Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: O=C=NC1CCCCC1
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.5 mg, 42%) having the following characteristics.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[CH:15][C:16]4[C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]=4[CH:22]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH2:31][CH2:32][CH3:33]>>[CH2:31]([O:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[CH:15][C:16]4[C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]=4[CH:22]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:32][CH3:33]
Reactant: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1O
Reactant: CCCI
Product: CCCOc1cc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)ccc1C(=O)OC
Yield: 52.8 %

Procedure:
Following the basic procedure of Example 12, by reacting 2 g (5.1 mmol) of methyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate with 600 μl (6.1 mmol) of 3-iodopropane, 1.16 g (54%) of methyl 2-propyloxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate was obtained.
Reaction SMILES: [NH+]1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]=1[CH3:30])=[O:10].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:16]1[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]([CH2:30][C:32]2[NH:31][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:9]([O:8][CH3:7])=[O:10]
Reactant: c1c[nH]cn1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(Cc2ncc[nH]2)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
Pyridinium perbromide hydrobromide (5.6 g, 17.5 mmol) was added to a stirred ice-cooled solution of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid dimethylester (5.55 g, 15 mmol) and pyridine (2 g) in methylene dichloride (80ml). The solution was stirred at ice temperature for 40 minutes then washed with ice cold water (1×100 ml). The organic phase was separated and imidazole (6.8 g, 0.1 mol) added followed by anhydrous Na2SO4. After drying for 20 minutes the solution was filtered to remove NaSO4, evaporated and the residue heated on a steam bath for 40 minutes. The residue was then dissolved in EtOAc, washed with water (2×50 ml), dried, evaporated and crystallised from methyl acetate (15 ml) to give the crystalline title compound (3.34 g). This was suspended in isopropyl alcohol/methyl acetate (2:3 v/v)and acidified with ethanolic HCl to give the hydrochloride salt on cooling, m.p. 167°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#N.[OH2:12].[OH-:13].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:13])=[O:12]
Reactant: N#CCc1ccc(I)cc1F
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(I)cc1F

Procedure:
A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 2.05 g, 7.83 mmol) in ethanol (50 mL and water (15 mL) was treated with potassium hydroxide (3.4 g, 60.7 mmol) and refluxed for 4 h. The volatiles were distilled off in vacuo and the residue was diluted with water and poured into cold, dilute hydrochloric acid and the precipitated solid was filtered. The solid was dissolved in diethyl ether, and the organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound a pale yellow solid (1.75 g, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14](CO)=[CH:13][CH:12]=1.CN(CC(O)=[O:24])C>O1CCOCC1.CN(C=O)C.[Cu]I>[F:10][C:11]1[CH:18]=[CH:17][C:14]([O:24][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: OCc1ccc(F)cc1
Reactant: CN(C)CC(=O)O
Reactant: COc1ccc(Br)cn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(F)cc2)cn1

