Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:34])[CH2:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31])#[N:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:34])[CH2:27][CH:28]([CH3:33])[CH2:29][C:30]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:31])#[N:18]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccccc1C#N
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccccc3C#N)ccc21
Yield: 40.4 %

Procedure:
A solution of 9-ethyl-9H-carbazol-3-amine (210 mg, 1.00 mmol), the compound obtained in Step 1 (239 mg, 0.97 mmol), HOBt (297 mg, 1.94 mmol) and WSC (372 mg, 1.94 mmol) in DMF (5 mL) was stirred at room temperature for 14 hr. The reaction mixture was poured into a mixed solution of aqueous sodium hydrogen carbonate solution and ethyl acetate, and the precipitate was collected by filtration, and recrystallized from methanol and THF to give the title compound (172 mg, 0.392 mmol, 40.4%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[I:11].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[O:8])=[CH:4][C:3]=1[I:11]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Br)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 1.2 using 4-bromo-3-iodobenzoic acid and 4-(trifluoromethoxy)aniline to afford a white solid. UPLC-MS (condition 1) tR=3.64 min, m/z=485.7 [M+H]+, m/z=483.8 [M−H]−; Br pattern. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.3 Hz, 2H) 7.82-7.93 (m, 4H) 8.47 (d, J=1.7 Hz, 1H) 10.52 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:17]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(#N)C>[Cl:17][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[NH2:16])[N:7]([C:5](=[O:6])[CH2:4][N:2]([CH3:1])[CH3:3])[CH2:8][CH2:9]2
Reactant: CN(C)CC(=O)N1CCc2ccc(N)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)CC(=O)N1CCc2cc(Cl)c(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.7 %

Procedure:
A solution of 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (3.0 g, 13.68 mmol) in acetonitrile (150 mL) was treated with N-chlorosuccinimide (2.010 g, 15.05 mmol) and stirred at room temperature for 15 minutes. The solution was poured into chloroform/saturated sodium bicarbonate (aq.) and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-chloro-1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.510 g, 15% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.01 (s, 1 H), 5.21 (s, 2 H), 4.08 (t, J=8.33 Hz, 2 H), 3.16 (s, 2 H), 2.95 (t, J=8.33 Hz, 2 H), 2.25 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[C@@H:24]([CH2:25]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:23][O:22][C:21]1([CH3:39])[CH3:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[C@@H:24](/[CH:25]=[CH:11]\[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:23][O:22][C:21]1([CH3:38])[CH3:39])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=CC1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C\C2(c3ccc(Cl)cc3)CC2)COC1(C)C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirred, cooled (0° C.) solution of 1-(4-chloro-phenyl)-cyclopropanecarbaldehyde (0.36 g) in tetrahydrofuran (15 ml) was added under an argon atmosphere (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) followed by a 1 M solution of LiHMDS in THF (4.8 ml). After 1 h at 0° C. the cooling bath was removed and stirring was continued overnight. The mixture was quenched by the addition of sat. aqueous NH4Cl (15 ml) and H2O (15 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane ->heptane/EtOAc 2:1) to give (S)-4-{(Z)-2-[1-(4-chloro-phenyl)-cyclopropyl]-vinyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.72 g) as light yellow viscous oil. MS (ISP): 378.3 ([M+H]+))
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][N:10]([C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=2)[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=O)C>C(O)(=O)C.[Fe]>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:4](=[O:3])[C:6]3([CH2:8][CH2:7]3)[CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:16]=2[N:17]=1
Reactant: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Ethyl1-[[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]methyl]cyclopropane-1-carboxylate (Intermediate 132; 35.92 g, 97.4 mmol) was dissolved in the acetic acid (750 mL) and the solution stirred and heated to 70° C. under nitrogen. Iron powder (14.61 g) was added in portions over 10 minutes. Over the next 10-15 minutes the resulting exotherm took the reaction mixture temperature up to a maximum of 92° C. The temperature then slowly dropped back to 75° C. The dark reaction mixture was then stirred at 75° C. for 3 hours. The reaction mixture was filtered whilst still hot through a bed of celite and the bed washed through with DCM. The acetic acid/DCM filtrate was evaporated to dryness and the resulting residue azeotroped three times with toluene. The residue was left under high vacuum at room temperature overnight, taken up in DCM and filtered through a small bed of celite. The celite was washed with DCM and the filtrate concentrated down to 250 mL and loaded onto a dry silica column pre-conditioned with DCM. The column was eluted with a 5-10% gradient of 7N NH3/MeOH in DCM and product containing fractions were combined and evaporated. The resultant material was recrystallised from isopropanol. The solid precipitate was collected by filtration, washed with chilled isopropanol and dried by desiccation under high vacuum at room temperature to constant weight to yield the title compound as a grey solid (17.1 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1N
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: O=c1[nH]cnc2ccc(Cl)nc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A suspension of 3-amino-6-chloropicolinamide (2.56 g, 14.9 mmol) in triethylorthoformate (45 mL, 271 mmol) was refluxed for 6 h. The reaction mixture was cooled to room temperature, diluted with hexane, and then filtered. The filter cake was washed with hexane and dried under vacuum to give 6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (2.55 g, 94%) as a pale yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.88 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz), 8.20 (1H, s), 12.65 (1H, brs). m/z=182.06 [M+1]+.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]=[C:23]([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]1[O:1][C:23]1([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C#N)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reactant: OO
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C#N)OC1c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl

