Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[I-:11].[Na+]>I>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([I:11])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: COc1nc(Cl)ncc1Br
Agent: I
Agent: [Na+]
Product: COc1nc(I)ncc1Br
Temperature: 40 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Prepared using General Procedure 16: To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (100 mg, 0.447 mmol) in 57% aq. HI (1.0 mL) was added sodium iodide (125 mg, 0.838 mmol). The reaction mixture was stirred at 40° C. for 16 h, cooled, then quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated to afford 22.0 mg (16%) of 5-bromo-2-iodo-4-methoxypyrimidine as an off-white solid. LCMS-ESI (m/z) calculated for C5H4BrIN2O: 314.9. found 315.9 [M+H]+, tR=8.22 min. (Method 2). 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[C:15]([C:17]3[N:18]=[C:19]([NH:22][CH3:23])[S:20][CH:21]=3)[O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:30][OH:31]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[C:15]([C:17]3[N:18]=[C:19]([NH:22][CH3:23])[S:20][CH:21]=3)[O:14][N:13]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CNc1nc(-c2cc(C(=O)Nc3ccc(F)c(Cl)c3)no2)cs1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CNc1nc(-c2cc(C(=NO)Nc3ccc(F)c(Cl)c3)no2)cs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-5-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxamide (22 mg, 0.062 mmol) was suspended in benzene (1.5 mL) and phosphorus pentachloride (33 mg, 0.16 mmol) was added. The mixture was stirred for 3 h at 80° C. and evaporated in vacuo to give a tan solid. Benzene (2.0 mL) was added and the mixture was reevaporated twice. The solid was dissolved in tetrahydrofuran (1.5 mL) and 20 M aqueous hydroxylamine (70 μL, 1.0 mmol) was added and the mixture was stirred for 2 h. The mixture was evaporated in vacuo and triturated with methanol to give a white precipitate which was filtered and washed with methanol to give the desired product (12 mg, 35%). MF=C14H11ClFN5O2S; LCMS calculated for C14H11ClFN5O2S; (M+H)+: m/z=368. 1H NMR (400 MHz, DMSO-d6) δ: 11.20 (s, 1H), 8.75 (s, 1H), 7.82 (m, 1H), 7.32 (s, 1H), 7.20 (m, 1H), 6.92 (m, 1H), 6.65 (m, 1H), 2.82 (m, 3H).
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH2:27]C2>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:29]2[CH:28]([CH3:27])[CH:5]3[CH2:6][NH:2][CH2:3][CH:4]3[C:25]=2[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH2Cl2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C10H9BrO2+H: 241, observed: 241.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 438.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:39]1([O:38][C:36]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)amine (86) (100 mg, 0.26 mmol), triethylamine (0.091 mL, 0.656 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (10 mL) is added phenyl chloroformate (0.033 mL, 0.262 mmol), and the mixture is stirred at RT overnight. The reaction mixture is diluted with dichloromethane and washed with water, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 100 mg of the product 123. 1H NMR (CDCl3) δ 7.50-7.40 (m, 2 H), 7.40-7.10 (m, 6 H), 7.10-6.90 (m, 8 H), 6.90-6.80 (m, 2 H), 6.70-6.60 (m, 2 H), 5.75-5.55 (m, 2 H), 4.75-4.55 (m, 2 H); MS: m/z 466 (M++1)
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[N:25]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:26]([NH:25][C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27]
Reactant: O=C=Nc1ccsc1
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1ccsc1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (50 mg) and triethylamine (35 mL) in tetrahydrofuran (3 mL) was added 3-isocyanatothiophene (26 mg). The reaction mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (74 mg, yield 99%) as yellow crystals. melting point 266° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:19]=[N:20][CH:21]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1

Procedure:
A 332 mg (1.2 mmol) sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and 240 mg (1.38 mmol) of 5-bromo-3-hydroxypyridine, prepared as in step b above, were reacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THF at room temperature for 16 hours, to give 355 mg of the title compound. MS (DCI/NH3) m/z 357/359 (M+H)+, 374/376 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H), 2.10-1.80 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: CN(C)CCC1C2C(O)=CC=C(F)C=2N(C)C=1.[CH2:18]([N:20]1[C:28]2[C:23](=[C:24]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-])=O)[CH:25]=[CH:26][C:27]=2[F:29])[C:22]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[CH:21]1)[CH3:19]>[Pd]>[CH3:44][N:42]([CH3:43])[CH2:41][CH2:40][C:22]1[C:23]2[C:28](=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[N:20]([CH2:18][CH3:19])[CH:21]=1
Reactant: CCn1cc(CCN(C)C)c2c(Oc3ccccc3[N+](=O)[O-])ccc(F)c21
Agent: [Pd]
Agent: CN(C)CCc1cn(C)c2c(F)ccc(O)c12
Product: CCn1cc(CCN(C)C)c2c(Oc3ccccc3N)ccc(F)c21