Procedure:
According to Scheme 32 Method A: 5-Bromo-2-methoxypyridine (5.32 mmol, 1.00 g), 4-fluorobenzylalcohol (7.98 mmol, 0.90 g), N,N-dimethylaminoacetic acid (15.9 mmol, 1.69 g), CuI (5.32 mmol, 1.01 g), CsCO3 (12.4 mmol, 4.05 g) in dioxane (25 mL) and DMF (2.5 mL) were heated at 150° C. for 25 min. under microwave irradiation conditions. Then the cooled crude reaction was filtered off over celite. The filtrate was washed with saturated aqueous NH4Cl solution and extracted with AcOEt. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (heptane/AcOEt, 80/20). The product fractions were collected and the solvent was evaporated to give a mixture of the desired product contaminated with 4-fluorobenzylalcohol. This residue was taken up in AcOEt and washed with aqueous solution of NaOH 1N. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure giving 5-(4-fluorophenoxy)-2-methoxypyridine (520 mg, 45%).
Reaction SMILES: [CH:1]([CH:4]([N:8]=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1OC)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:22]([Li])([CH3:24])[CH3:23]>C1COCC1>[CH:22]([C:11]1[CH:12]=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH:9]=[N:8][CH:4]([CH:1]([CH3:2])[CH3:3])[CH:5]([CH3:6])[CH3:7])([CH3:24])[CH3:23]
Reactant: [Li]C(C)C
Reactant: COc1cc(OC)c(OC)cc1C=NC(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C=NC(C(C)C)C(C)C)c(C(C)C)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-isopropyl-2-methyl-propyl)-(2,4,5-trimethoxy-benzylidene)-amine (1.024 g, 3.5 mmol) in 35 ml THF at −78° C. was added isopropyllithium (6.0 mL, 0.7 M in pentane) drop-wise over 5 minutes. The solution was allowed to stir 30 min at −78° C. After warming to room temperature over 45 minutes the mixture was quenched by the addition of 5 mL of 10% NH4Cl and concentrated in vacuo. 100 mL of H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and then brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give (2-isopropyl-4,5-dimethoxy-benzylidene)-(1-isopropyl-2-methyl-propyl)-amine as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH3:15][NH:16][CH2:17][CH2:18][OH:19].C(OCC)(=O)C>C(O)C>[OH:19][CH2:18][CH2:17][N:16]([CH3:15])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: CNCCO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCO)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a suspension of 2.946 g (13.73 mmol) of 2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added 3.31 mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature and condensed, then, the residue was treated with ethyl acetate. The organic layer was washed with water and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 2.05 g (59%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH:25]=O)[CH3:20].[NH2:34][C:35]([NH2:37])=[O:36].Cl>C(O)C>[CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:25]([C:24]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]([OH:30])=[C:22]([O:21][CH2:19][CH3:20])[CH:23]=3)[NH:34][C:35](=[O:36])[NH:37][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CN(C)c1ccc(CC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(N(C)C)cc2)cc([N+](=O)[O-])c1O
Temperature: 130 °C
Reaction time: 48 h
Yield: 13.7 %

Procedure:
To a solution of 2-(4-(dimethylamino)phenyl)-1-phenylethanone (Intermediate 44) (235 mg, 1 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (212 mg, 1 mmol), and urea (138 mg, 3 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was stirred at 130° C. for 2 days. After the solvent was removed under reduced pressure, the residue was purified by preparative HPLC (40-80% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) to give the Compound 88 (65 mg, yield 13.9%). 1H NMR (CD3OD 400 MHz): δ 7.43 (s, 1H), 7.25-7.19 (m, 8H), 7.02 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 4.06-4.00 (m, 2H), 3.06 (s, 6H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 475.3 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(CCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Oc2ccc(Br)cc2C=O)cc1
Yield: 98.9 %

Procedure:
In a manner similar to the method described in Example 60b, 5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde (9 g, 27 mmol) was reacted with tert-butyldimethylchlorosilane (4.45 g, 30 mmol) and imidazole in N,N-dimethylformamide to give 5-bromo-2-{4-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-phenoxy}-benzaldehyde as a brown oil (Yield 12 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:12]=3[O:11][C:10]([CH3:22])([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=3[O:11][C:10]([CH3:22])([CH3:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)N=C(c2ccc(F)cc2)c2ccc([N+](=O)[O-])cc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1(C)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Temperature: 25 °C

Procedure:
A mixture of the compound obtained in (2) described above (2.2 g), reduced iron (2.0 g), ammonium chloride (780 mg), ethanol (40 mL) and water (10 mL) was heated under reflux for an hour. After cooling to room temperature, the reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. Dichloromethane (50 mL) and water (50 mL) were added to the residue, and the aqueous layer was separated and extracted with dichloromethane (40 mL×2). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the titled compound (2.0 g) as a yellow powder, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(C(C)C)CC)(C)C.[NH:22](C(OC(C)(C)C)=O)[CH2:23][C:24]([O:26]N1C(=O)CCC1=O)=[O:25]>ClCCl>[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH-:10])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC(=O)O
Product: [NH-]Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrobenzylamine hydrochloride (1 g; 5.3 mmol) and diisopropylethylamine (1.8 ml; 10.6 mmol) were dissolved in 70 ml of dichloromethane at RT. BOC-Gly-OSu (1.44 g; 5.3 mmol) was added and the solution was stirred at RT overnight. After evaporating the solvent in a rotary evaporator, the residue was taken up in 50 ml of ethyl acetate and extracted in each case 2× with 5% KHSO4, 5% NaHCO3 and distilled water. The organic phase was dried over Na2SO4, the solvent was evaporated and toluene was then added and evaporated in a rotary evaporator. The resultant oil was dissolved, without further work-up, directly in 15 ml of 4M HCl/dioxane and stirred at RT. After a short time, the product starts to precipitate. After 1 h, the solvent was evaporated, the solid was suspended in 100 ml of ethyl acetate, filtered off and washed with petroleum ether. The white solid was dried under vacuum.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1cc(-c2ccccn2)ccn1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2cc(-c3ccccn3)ccn12