Procedure:
1.4 g (12 mmol) of 30% strength aqueous hydrogen peroxide solution were added to 2.7 g (6 mmol) of ethyl 3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)Phenyl)-2-cyanopropenoate in 30 ml of ethanol. After 12 hours the mixture was poured into water. The product was extracted from the aqueous phase using ethyl acetate, after which the organic phase was dried over magnesium sulfate and then concentrated. Purification of the crude product was carried out by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]#[N:35])[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(=O)([O-])[O-:37].[K+].[K+].OO>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]([NH2:35])=[O:37])[CH2:25][CH2:26][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:32][CH2:33]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCC4(CC3)OCCO4)s2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCC4(CC3)OCCO4)s2)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carbonitrile (250 mg, 0.50 mmol) in anhydrous DMSO (4 ml) were added potassium carbonate (172 mg, 1.25 mmol) and hydrogen peroxide (218 μL, 2.49 mmol). The resulting solution was stirred at 70° C. for 1.5 h, cooled to room temperature and diluted with water (70 ml) and washed with EtOAc (2×60 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude oil was triturated with diethyl ether and hexanes, and the resulting tan solid was collected via filtration and air dried to provide 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carboxamide (171 mg, 0.31 mmol, 63% yield) as a tan solid. MS ESI: [M+H]+ m/z 520.1. 1H NMR (500 MHz, CD3OD): δ 11.0 (s, 1H), 9.64 (d, 1H, J=4.9 Hz), 8.79 (s, 1H), 8.76 (bs, 1H), 8.28 (bs, 1H), 8.12-8.05 (m, 3H), 7.97 (s, 1H), 4.68-4.64 (m, 4H), 3.23-3.15 (m, 2H), 3.12 (s, 3H), 2.95-2.85 (m, 2H), 2.44-2.38 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])C(C#N)=[N:14]2)=[CH:8][C:7]=1[CH3:23].Cl.[C:30]([OH:33])(=[O:32])[CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:5][C:6]1[C:7]([CH3:23])=[CH:8][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:31]([C:30]([OH:33])=[O:32])=[N:14]2)=[CH:10][C:11]=1[CH3:12]
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2C)cc1Br
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br

Procedure:
A solution of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (700 mg) of EXAMPLE 1, hydrochloric acid (5 ml) and acetic acid (5 ml) was heated to 120° C. for 3 h. The resulting solids were filtered, rinsed and dried to afford the title compound as a brown solid (593 mg). MS Calc.: 461.0; Found: 459.7 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CS(C)=O>[CH2:25]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:16])[CH:24]=[CH2:23]
Reactant: Cc1cc(Cl)ccc1-c1c(O)cccc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1C
Yield: 66.6 %

Procedure:
Treatment of 4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol (2.7 g, 11.4 mmol) with potassium carbonate (2.4 g, 17.1 mmol) and allyl bromide (1.5 mL, 17.1 mmol) in DMSO (100 mL) according to the procedure described for Example 69, Step 3 provided 2.1 g (66%) of 2′-allyloxy-4-chloro-6′-fluoro-2-methylbiphenyl as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([OH:23])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1
Solvent: O
Product: O=C(O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylate followed the procedure of Example 1 Step 4 as an off-white solid: 1H NMR (DMSO-6) δ 6.21 (s, 2 H), 7.20 (s, 2 H), 7.20-7.60 (m, 7 H), 11.92 (s, 1H), 13.0 (br s, 1 H); MS (ESI) m/z 303 (MH+); MS (ESI) m/z 301 ([M-H]−); HRMS calcd for C19H15N2O2: 303.1134; found (ESI+): 303.1124; Anal. calcd for C19H14N2O2.1.3 H2O: C, 70.06; H, 5.13; N, 8.60. Found: C, 70.22; H, 5.08; N, 8.21.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[CH3:47][C:48]1[C:52]([C:53](Cl)=[O:54])=[C:51]([CH3:56])[O:50][N:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:53]([C:52]2[C:48]([CH3:47])=[N:49][O:50][C:51]=2[CH3:56])=[O:54])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1C(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials in 36% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[N:7][CH:6]=1>N1C=CC=CC=1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:9]=[C:10]2[C:11]([NH2:12])=[N:3][NH:2][C:5]2=[CH:6][N:7]=1
Reactant: NN
Reactant: N#Cc1cc(-c2cccc(F)c2F)ncc1Cl
Solvent: O
Solvent: c1ccncc1
Product: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12