Procedure:
Following the procedure (step 8, scheme 1) used to prepare compound 1-9c, compound 2-2 was used as starting material, using Pd/C (10%) as source of Pd to obtain compound 2-3.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:13][CH:14]=[CH:15][C:8]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: OC1CSC(O)CS1
Reactant: Cc1ccc(C(=O)CC#N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2ccsc2N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 130.2 %

Procedure:
To a suspension of 4-methylbenzoylacetonitrile (0.325 g; 2.042 mmol) and p-dithiane-2,5-diol (0.155 g; 1.018 mmol) in ethanol (4.3 mL) cooled at 0° C. was added triethylamine (0.283 mL; 2.042 mmol). After 10 min at room temperature, the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-25%) in heptane to afford the title compound (0.288 g; 65%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:24]=[N:15][C:14]=2[CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)ncn4C3CCOCC3)nc2c1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.20 g, 0.646 mmol), triethyl orthoformate (5 mL) was added a catalytic amount of p-toluenesulfonic acid monohydrate, and this was heated to 100° C. for 1.5 hours. The reaction mixture was cooled, ethyl acetate and water added, and this was extracted. This was washed with water, dried over magnesium sulfate, and after concentration the precipitated crystals were filtered off. These were washed with a hexane/ethyl acetate mixture solution, and dried to yield the title compound (65 mg, 31.5% yield) as light reddish-brown crystals.
Reaction SMILES: [CH:1]([CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:17][NH2:18]>C1C=CC=CC=1>[CH3:17][N:18]=[CH:1][CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: Cn1c2c(c3ccccc31)SCCC2C=O
Reactant: CN
Solvent: c1ccccc1
Product: CN=CC1CCSc2c1n(C)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.2 g) in benzene (12 ml) is added 10% solution (3.2 g) of methylamine in benzene. The mixture is stirred at room temperature for 2.5 hours and then evaporated to give 4-methyliminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, 110.0 mg, 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 89.0 mg (88%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].[Li+].[OH-]>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
2-Methylpiperidine (744 mg; 7.5 mmol; 5 eq.) was added to a solution of methyl 3-cyano-4-fluorobenzoate (269 mg; 1.5 mmol; 1 eq.) in DMF (2 mL) and the resulting mixture was stirred at room temperature for 2 days. The solution was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with HCl 0.1M then brine, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in THF (5 mL) and LiOH (126 mg; 3 mmol; 2 eq.) then water (5 mL) were added and the reaction mixture was stirred at room temperature for 5 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 2 with HCl 0.1M and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (294 mg, 80%) as an off-white solid.
Reaction SMILES: CCC1C2N=C(C=C3C(C=C)=C(C)C(=CC4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=O)C(=C(CC(O)=O)C5NC(C=2)=C(C)C=5C(O)=O)N=4)N3)C=1C.Br.C(O)(=O)C.[CH2:50](O)[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].CCC1C(C)=C2NC=1C=C1N=C3C(C(C(C(OC)=O)C3=C3N=C(C=C4NC(=C2)C(C=C)=C4C)C(C)C3CCC(OC)=O)=O)=C1C>>[CH2:50]([O:38][CH2:36][CH2:35][CH2:34][CH2:31][CH2:32][CH3:33])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Reactant: CCCCCCO
Agent: Br
Agent: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(=O)O
Product: CCCCCCOCCCCCC
Yield: 68 %

Procedure:
The chlorin-e6 tetramethyl ester prepared in Example 2 (50 mg) was reacted with HBr/acetic acid and n-hexyl alcohol as described in Example 1 for methyl pheophorbide. The desired product was isolated in 68% yield, and the purity confirmed by TLC and HPLC. The structure was confirmed by NMR and mass spectroscopy; the spectra also showed evidence for aggregation of two chlorin units.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=1)=[O:4].CN(C)/[CH:23]=[C:24](\[F:36])/[C:25]([C:27]1[N:31]([CH:32]([CH3:34])[CH3:33])[C:30]([CH3:35])=[N:29][CH:28]=1)=O>C(O)CCC>[CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:19]=[C:25]([C:27]3[N:31]([CH:32]([CH3:33])[CH3:34])[C:30]([CH3:35])=[N:29][CH:28]=3)[C:24]([F:36])=[CH:23][N:18]=2)=[CH:12][CH:11]=1)=[O:4]
Reactant: CN(C)C(=O)[C@@H]1CCCN1c1ccc(NC(=N)N)cc1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Solvent: CCCCO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCC[C@H]4C(=O)N(C)C)cc3)ncc2F)n1C(C)C
Temperature: 200 °C
Yield: 26.9 %

