Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>OS(O)(=O)=O>[I:1][C:13]1[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]([CH3:9])=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 2.5 °C
Reaction time: 0.67 h

Procedure:
To H2SO4 (110 mL, 96%) stirring under a nitrogen atmosphere at 0-5° C. was added N-iodosuccinimide (41.13 g, 1.5 eq). The resulting black/dark red mixture was stirred at 0-5° C. for 40 minutes. To this was added dropwise commercially available 2-methyl-3-nitrobenzotrifluoride (25.0 g, 121.9 mmol) in H2SO4 (75 mL). Once the addition was completed, ca. 1 hour, the mixture was stirred at 5-10° C. for 5 hours. The resulting mixture was poured into ice (600 mL) and extracted with EtOAc (400 mL, 3×200 mL). The extracts were combined, washed with saturated aqueous Na2SO3 (500 mL) and H2O (400 mL). The organic phase was then dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give a dark oil. Purification was carried out by column chromatography (silica gel, eluting hexane) to give the title compound as a light yellow/green oil which solidified on standing (34.81 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][OH:48])=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:55]([CH3:56])=[CH:54][C:53](O)=[CH:52][C:51]=1[CH3:58]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][O:48][C:53]4[CH:54]=[C:55]([CH3:56])[C:50]([Cl:49])=[C:51]([CH3:58])[CH:52]=4)=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Cc1cc(O)cc(C)c1Cl
Product: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCOc4cc(C)c(Cl)c(C)c4)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E2 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.27 min, ES+: 821.24.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:20][C:19]1[N:18]=[C:25]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]=2[NH2:1])[N:24]=[C:22]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]=2[NH2:1])[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c(-c2nc(Cl)nc(-c3ccc4c(c3N)C(=O)c3ccccc3C4=O)n2)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 2 h

Procedure:
A dispersion of 22.3 parts of 1-aminoanthraquinone in 200 ml of nitrobenzene was brought to 100° C. and additioned with 9.22 parts of cyanuryl chloride and successively brought to 190° C. for 2 hours. The reaction mixture was filtered at a temperature of 150° C. and the cake was washed several times with methanol and then with n-heptane and was dried in an oven at a temperature of 110° C. About 23 parts of 2-chloro-4,6-bis-(1-aminoanthraquinonyl)-s-triazine were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Yield: 55 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 32, 1.5 g, 3.92 mmol), potassium hydroxide (1.54 g, 27.48 mmol), and hydrazine hydrate (1.38 mL, 27.48 mmol) in ethylene glycol (200 mL) was stirred for 60 h at 120° C. The reaction mixture was poured in to water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product which was triturated with water (150 mL) to afford 4-chloro-3-cyano-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (670 mg, 55%) as solid.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C([Sn](CCCC)(CCCC)[C:39]1[O:40][CH:41]=[CH:42][CH:43]=1)CCC.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccco3)cc2)CC1

Procedure:
A mixture of intermediate (29) (0.0036 mol), tributyl-2-furanyl-stannane (0.029 mol), PdCl2(PPh3)2 (0.0007 mol) and Na2CO3 (0.0576 mol) in dioxane (30 ml) was stirred and refluxed for 1 hour. Water was addedd. The mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:cyclohexane/ethyl acetate 80/20). The pure fractions were collected and the solvent was evaporated, yielding 4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineacetic acid, methyl ester (intermediate 30, mp. 90° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=1.[OH-].[Na+].Cl>O1CCOCC1>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1
Reactant: COC(=O)c1cnc(OCc2ncco2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc(OCc2ncco2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate (0.761 g, 3.23 mmol) in 1,4-dioxane (16.17 mL) was added sodium hydroxide 1.0N solution (3.23 ml, 3.23 mmol) to stir at room temperature for 16 h. Then HCl, 4.0M solution in 1,4-dioxane (1.617 ml, 6.47 mmol,) was added to stir for 10 min. The reaction mixture was concentrated in vacuo. MS m/z=221.9 [M+H]+. Calculated for C9H7N3O4: 221.044
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)([O-:27])=[O:26]>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc([N+](=O)[O-])c3)c12
Yield: 83 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-nitrobenzyl bromide as starting materials, the title compound was obtained in a yield of 83% as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH:18]1([CH:24]=[CH:25]B(O)O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]1(/[CH:24]=[CH:25]/[C:2]2[N:7]=[C:6]3[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]3=[N:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Reactant: OB(O)C=CC1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1ccc2ncc(/C=C/C3CCCCC3)nc2n1
Temperature: 90 °C

