Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12](OCC)=O)=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1.[Li+].[B-](CC)(CC)[CH2:24]C>C1COCC1>[CH2:12]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[C:5]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]1=[N:3][C:2]=2[NH2:1])[CH3:24]
Reactant: CCOC(=O)c1cnc2c(N)nc3cc(C)ccc3c2c1
Reactant: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cnc2c(N)nc3cc(C)ccc3c2c1

Procedure:
To a stirred solution of ethyl 5-amino-8-methylbenzo[f][1,7]naphthyridine-2-carboxylate (from the previous step) in THF (0.2 M) cooled in an ice-water bath was added 1 N solution of super hydride in THF (10 eq.). Upon completion of the reaction the reaction was quenched with 1 N HCl, and extracted with EtOAc. Combined organic extracts were concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)methanol as a white solid. 1H NMR (CDCl3): δ 8.68 (d, 1H), 8.52 (d, 1H), 8.04 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 4.90 (s, 2H), 2.45 (s, 3H). LRMS [M+H]=240.1
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O)C.N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccc(F)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
4-Fluorophenylhydrazine hydrochloride (1.63 g, 10.0 mmol) was mixed with ethanol (150 mL) and pyridine (2.43 mL, 30.0 mmol, 3.0 eq.). The mixture was heated to reflux, and more pyridine (2.43 mL, 30.0 mmol, 3.0 eq.) was added. After stirring for 5 minutes at room temperature, thiophenecarbonyl chloride (10.8 mL, 1.47 g, 10.0 mmol, 1.0 eq.) was added. The suspension was stirred for 2 hours at room temperature, and then at reflux temperature for 30 minutes under a nitrogen atmosphere. Water (375 mL) was added, and the mixture was extracted with ethyl acetate (2×300 mL). The combined organic layers were then washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the crude product (2.3 g) as a brown solid. Purification using ISCO flash chromatography (silica, gradient heptanes/ethyl acetate) gave N′-(4-fluorophenyl)thiophene-2-carbohydrazide (575 mg, 2.43 mmol, yield 24.3%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[N:46]1([CH2:51][CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:55]3[CH2:54][CH2:53][CH:52]([CH2:51][N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[CH2:57][CH2:56]3)=[O:23])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C1CCN(CC2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCC(CN4CCCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.17 mmol), EDCI (33 mg, 0.17 mmol), HOAt (24 mg, 0.17 mmol and 4-(pyrrolidin-1-ylmethyl)piperidine (28 mg, 0.17 mmol) in DMF (1 mL). The crude product was purified by FCC and then using prep method C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1/[CH:4]=[C:5]1/[C:6](=[O:22])[C:7]2[C:12]([CH2:13]/1)=[CH:11][C:10]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[C:9]([O:20][CH3:21])[CH:8]=2>CO.[Pd]>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:11]=2)[C:6]1=[O:22]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(F)cc1F)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(F)cc1F)C2=O
Reaction time: 6 h