Procedure:
A mixture of 2.0 g of 2'-hydrazino-2,4'-bipyridine and 50 ml of triethyl orthoacetate was heated on a steam bath for 18 hours, then chilled, filtered and the crystals washed with hexane. These crystals were recrystallized from methylene chloride, giving 1.8 g of the desired product as white crystals, mp 239°-241° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:22]([O:24][CH3:25])=[O:23])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1C(O)=O)=[O:4].[N-]=[N+]=[N-].[Na+].[N:30]1[CH:35]=CC=CC=1.[Cl-].C[N+](C)=CS(Cl)(=O)=[O:41]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:22]([O:24][CH3:25])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=2[NH:30][C:35]1=[O:41])=[O:4]
Reactant: COC(=O)C(C(=O)OC)c1c(C(=O)O)cc([N+](=O)[O-])c2ccccc12
Reactant: C[N+](C)=CS(=O)(=O)Cl
Reactant: c1ccncc1
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)C(=O)Nc2cc([N+](=O)[O-])c3ccccc3c21
Temperature: -5 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A stirred suspension of 6 (7.00 g, 20.16 mmol) and powdered NaN3 (3.28 g, 50.44 mmol) in CH2'Cl2 (100 mL) was treated with pyridine (3.99 g, 50.44 mmol), then cooled to -5° C. and treated in one portion with N,N-dimethyl(chlorosulfonyl)methaniminium chloride [SOCl2 /DMF adduct] (4.26 g, 22.18 mmol). After stirring at 20° C. for 2 h, the mixture was washed twice with water, dried (Na2SO4) and filtered through a short column of silica gel, eluting with further CH2Cl2 (400 mL). Removal of the solvent under reduced pressure below 30° C. gave the crude carbonyl azide (7), which was immediately heated with stirring in dry toluene (65 mL) under reflux for 8 min. The mixture was cooled to 0° C. to complete precipitation of the product, which was collected and washed with toluene. This was stirred as a suspension in CH2Cl2 (25 mL) for 10 min at 20° C., diluted with iPr2O, and the resulting solid collected to give 1,1-di(methoxycarbonyl)-5-nitro-1,2-dihydro-3H-benz[e]indole-2one (8) (5.60 g, 81%). A sample crystallised from CH2Cl2 had mp 218-222° C. (dec.). 1H NMR [CD3)2SO] δ 11.59 (s, 1H, NH), 8.21 (d, J=8.7 Hz, 1H, H-7), 7.95 (s, 1H, H-9), 7.87 (d, J=8.5 Hz, 1H, H-4), 7.74 (t, J=7.6 Hz, 1H, H-6), 7.65 (t, J=7.7 Hz, 1H, H-5), 3.72 (s, 6H, 2×CO2CH3). Anal. Calculated for C16H12N2O7.1.5 H2O: C, 51.8; H, 4.1; N, 7.5. Found: C, 52.1; H, 3.1; N, 7.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20].Cl.C(N(CC)CC)C.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20])(=[O:35])[CH:33]([CH3:37])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)C(C)C)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.15 g, 0.44 mmol) dissolved in methylene chloride (5 mL) was added triethylamine (0.30 mL, 2.2 mmol) and 2-methylpropanoyl chloride (0.09 mL, 0.87 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(isobutyrylamino)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 88%). LC-MS: (FA) ES+ 379.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C1COCCN1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1

