Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:11]>>[OH:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C=O)cc1
Reactant: O=S(=O)(O)O
Product: O=Cc1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
The procedure of Example 8 was followed except that the reaction of p-aminobenzaldehyde with sulphuric acid in 40% aqueous solution was effected at 120° C. for 15 minutes, to obtain 2.6 g (0.021 mol) of p-hydroxybenzaldehyde, accompanied with formation of tarry materials in large quantities. The yield of p-hydroxybenzaldehyde so obtained was 53%, based on the weight of p-aminobenzaldehyde used.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CCO>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: Clc1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 4-chlorobenzylchloride (0.242 mg, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[CH3:15][O:16][CH2:17][C:18](Cl)=O>O1CCOCC1>[CH3:15][O:16][CH2:17][C:18]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: COCC(=O)Cl
Reactant: NNc1ccc(-c2ccccc2)nn1
Solvent: C1COCCO1
Product: COCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
To a mixture of 0.01 mole of 3-hydrazino-6-phenylpyridazine in 25 ml. of dioxane is added 0.005 mole of methoxyacetyl chloride. The mixture is refluxed for 2 hours to give the product of the Example, m.p. 133° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1.CCN(CC)CC>C1COCC1>[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42]([N:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=2)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 3-((4-fluorobenzylamino)methyl)-5-(4-fluorophenoxy)benzylcarbamate (0.72 g, 1.58 mmol) in THF (15 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (0.41 g, 1.58 mmol) and Et3N (0.66 mL, 4.75 mmol). The reaction mixture was stirred at rt for 1.5 h. The mixture was concentrated. The sample was purified by flash chromatography. Elution with 0 to 35% of ethyl acetate in dichloromethane gave the product as a white solid (0.65 g, 61%). 1H NMR (CDCl3): δ 9.01 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.15-7.06 (m, 4H), 7.01-6.92 (m, 4H), 6.76 (s, 2H), 6.54 (s, 1H), 4.41 (s, 2H), 4.32 (s, 2H), 4.21 (d, J=5.6 Hz, 2H), 1.49 (s, 9H); MS (ESI): (M−H)−=677.1.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH:34]([C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2)=O>O1CCCC1.CCCCCC>[NH:40]1[C:41]2[C:37](=[C:36]([CH:34]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:28][CH:27]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:39]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
31 g of p-hydroxybenzyltriphenylphosphonium bromide ware suspended in 350 ml of tetrahydrofuran under an inert atmosphere, and over one hour 86 ml of a 1.6 M solution of butyllithium in hexane were added thereto. After stirring for 30 minutes, a solution of 5 g of 4-formyl-indole in 100 ml of tetrahydrofuran was added over 30 minutes, and the mixture was stirred for 24 hours. After dilution with 500 ml of water, the mixture was extracted with ethyl acetate. The fractions with an Rf=0.15 were isolated by chromatography on silica (eluent:methylene chloride) were triturated with petroleum ether (b.p. 60°-80° C.), filtered and dried under reduced pressure to obtain 7 g of 4-[(1H-indol-4-yl)-ethenyl]-phenol melting at ≃145° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[S:25][C:24]([O:26][CH2:27][C@@H:28]([NH:40]C(=O)OC(C)(C)C)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[N:23][N:22]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[S:25][C:24]([O:26][CH2:27][C@@H:28]([NH2:40])[CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=4)=[N:23][N:22]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A 50% TFA/DCM mixture (2 mL) was added to tert-butyl (S)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate. After 30 minutes, the reaction mixture was concentrated. The residue was purified by reverse phase C-18 HPLC chromatography to provide (2S)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)-3-(4-(trifluoromethyl)phenyl)propan-2-amine (50 mg, 42% over two steps). LCMS 431 (M+H) calc. for C21H18F3N4OS 431.1. 1H NMR (400 MHz, CDCl3): δ ppm 3.14 (d, J=6.46 Hz, 2H) 3.81-3.88 (m, 2H) 3.95-4.00 (m, 1H) 7.43 (d, J=8.02 Hz, 2H) 7.60 (d, J=8.22 Hz, 2H) 8.03 (d, J=6.26 Hz, 1H) 8.17 (s, 1H) 8.22-8.28 (m, 2H) 8.62 (d, J=6.26 Hz, 1H) 9.58 (s, 1H). 2H not detected.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C([O-])(=O)C.[K+].[N+](C1C=CC=CC=1)([O-])=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:25][CH2:24][CH2:23][C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3ccc(CCO)cc3)cccc21

Procedure:
HEPAAQ was prepared by a procedure described in Lord, M. W.; Peters, A. T.; J. Chem. Soc., Perkins Trans., 1,(20)2305-8, incorporated herein by reference, with a slight modification. In a 250 mL single-necked round-bottom flask equipped with a reflux condenser was placed 1-chloroanthraquinone (10.5 g), 4-aminophenethyl alcohol (11.2 g), potassium acetate (7.87 g), copper acetate (0.46 g), and nitrobenzene (75 mL). The flask was flushed with nitrogen and then heated to reflux for about 2 hours. The mixture was filtered. The solvent was removed from the filtrate, and the resultant solid was washed with methanol. The product was purified by dissolving the dried filtrate in dichloromethane and chromatographing on a silica column using a 10/90 (v/v) acetone/dichloromethane mixture as the eluent. The solvent was removed from the chromatographed material and dried in vacuo.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC(=O)O
Product: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Thus 1 part of triphenylcarbinol is reacted with 2 parts of malonic acid at 170° for 3 hours to provide 3,3,3-triphenylpropionic acid and this acid is converted into the acid chloride by reaction with thionyl chloride. Reacting the acid chloride with 2 parts of 2-azabicyclo[2.2.2]octane provides the amide, 2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane and reduction of this amide with 1 part of LiAlH4 in tetrahydrofuran provides 2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane. The addition of concentrated hydrochloric acid to an ethereal solution of above amine provides 2-(3,3,3-triphenyl propyl)-2-azabicyclo[2.2.2]octane hydrochloride, melting at 221°-223° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[C:15]3[N:21]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:30][CH2:29][CH2:28][C:27]=5[CH:31]=4)[N:20]=[N:19][C:16]3=[N:17][CH:18]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:21]3[C:15]4[C:16](=[N:17][CH:18]=[C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]5)[N:14]=4)[N:19]=[N:20]3)=[CH:31][C:27]=2[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.5 %