Procedure:
To 27 (45 mg, 0.121 mmol), dissolved in methanol, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude, which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 23% ethyl acetate in hexane as half white coloured solid compound 2-(2,4-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 28. 1HNMR (400 MHz, CDCl3) δ ppm 7.18 (m, 2H), 6.82 (m, 3H), 3.88 (m, 3H), 3.86 (m, 4H), 3.31 (m, 1H), 3.16 (m, 4H), 3.06 (m, 1H), 2.95 (m, 1H), 2.73 (m, 2H); MS (ESI) m/z 373.9 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.C(O)(=O)C.Br[C:17]1[C:23](=[O:24])[C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:40]=[CH:39][C:38]4[O:37][CH2:36][O:35][C:34]=4[CH:33]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[Cl-].[Cl-].[Zn+2].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.[Pd]>[CH2:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[C:23](=[O:24])[C:17]([C:2]3[S:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:30][CH2:29]1)[C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1
Reactant: Brc1cccs1
Reactant: O=c1c(Br)ccccc1N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1c(-c2cccs2)ccccc1N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
To a solution of 2-bromothiophene (1.0 g, 6.1 mmol) in tetrahydrofuran (50 mL) at -78° C., was added n-butyl lithium (1.6 M in cyclohexane, 4.0 mL) and the resulting solution was stirred for 5 minutes. At this time, ZnCl2 (0.5 M in THF, 20 mL) was added and the solution was warmed to room temperature over 2 hours. To the reaction mixture was then added palladium tetrakis(triphenylphosphine) (200 mg) and a solution of the acetic acid salt of 7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatriene-1-one (300 mg, 0.74 mmol, example 1b) in tetrahydrofuran (5 mL) and the resulting mixture was refluxed for 18 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution and the product, extracted into methylene chloride (3×200 mL). The crude product was purified by silica gel chromatography to provide the title compound as a dark yellow oil (50 mg, 50%).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C:5]1([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:36](=[O:37])[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:34])(=[O:33])[N:31]=3)=[C:3]([OH:19])[CH2:4][C:5]32[CH2:6][CH2:7][CH2:8][CH2:9]3)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)CC1(NCc2ccc(F)cc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)CC3(CCCC3)N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
A solution of [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (109 mg, 0.41 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (150 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (4 mL) was treated sequentially with N-methylmorpholine (100 μL, 0.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 1 h, diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL), treated with a 21 wt % solution of sodium ethoxide in ethanol (1.0 mL, 2.73 mmol). The reaction was stirred and heated at 60° C. for 1.5 h, allowed to cool to 25° C., and quenched with a 0.5 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-HPLC [Column Luna 5μ C18(2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[6-(4-fluoro-benzyl)-9-hydroxy-7-oxo-6-aza-spiro[4.5]dec-8-en-8-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (50 mg, 22%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.55-1.73 (m, 6H), 1.75-1.87 (m, 2H), 2.93 (s, 2H), 3.05 (s, 3H), 4.66 (s, 2H), 7.12 (t, J=8.8 Hz, 2H), 7.34 (dd, J1=8.8 Hz, J2=5.2 Hz, 2H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.52-7.58 (m, 2H), 10.16 (s, 1H), 13.68 (s, br, 1H). LC-MS (ESI) calculated for C24H25FN4O6S2: 548.6, found 549.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:28]=1.O>O1CCCC1.C(#N)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:2]3[CH:3]=[CH:4][C:5]([N:13]4[CH2:17][CH2:16][O:15][C:14]4=[O:18])=[C:6]([CH:12]=3)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:34]=2)[N:29]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[N:28]=1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N1CCOC1=O
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCOC4=O)c(C(=O)N(C)C)c3)cc12

Procedure:
In a microwave vial 5-bromo-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide (150 mg, 0.45 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (2.169 g, 0.45 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (4 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II)-dichloride dichloromethane adduct (36.8 mg, 0.05 mmol) was added and the vial sealed. This reaction mixture was irradiated to 100° C. for 30 minutes in a microwave reactor. 100 ml water was added and this mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to yield crude 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide which was dissolved in 2 ml trifluoroacetic acid and stirred for 16 hours. The volatiles were removed and the residue purified by preparative mass-triggered reverse-phase HPLC to give 5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide as a white solid (62 mg, 49% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.92 (s, 3H); 2.97 (s, 3H); 3.57 (s, 3H); 3.99 (m, 2H); 7.10 (t, J=8 Hz 1H) 7.23 (d, J=8 Hz 1H); 7.47 (t, J=8 Hz, 1H); 7.58 (d, J=8 Hz 1H); 7.66 (d, J=8 Hz 1H); 7.74 (s, 1H); 7.89 (d, J=8 Hz 1H); 8.39 (s, 1H); 8.89 (s, 1H); 13.83 (s, br, 1H) MS: m/z 458.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N+:10]([O-])[C:9]=2[C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccc(F)cc2)c(-c2cc[nH]c(=O)c2)[n+]([O-])c1-c1ccccc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2)nc(-c2cc[nH]c(=O)c2)c1-c1ccc(F)cc1
Temperature: 60 °C
Yield: 40.7 %