Procedure:
Hydrazine hydrate (0.52 ml, 10.7 mmol) was added to a stirred solution of 5-chloro-2-(2,3-difluorophenyl)isonicotinonitrile (1.22 g, 4.9 mmol) in pyridine (12.5 mL). The reaction mixture was stirred at reflux for 2 hours, allowed to cool and concentrated. Purification by column chromatography using a gradient of 5–10% methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: [O-][O-].[Mg+2].[C:4]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH3:20])[CH2:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC=CC=1>[C:4]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1CN=C(c2ccccc2)c2ccccc21
Agent: [Mg+2]
Agent: [O-][O-]
Solvent: c1ccccc1
Product: Cc1cnc(-c2ccccc2)c2ccccc12
Yield: 42.5 %

Procedure:
To a suspension of activated magnesium dioxide (270 g, 0.132 mol) in 550 mL of benzene was added 1-phenyl-4-methyl-3,4-dihydroisoquinoline (29.0 g, 0.131 mol) with stirring. The reaction mixture was heated at reflux for 16 hours. The magnesium dioxide was removed by vacuum filtration and washed with methylene chloride. Evaporation of the solvent yielded 12.2 g (42%) of pure yellow crystals of 1-phenyl-4-methylisoquinoline.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: OC1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CCCCC2)c(O)c1
Yield: 156 %

Procedure:
Resorcinol (2.2 g, 0.02 moles) was mixed with cyclohexanol (1 g, 0.01 moles) and zinc (II) chloride (0.48 g, 0.0035 moles) and the reaction mixture heated to 150° with stirring. After heating 2 hours, the reaction mixture was allowed to cool and then dissolved in ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated to give a brown oil (3.0 g). Excess resorcinol was evaporated by heating in a Kugelrohr oven under reduced pressure (200°, 2 mmHg). Purified using a silica column eluted with ethyl acetate:isohexane 2:8 to give the product as a yellow oil (0.5 g). Trituration with isohexane gave the product as a white solid (0.2 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH3:31].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C(=O)(O)[O-].[Na+].C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH3:31])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)c1ccccc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
Triethylamine (0.32 mL, 2.29 mmol, 1.2 eq) was added to a solution of 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine (0.626 g, 1.91 mmol, 1.0 eq), prepared as described in Parts A-H of Example 1, in dichloromethane (10 mL) and cooled to −8° C. Benzoyl chloride (0.22 mL, 1.91 mmol, 1.0 eq) was added dropwise and the reaction mixture was stirred for 2 hours. The reaction was then diluted with dichloromethane (80 mL) and saturated aqueous sodium bicarbonate (40 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by HPFC (silica gel eluting with 0-25% CMA in chloroform) to afford 0.47 g of a pale yellow substance. The material was dissolved in acetonitrile, sonicated, filtered, and dried under vacuum at 100° C. for 24 hours to afford 0.225 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxybenzamide as off-white needles, mp 125-127° C. Anal. calcd for C24H28N6O2: C, 66.65; H, 6.53; N, 19.43. Found: C, 66.43; H, 6.47; N, 19.60.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:4][N+:5]([O-:7])=[O:6].[CH3:32][NH2:33]>>[CH3:32][NH:33][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCCSCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CN
Product: CNC(=C[N+](=O)[O-])NCCSCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
2-Methylthio-1-nitro-2-[2-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ylthio)ethylamino]ethylene [12.5 g, 26.8 mmol, prepared as described in Item a)] was dissolved in 40% methylamine solution (134 ml, 1.34 mol, 40% methanol solution) and stirred at 20° C. for 30 minutes. The reaction mixture was evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (30:1) to afford 11.6 g (96.7%) of the desired compound, as a pale yellow oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.[N:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>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].O.O1CCOCC1>[N+:19]([C:15]1[CH:14]=[C:13]([C:3]2[N:4]=[C:5]([CH:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[S:6][C:2]=2[C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccc(-c2nc(C3CCOCC3)sc2Br)c1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2)c1
Yield: 70.4 %

Procedure:
5-bromo-4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole (140 mg, 0.379 mmol) was dissolved into a mixture of degassed dioxane (8 mL) and water (1.6 mL). 2-(4-pyridyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.379 mmol, 1 eq.), cesium carbonate (370 mg, 1.137 mmol, 3 eq.) and PdCl2(dppf)2.CH2Cl2 (31 mg, 0.0379 mmol, 0.1 eq) were subsequently added to the solution. The mixture so obtained was stirred and heated to reflux under argon atmosphere for 5 h. After cooling, the suspension was filtered through a celite pad, and evaporated to dryness. The crude was re-dissolved in ethyl acetate and washed twice with brine. The organic layer was dried over sodium sulphate and evaporated to dryness. The solid material so obtained was then purified by silica gel column chromatography eluting with ethyl acetate/Hex (6/4) yielding the title compound (98 mg, 70%).