Procedure:
Generally, the process described in U.S. Pat. No. 4,367,346 can be used to synthesize long chain carbon compounds. The Patent 4,367,346 synthesis route consists of: (a) reacting cyclododecanone with morpholine in the presence of a catalyst to form 1-morpholino-1-cyclododecene; (b) separating the 1-morpholino-1-cyclododecene and reacting it with an organic acid halide of 15-20 carbon atoms in the presence of a tertiary amine in an organic solvent while maintaining the reaction temperature at 0°-10° C. followed by (c) hydrolysis under acidic conditions, thereafter (d) separating the 2-n-alkyl-cyclotetradecanedione and reacting with a solution of alkali metal hydroxide and diethylene glycol at 90°-110° C. followed by (e) addition of hydrazine hydrate and the reaction mixture is refluxed at 125°-135° C., thereafter (f) the distillate is removed until the temperature of the reaction mixture climbs to 190°-210° C. where it is refluxed for 3 to 20 hours with slow stirring, and then (g) cooled to 110°-125° C. followed by addition of hot (80°-95° C.) water with rapid stirring followed by (h) neutralization with aqueous acid to a pH of 2 to yield the carboxylic acid which is separated and purified by recrystallization which is then (i) dissolved in tetrahydrofuran under an inert atmosphere and has added thereto the reducing agent, borane-methyl sulfide complex with stirring and heated to 40°-65° C. for 2 to 3 hours before cooling to ambient temperature followed by the sequential addition of ethanol and water to quench excess borane reagent followed by (k) separation and purification of the long chain alcohol.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:50]CCC(OCC)=O>N1C=CC=CC=1>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[N:50]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: O=C(O)C(F)(F)c1ccc(F)cn1
Reactant: CCOC(=O)CCN
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 150 °C
Yield: 30.7 %

Procedure:
To a mixture of 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (1.05 g, 5.49 mmol) and 2-amino-3-nitrobenzoic acid (1 g, 5.49 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.59 mL, 6.03 mmol), and the mixture heated in a microwave synthesizer at 150° C. for 10 min. The mixture was allowed to cool to rt, and then ethyl 3-aminopropanoate hydrochloride (945 mg, 6.03 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min, and then concentrated under reduced pressure. THF (20 mL) and sodium ethoxide (21% in EtOH, 10 mL) were added and the mixture was heated at 50° C. for 0.5 h with stirring. The mixture was concentrated under reduced pressure and then partitioned between EtOAc and 4 N HCl. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by silica gel chromatography eluting with 10-100% EtOAc/hexanes. The residue was triturated with Et2O and the solid was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-nitroquinazolin-4-ol (566 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.77 (t, J=7.91 Hz, 1H) 7.97-8.11 (m, 2H) 8.30-8.48 (m, 2H) 8.68 (s, 1H) 13.61 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: NCc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1CCN(c2ccc(Nc3ncc4ccc(NCc5cccnc5)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (66.6 mg, 0.000172 mol), [3-(Aminomethyl)-pyridine (22.33 mg, 0.2065 mmol) Palladium Acetate (4.00 mg, 0.0178 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.0 mg, 0.0518 mmol), and Cesium Carbonate (240.0 mg, 0.7366 mmol) were added. The mixture was purged with nitrogen for 15 minutes. 1,4-Dioxane (2.00 mL) was added. The reaction vessel was sealed and heated at 120° C. for 2 hours. The reaction mixture was partitioned with DCM. The solid was filtered through celite and washed with DCM. The filtrate was evaporated to give a semi-solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN (0 to 20% ACN). The collected fractions were lyophilized to give N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(7)-pyridin-3-ylmethyl-pyrrolo[2,1-f][1,2,4]triazine-2,7-diamine a solid. The solid was triturated with Et2O to give a yellow solid 78 mg, 85%). LCMS (E/I+) 415.17 (M+H). NMR 1H (DMSO-d6)-9.80 (bs, 1H), 9.34 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.89 (d, 1H, J=7.04 Hz), 7.65 (d, 2H, J=8.04 Hz), 7.54 (t, 1H, J=5.53 Hz), 7.49 (bs, 1H), 7.13 (s, 1H), 6.99 (d, 2H, J=8.04 Hz), 6.33 (s, 1H), 4.72 (s, 2H), 3.75 (d, 2H, J=12.56 Hz), 3.54 (d, 2H, J=11.06 Hz), 3.18 (bs, 2H), 2.6-3.00 (m, 5H).