Procedure:
To a solution of 4-[5-(4-fluorophenyl)-1-methyl-3-oxido-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-one of Step A (56 mg, 0.155 mmol) in CHCl3 (2 mL) was added phosphorous trichloride (16 μL, 0.186 mmol) dropwise at room temperature. The reaction mixture was heated at 60° C. for 2 hours, cooled, and poured into 1N NaOH/ice solution. The aqueous layer was extracted with CH2Cl2, and the combined organic extracts were washed with H2O followed by brine. After drying over Na2SO4, the solvent was removed in vacuo. The crude material was purified by preparative thin layer chromatography (1:10 MeOH:CH2Cl2 as an eluent) to obtain 21.8 mg of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: O=C1CCc2ccccc2N1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CCc2cccc(Br)c2N1

Procedure:
An example for a compound in accordance with Formula 2 is 4-iso-propylaniline that serves as the starting material for the presently preferred compounds of the invention. The aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 2A in a basic solvent, such as pyridine, to provide the phenyl amide derivative of the acryloic acid of Formula 3. An example of the acryloyl chloride derivative of Formula 2A that is used for the synthesis of the presently preferred compounds of the invention is commercially available 3,3-dimethylacryloyl chloride. The acryloic acid amide derivative of Formula 3 is cyclized under Friedel Crafts conditions to provide the 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4. The 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4 is reacted with bromine in acetic acid to provide the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5. The numbering of the quinoline ring system and of the heptatrienoic acid moiety that is attached to it in the 8 position of the quinoline nucleus in the compounds of the invention, is shown in Formula 1. The endocyclic oxo function of the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5 is reduced by treatment with borane-methyl sulfide to give the 8-bromo-1,2,3,4-tetrahydro-quinoline derivative of Formula 6. An alkyl group, designated R3, where R3 is defined as in connection with Formula 1, is introduced to the nitrogen of the quinoline nucleus by treatment of the compound of Formula 6 with an alkylating agent, such as R3-I, in the presence of base, to give the 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7. The 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7 is reacted with dimethylformamide (DMF) in the presence of strong base, such as n-butyl lithium to give a 1-alkyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde of Formula 8. The carbaldehyde of Formula 8 is reacted with a Grignard reagent of the formula R5MgBr, where R5 is defined as in connection with Formula 1, to provide a (1-alkyl-1,2,3,4-tetrahydro-quinoline-8-yl)-alkan-1-ol of Formula 9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1I)=[CH:9][CH:8]=[CH:7][CH:6]=2.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[N:24]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[CH2:26][CH2:25]1
Reactant: Fc1cnc2ccccc2c1I
Reactant: c1cc2c(cn1)CCN2
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cnc2ccccc2c1N1CCc2cnccc21
Temperature: 80 °C
Yield: 68.2 %

Procedure:
3-Fluoro-4-iodo-quinoline (0.2 g, 0.73 mmol) was placed in a 25 ml round bottomed flask and to it was added tetrahydrofuran (15 ml), xantphos (0.015 g, 0.02 mmol), cesium carbonate (0.476 g, 1.4 mmol), 5-azaindoline (0.087 g, 0.73 mmol). The mixture was degassed for 5 mins. Tris(dibenzylidineacetone) dipalladium(0) (0.0025 g, 0.0025 mmol) was added and the mixture was heated to 80° C. for 48 hrs. Water was and compound extracted into ethyl acetate, dried over sodium sulfate and concentrated in rotary evaporator to yield desired compound (0.132 g, 67%). MS (ES) 266.1 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([O-])=O.NN>CO.C(OCC)(=O)C.[Ni].O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccn(Cc2cccnc2)n1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1ccn(Cc2cccnc2)n1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
3-(3-Nitro-pyrazol-1-ylmethyl)-pyridine (113 mg, 0.55 mmol) was dissolved in a mixture of methanol and ethyl acetate (1 mL each). Hydrazine (156 μL, 4.97 mmol) was added followed by a slurry of Raney nickel in water (1.5 mL) causing vigorous gas evolution. After stirring 1 h, the reaction mixture was filtered and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 3% methanol/chloroform) to afford 1-pyridin-3-ylmethyl-1H-pyrazol-3-ylamine (72 mg, 75%) as a white solid: LC-MS (ESI) m/e calcd for C9H10N4 [M+] 174.09, found 175 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Reactant: O=C=Nc1ccccc1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)c1[N+](=O)[O-]
Yield: 73.9 %