Procedure:
99.6 mg of 1-(3-chloropyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (0.40 mmol), 73.6 mg of cyclohexylvinylboronic acid (0.48 mmol), 84.4 mg of sodium carbonate (0.80 mmol) and 33.4 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.04 mmol) were initially charged in 6 ml of dimethylformamide/water (1:1) under nitrogen. The mixture was then heated to 90° C. for 6.5 h. Distilled water was then added to the reaction mixture and the resulting precipitate was filtered off with suction. The further purification was effected by column chromatography on silica gel (ethyl acetate/heptane eluent mixture). A light brown solid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cc(F)cc(Br)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cc(F)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (5.7 g, 30 mmol), prepared as described in Procedure 3, and imidazole (4.0 g, 60 mmol, 2 eq) in anhydrous THF (100 mL) at 0° C. was added tert-butyldiphenyl-silyl chloride (9.6 mL, 1.3 eq). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with hexane/EtOAc (1:1). The combined organic layers were washed with H2O (2×) and sat. NaCl (2×), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexanes/EtOAc) to give (3-bromo-5-fluorophenoxy)(tert-butyl)diphenylsilane as colorless oil (7.5 g, yield 58%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH3:40])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([C:33](OC)([O:36]C)[O:34][CH3:35])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:35][O:34][C:33]([C:31]1[CH:30]=[N:29][C:28]2[N:27]([N:26]=[CH:25][C:24]=2[C:22]2[CH:23]=[C:19]([C:17](=[O:18])[NH:16][C@@H:9]3[C@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][C:10]3([F:14])[F:15])[S:20][C:21]=2[CH3:40])[CH:32]=1)=[O:36]
Reactant: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](NC(=O)OC(C)(C)C)CCCC4(F)F)sc3C)cnn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](N)CCCC4(F)F)sc3C)cnn2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl{(1R,2R)-3,3-difluoro-2-[({5-methyl-4-[6-(trimethoxymethyl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophen-2-yl}carbonyl)amino]cyclohexyl}carbamate (45 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (275 μL, 3.55 mmol) added. The reaction mixture was stirred at room temperature for 1 h, neutralized with saturated sodium bicarbonate (aq) and extracted 3× with dichloromethane. The organic layers were combined and dried with sodium sulfate, concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C20H21F2N5O3S) [M+H]+, 450.1; found 450.1. 1H NMR (CDCl3, 500 MHz) δ 9.33 (s, 1H), 9.03 (s, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 6.98 (d, J=8.1, 1H), 4.45 (d, J=25.3, 1H), 4.01 (s, 3H), 3.34 (s, 1H), 2.60 (s, 3H), 2.18 (s, 1H), 1.70-1.90 (s, 5H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=1[Cl:28])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CS(C)=O>[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[Cl:28])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57.2 %

Procedure:
Potassium t-butoxide (24.7 g) was dissolved in dimethylsulfoxide (221 ml) and admixed with methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (4.52 g) and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into water (200 ml), which was then acidified with 1N hydrochloric acid (225 ml) and then extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2:5). A desired fraction was concentrated under reduced pressure to obtain 4-benzyloxycarbonylamino-3-chlorobenzoic acid (2.47 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20](C2C=CC=CC=2)[C:19]([O:31][CH3:32])(C([O-])=O)[CH2:18][C:17]=1[N+]([O-])=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:31][CH3:32])=[CH:11][CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC1(C(=O)[O-])CC([N+](=O)[O-])=C(Cl)C=C1c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Yield: 55 %

