from Step B of Example 118 (24 mg) in aqueous ammonia (30%, 10 mL) was heated in a stainless steel autoclave at 100° C. overnight, then cooled and evaporated. The residue was purified on a silica gel column with CH2Cl2/MeOH (10/1 and 5/1) as the eluent to afford the title compound (15 mg).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10](O)([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2ccc(F)cc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (99%): mp 121-123° C. (methanol); 1H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 11H), 6.95 (s, 1H), 6.77-6.71 (m, 1H), 6.67 (s, 1H), 6.46 (s, 1H), 6.25-6.21 (m, 1H), 5.00 (s, 1H), 4.53 (t, J=9.0 Hz, 2H), 3.08-3.01 (m, 2H); MS (ES+) m/z 451.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH2:15])=[O:14].C(N)CN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH:15][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: NC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: Fc1c(I)ccnc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A mixture of 2-chloro-3-fluoro-4-iodopyridine (4.78 g, 18.6 mmol), 2-chloro-6-nitrobenzamide (3.91 g, 19.5 mmol), ethane-1,2-diamine (0.2 mL, 2.97 mmol), copper(I) iodide (0.57 g, 2.97 mmol) and K3PO4 (7.90 g, 37.2 mmol) in dioxane (80 mL), was degassed with a stream of argon and the reaction mixture was then heated under reflux for 4 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with dioxane. The filtrate was concentrated to dryness under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in petroleum ether (40-60° C.), to afford the title compound as a pale yellow solid (1.87 g, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.42-11.37 (br s, 1H), 8.35-8.24 (m, 3H), 8.08 (dd, J=1.1, 8.1 Hz, 1H), 7.81 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH:9]1[CH3:19])=[O:7].[NH:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2
Reactant: COc1cccc(C(=O)N2c3ccccc3C(O)CC2C)c1
Product: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Yield: 25.6 %

Procedure:
Starting with 1-(3-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.0 g, 3.36 mmol) prepared in Reference Example 21 and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl)oxy]pentanoate (2.14 g, 7.73 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (479 mg, yield: 26%) as a colorless oil. (cis:trans=1:3.5)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH2:31][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: COc1ccc(Br)cc1C=O
Product: COc1ccc(Br)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-bromo-2-methoxybenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 529.9.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([CH3:13])[C:11]=2[N:12]=1.C(OC([C:27]1[NH:28][CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C>>[CH3:19][N:6]1[C:7](=[O:18])[C:8]2[CH:17]=[CH:16][CH:15]=[N:14][C:9]=2[N:10]([CH3:13])[C:11]2[N:12]=[C:2]([C:27]3[NH:28][CH:29]=[CH:30][CH:31]=3)[CH:3]=[CH:4][C:5]1=2
Reactant: CN1C(=O)c2cccnc2N(C)c2nc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Product: CN1C(=O)c2cccnc2N(C)c2nc(-c3ccc[nH]3)ccc21

Procedure:
The title compound (mp 158°-160° C.) was prepared from 2-chloro-5,11-dihydro-5,11-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (t-butoxycarbonyl)pyrrole in a manner analogous to that described in Example 23.
Reaction SMILES: [CH2:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH3:27])C(OC(C)(C)C)=O)[CH:2]=[CH2:3].[ClH:49]>>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[CH2:25]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:1][CH2:2][CH3:3])[CH:26]=[CH2:27]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCN(CCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: C=CCNCCCNC/C=C/CNCCCNCCC

Procedure:
A mixture of 0.55 g (0.805 mmol) of (E)-1-allyl-14-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 8.2 ml of 3N methanolic hydrochloric acid is reacted analogously to Example 8. The resulting title compound melts at >260° C. 1H-NMR (D2O): δ0.97(t,3H); 1.63-1.76(m,2H); 2.05-2.16(m,4H); 3.02(t,2H); 3.11-3.19(m,8H); 3.69(d,2H); 3.77(d,4H); 5.48-5.55(m,2H); 5.83-5.98(m,1H); 6.04-6.07(m,2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc(-c2nccnc2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
Dissolve 3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (0.560 g, 1.51 mmol) in DCM (10 mL) and add trifluoroacetic acid (2 mL) and allow the mixture to stir at room temperature for six hr. Evaporate the solution then dilute with DCM and wash with saturated sodium bicarbonate. Dry the organics over sodium sulfate then filter and evaporate. Chromatograph the residue over silica gel (eluting with 8:92 methanol (with 2 M ammonia):DCM), to give [4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-methanol as a yellow solid (340 mg, 83%). MS (ES): m/z=271 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]([CH3:22])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][C:20]#[CH:21])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=C(C)C=C(C)C=1>[C:1]([Si:5]([CH3:23])([CH3:24])[O:6][C@H:7]([CH3:22])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:18][CH2:19][CH:20]=[CH:21][C:16]3=2)[CH:11]=[N:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C#CCOc1ccc2cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c2c1
Solvent: Cc1cc(C)cc(C)c1
Product: C[C@H](Cn1ncc2ccc3c(c21)C=CCO3)O[Si](C)(C)C(C)(C)C
Temperature: 190 °C
Yield: 87 %

Procedure:
A solution of the product from Step A (10.9 g, 31.8 mmol) in mesitylene (60 mL) was placed in a pressure tube and degassed under vacuum. The tube was sealed and heated at 190° C. for 20 h. The solution was cooled and purified by chromatography (silica, 10% ethyl acetate in hexane) to give a solid (9.53 g, 87%): mp 58-59° C.; LC/MS (+APCI) m/z 345 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=NCC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C(O)=[O:26]>O.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=NCc2ccccc2)CC1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1

Procedure:
A solution of trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.50 g, 8.00 mmol) and oxalic acid (0.80 g) in water/THF (50 mL, 1:1) was stirred for 10 h at room temperature. The reaction mixture was concentrated under reduced pressure and methylene chloride (50 mL) was added to the residue. The organic phase was dried and concentrated under reduced pressure to give trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.3 g, 80%).