Procedure:
Method H3 was used with 4-(4-aminophenoxy)-3-nitropyridin-2-amine (50 mg, 0.2 mol) and phenyl isocyanate (22 μL, 0.2 mmol) to afford the title compound (54 mg, 74%). 1H-NMR (δ, ppm, DMSO-d6): 5.96 (d, 1H, HPy,5, J=5.72 Hz), 6.99 (t, 1H, Harom,Ph′,4), 7.13-7.16 (m, 4H, NH2,Py+Harom,Ph,3+5), 7.30 (t, 2H, Harom,Ph′,3+5, J=7.90 Hz), 7.48 (d, 2H, Harom,Ph′,2+6′J=7.69 Hz), 7.55 (d, 2H, Harom,Ph,2+6, J=8.93 Hz), 8.00 (d, 1H, HPy,6, J=5.78 Hz), 8.69 (s, 1H, NHurea,1), 8.81 (s, 1H, NHurea,3); LC-MS (m/z): 366 (M+H, 100).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:13]=1[O:14][CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:13]=1[O:14][CH:15]1[CH2:18][N:17]([C:1]([Cl:4])=[O:2])[CH2:16]1
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c(Cl)c1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 9.0 g (0.09 mole) of phosgene in 200 mL of methylene chloride under nitrogen was treated with 12.5 g (0.09 mole) of anhydrous potassium carbonate and stirred for 30 min. The reaction mixture was cooled in an ice bath while 28 g (0.08 mole) of 3-(2-chloro-4-fluorophenoxy)-1-(diphenylmethyl)azetidine in 100 mL of methylene chloride was added dropwise. After stirring for 16 hr at ambient temperature the reaction mixture was cooled to 0° C. in an ice water bath and small pieces of ice were added to destroy the excess phosgene, being careful to control the evolution of carbon dioxide gas. When the evolution of gas ceased, the reaction mixture was decanted from the inorganic slurry, dried (filtered through Whatman PS paper) and concentrated in vacuo, 41.9 g. Upon standing, a semisolid residue formed and the solid was collected by filtration after trituration with hexane to obtain 13.2 g (62.5%). A sample was recrystallized from hexane for analysis yielding fine white crystals, mp 93°-94° C.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.COC([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH2:30][O:31][C:26]=2[CH:25]=1)=O.Cl>C(OCC)C.C1COCC1.O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH2:30][O:31][C:26]=2[CH:25]=1)=[O:19]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2C
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc3c(c2)OCC(=O)N3C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of tert-butylmagnesium chloride (CAS Reg. No. 677-22-5) in diethyl ether (2.1 ml) was added to 2-chloro-4-methoxyphenylacetic acid (CAS 91367-09-8) (200 mg) in THF (5 ml). The mixture was stirred at room temperature for 30 min. A solution of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester (200 mg, CAS Reg. No. 201294-27-1) in THF (3 ml) was added and the resulting mixture was stirred overnight. Aqueous HCl (25%, 0.5 ml) and water (10 ml) were added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 10 to 50% EtOAc/heptane) to give the title compound (100 mg) as a light yellow solid. MS (m/e)=346.1 [M+H+].
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([OH:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[N:15]=[N:14]C(C(OC)=O)=[CH:12][CH:11]=1.Cl>CC1OCCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[N:14][C:4]([C:5]([OH:8])([CH3:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)O
Agent: C[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Cl)nn1
Temperature: -20 °C

Procedure:
To a solution of MeTHF (2.5 mL) and toluene (10 mL) was added MeMgCl (3.0 M, 9.7 mL) and stirred at −20° C. under N2 atmosphere followed by the addition of t-BuOH (0.5 mL, 5.79 mmol) in MeTHF (7 mL) dropwise. The solution was allowed to stir for 30 min and warmed to 3° C. and cooled backed down to −20° C. followed by the addition of the methyl 6-chloropyridazine-3-carboxylate (1.0 g, 5.79 mmol) in portions. The solution quickly turned dark violet and stirred at 0° C. for 30 min. The solution was then poured into a flask containing 1 N HCl at −5° C. and diluted with EtOAc followed by stirring for 10 min. The layers were separated and the organic layers were washed with sat. NaHCO3 and brine. The acidic aqueous layer was neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layers were combined and concentrated under rotary evaporation. Column chromatography Hex to 100% EtOAc provided the title compound.