Procedure:
This compound was prepared in a manner similar to that of methyl-(5'-fluoro-2'-fluoro-2'-methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equivuiv), tetrakis(triphenylphosphine) palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol%), and 5-chloro-2-methoxy-4-nitro-2-biphenylcarboxylate as a to afford 0.85 g (55%) of methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate as a yellow-orange solid. Data for methyl-5'-2'-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3): 8.73 (d, J=2.4, 1 H); 8.38 (dd, J=8.5, 2.5, 1 H); 7.49 (d, J=8.5, 1 H); 7.36 (dd, J=8.7, 2.5, 1 H); 7.23 (d, J=2.5, 1 H); 6.85 (d, J=8.7, 1 H); 3.76 (s, 3 H); 3.70 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[C:14]([CH:16]=O)[CH:13]=[C:12]2[C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[C:14]([CH2:16][NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)[CH:13]=[C:12]2[C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccc3c(c2)OCO3)n(S(=O)(=O)c2cccc(Cl)c2)c1
Reactant: CN1CCN(CCCN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN1CCN(CCCNCc2cc(-c3ccc4c(c3)OCO4)n(S(=O)(=O)c3cccc(Cl)c3)c2)CC1

Procedure:
1-(m-Chlorobenzenesulfonyl)2-(3,4methylenedioxyphenyl)-pyrrole-4-carboxaldehyde and 1-(3-aminopropyl)-4-methylpiperazine are condensed and reduced with NaBH(OAc)3 following the procedure of Example 2. HPLC: RT (program 1) 3.26, MS: 531.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: COc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2ncccc2c1Br
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a mixture of 6-methoxy-quinoline (13.0 g, 0.082 mol) and pyridine (13.2 mL, 0.164 mol) in CCl4 (130 mL) was added bromine (8.4 mL, 0.164 mol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with saturated aqueous NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 7 g of 5-bromo-6-methoxy-quinoline as a red solid (36% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].C(OCC)(=O)C.[Br:18]N1C(=O)CCC1=O>CS(C)=O>[Br:18][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[O:20][C:19]([C:21]([NH:23][NH2:24])=[O:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:21]([C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)=[O:22]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])o1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc([N+](=O)[O-])o1
Temperature: 100 °C
Yield: 74 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-nitro-2-furohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 158 mg of the title compound (74%) as a Orange solid in 98.3% purity by HPLC (Rt: 5.31, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15](C#N)[C:16]([CH3:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.N1C=CC=C2CC3C=C(CC#N)C=CC=3OC=12.S(=O)(=O)(O)O.[OH-].[Na+]>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:17])[CH3:18])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(=O)C(C#N)c1ccc2c(c1)Cc1cccnc1O2
Agent: N#CCc1ccc2c(c1)Cc1cccnc1O2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2

Procedure:
1-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-1-cyano-acetone prepared from 33 g of 5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetonitrile and 75 ml of ethyl acetate is added in small portions to 75 ml of concentrated sulfuric acid with stirring, while the temperature is maintained at below 20°C by cooling with ice. 225 ml of water is added at a stretch to the mixture, and the whole mixture is stirred under reflux for 5 hours. The reaction mixture is ice-cooled and strongly alkalified by adding 30% sodium hydroxide with stirring. The crystalline precipitate is extracted with chloroform, and the extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is distilled off, and the residue is recrystallized from isopropyl alcohol to give 25 g of 5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetone as white needles melting at 124°-125°C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10](F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:24]1[CH:29]=CC=[CH:26][CH:25]=1.C(O)CO.CCCCCCCCCCCC.N>C(OCC)(=O)C.[Cu]I.C(O)(C)C>[C:9]1([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:26][CH:25]=[CH:24][CH:29]=1
Reactant: O=C(NCc1ccccc1)C(F)(F)F
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCCCC
Product: c1ccc(CNc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), N-benzyl-trifluoroacetamide (244 mg, 1.20 mmol), K3PO4 (640 mg, 3.01 mmol), evacuated, backfilled with Ar. Iodobenzene (112 μL, 1.00 mmol), ethylene glycol (0.11 mL, 2.0 mmol), and isopropanol (1.5 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 24 h. The resulting white suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL), ethyl acetate (2 mL), and 30% aq ammonia (2 mL) were added. A 0.1 mL sample of the top layer was diluted with ethyl acetate (1 mL) and analyzed by GC to provide a 76% yield of N-phenylbenzylamine.