Procedure:
(S)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid dimethylamide (Method 54; 0.5 g, 1.82 mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 0.2 g, 0.83 mmol) were heated at reflux in butanol (7 ml) overnight. LCMS indicated only 7% product. The reaction was transferred to a microwave tube and heated at 200° C. for 2 hours. LCMS indicated 15% starting material and mainly product. The solvent was removed in vacuo and chromatographed. The product was purified by HPLC and the required fractions were combined and basified with K2CO3 (0.5 g), extracted with DCM (2×50 ml), dried and the solvent removed in vacuo to yield a yellow solid (101 mg, 31%). NMR (400.132 MHz, CDCl3) 8.18 (d, 1H), 7.56 (d, 1H), 7.24 (d, 2H), 6.69 (s, 1H), 6.42 (d, 2H), 5.59 (septet, 1H), 4.51 (dd, 1H), 3.64 (dt, 1H), 3.41 (q, 1H), 3.16 (s, 3H), 2.98 (s, 3H), 2.56 (s, 3H), 2.38-2.28 (m, 1H), 2.25-2.14 (m, 1H), 2.08-1.98 (m, 2H), 1.39 (t, 6H); m/z 452.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]2[CH:14]=[N:15][N:16]=[C:12]2[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:10]([C:27]2[CH:32]=[CH:31][N:30]=[C:29](Cl)[CH:28]=2)[N:9]=1.C(OC(N1CC=C(C2N3C=NN=C3C(C3C=CC=C(C(F)(F)F)C=3)=C(C3C=CN=C([NH:72][C@H:73]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=4)[CH3:74])C=3)N=2)CC1)=O)(C)(C)C>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]2[CH:14]=[N:15][N:16]=[C:12]2[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:10]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:72][C@H:73]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[CH3:74])[CH:28]=2)[N:9]=1
Reactant: OC[C@H]1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Reactant: C[C@H](Nc1cc(-c2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Product: C[C@H](Nc1cc(-c2nc(N3CCC[C@@H]3CO)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1

Procedure:
The title compound was synthesized from 5-(2(R)-(hydroxymethyl)-pyrrolidin-1-yl)-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine in the same manner as 5-(1-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyrid-4-yl)-7-(2-(1(S)-phenylethyl)amino-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine; MS (m/z) 560.4 (M+H)+; C30H28F3N7O requir. 559.59.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:75][NH:76][O:77][CH3:78]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:76]([O:77][CH3:78])[CH3:75])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid (4.56 g, 9.18 mmol), DIPEA (3.55 g, 4.79 mL, 27.53 mmol), BOP (4.26 g, 9.63 mmol) and N,O-dimethylhydroxylamine hydrochloride (940 mg, 9.63 mmol) in DMF (100 mL) were stirred overnight. The DMF was removed and CH2Cl2 added. The solution was washed with dilute aqueous HCl (1M, 4X), water and brine. The solution was dried, filtered and the solvent removed. The product was chromatographed (silica gel, EA/PE, Rf 0.38 EA) to afford the title compound (4.475 g, 90.4%). ESMS 541 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.92 (1H, dd, J=6.13, 14.45), 2.98 (1H, dd, J=5.63, 14.45), 3.13 (3H, s), 3.73 (3H, s), 4.87 (1H, m), 5.61 (1H, d, J=6.95 Hz), 6.57 (1H, s), 7.11 (6H, m), 7.32 (9H, m), 7.46 (1H, s). 13C NMR (CDCl3) 28.19, 30.34, 31.02, 50.55, 61.49, 75.62, 79.34, 119.74, 127.98, 129.59, 135.19, 137.95, 141.77, 155.19, 171.77.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1OCC1CC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of 2-(cyclopropylmethoxy)aniline (1.03 g, 6.31 mmol) in pyridine (20 ml) was cooled to 0° C., and methanesulfonyl chloride (0.541 ml, 6.94 mmol) was added. The mixture was warmed to RT and stirred for 2 hours. The solvent was removed, and the crude was portioned between EtOAc and HCl 1N. The organic phase was washed with brine and dried over Na2SO4. The solvent was removed and the crude was purified by filtration on silica gel cartridge (petroleum ether:EtOAc=80:20) affording N-(2-(cyclopropylmethoxy)phenyl)methanesulfonamide (1.456 g, 6.03 mmol, 96% yield, MS/ESI+ 263.9 [MNa]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCC(N)CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CO)Nc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 223.0 g (1.58 mol) of 1-fluoro-4-nitrobenzene, 168.5 g (1.89 mol) of 2-amino-1-butanol and 146.8 g (1.06 mol) of potassium carbonate in 630 ml of water was refluxed for 2 hours.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:6][CH:7]=1)#[N:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(OCCBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 95 °C

Procedure:
4-(2-Bromoethoxy)benzonitrile (7.3 g) was reacted with potassium phthalimide (5.98 g) in DMF (35 ml) by heating at 95° C. for 3 hours. The N-[2-(4-cyanophenoxy)ethyl]phthalimide obtained after extractive workup (7.30 g) was suspended in IMS (350 ml) and treated with hydrazine hydrate (6.25 g). The mixture was stirred for 22 hours and filtered. The solid obtained was washed with IMS and the combined filtrate and washings were evaporated to dryness. Water was added to this residue and the mixture basified with 10M sodium hydroxide solution. The mixture was extracted with dichloromethane to give 4-(2-aminoethoxy)benzonitrile as an oil.