Procedure:
To a solution of {(R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (67 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added 4M HCl/Dioxane dropwise (2 mL). The reaction was stirred at room temperature for 2 hours. The organic layer was decanted and the crude solid was purified with a reverse-phased preparative HPLC eluting with acetonitrile-water having 0.1% acetic acid to provide 61 mg of (R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-ylamine as the acetate salt (99% yield).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-n-propylbenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[O:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:22]1[C:17]2[O:16][CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c(C3=CCNCC3)coc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-(7-methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in methylene chloride (10 mL), was added drop wise a solution of TFA (1 mL) in methylene chloride (5mL). The reaction was stirred at room temperature for one hour, then was diluted with 250 mL of methylene chloride, washed with 1N NaOH (100 mL) and with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 0.30 g of the title compound. 1H NMR (300 MHz, CDCl3); δ 2.5 (t, 2H), 3.19 (t, 2H), 3.64 (dd,2H), 4.01 (s, 3H), 6.30 (br s, 1H), 7.10 (d, 1H), 7.21 (t, 1H), 7.52 (d, 1H), 7.64 (s, 1H); MS (ES) m/z (relative intensity): 230 (M+H,100).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[NH2:15][NH2:16]>C(O)C>[CH:2]([C:1]1[CH2:6][C:7](=[O:9])[NH:16][N:15]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C1=NNC(=O)C1
Reaction time: 24 h

Procedure:
Methyl isobutyrylacetate (0.5 g, 3.47 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL) and treated with hydrazine (0.13 mL, 4.16 mmol). After 24 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-isopropyl-1H-pyrazol-5(4H)-one. Then, the 3-isopropyl-1H-pyrazol-5(4H)-one (0.169 g, 1.34 mmol) and 4-chloroquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid was filtered off and washed with a minimum amount of ether to yield Example 18. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 3.98 (bs, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH2:20][CH2:21]I>CN(C)C=O>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]3[CH2:21][CH2:20][CH2:19][S:1][C:2]3=[N:3][C:4]=2[CH:10]=1
Reactant: ICCCI
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nc1n2CCCS1
Yield: 25.3 %

Procedure:
To a flask were added 2 g 2-mercapto-5-methylbenzimidazole, 4.2 g potassium carbonate, 4.0 g 1,3-diiodopropane and 60 ml N,N-dimethylformamide. The mixture was heated to 50 C under nitrogen for 5 hours and then cooled to 22 C. The reaction was quenched with 100 ml water and the product was extracted twice with ethyl acetate and washed twice with water. Following removal of the solvent, the product was recrystallized by dissolving in a hot mixture of 50 ml hexane with 10 ml 2-propanol. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 0.63 g of an off-white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:30][CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:34][CH:31]([NH:30][C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[O:29])=[CH:15][CH:14]=3)[N:10]=2)[CH2:32]1
Reactant: Cc1ccc(NC(=O)Nc2ccc(-c3nc(NC4CN(C(=O)OC(C)(C)C)C4)nc(N4CCOCC4)n3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(NC4CNC4)nc(N4CCOCC4)n3)cc2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-methyl-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 130 mg (0.23 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 40 (37%); (M+H) 461.5.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13].C(OC([N:25]1[CH2:29][C@H:28]([F:30])[CH2:27][C@H:26]1[C:31](O)=[O:32])=O)(C)(C)C>>[Cl:8][C:9]1[C:10]([F:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:13][C:31]([C@@H:26]1[CH2:27][C@@H:28]([F:30])[CH2:29][NH:25]1)=[O:32]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@@H](F)CN1

Procedure:
The title compound was prepared as a TFA salt according to Scheme D5 (steps A and B) from 3-chloro-2-fluoro-benzylamine and (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. MS (LC-MS): 274.9 [M+H]+; tR (HPLC conditions b): 2.23 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:19]1[C:20]2[CH:27]=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][N:11]([C:19]3[C:20]4[CH:27]=[CH:26][NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NCC1(Cc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NCC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 55.8 %

Procedure:
A solution of C-[4-(4-chlorobenzyl)piperidin-4-yl]methyl amine hydrochloride (0.063 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (15% methanol in DCM) gave a white solid (0.040 g, 56%). LC-MS (LCT2) m/z 356 [M+H+], Rt 2.97 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[C:7](=[O:21])[CH:6]=2.[C:22]1([CH2:28][C:29]#[CH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][N:8]1[C:7](=[O:21])[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([C:30]#[C:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=[N:4]2)=[CH:9]1
Reactant: O=c1cc2ncc(Br)nc2cn1Cc1ccc(F)c(F)c1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1cc2ncc(C#CCc3ccccc3)nc2cn1Cc1ccc(F)c(F)c1

Procedure:
The coupling of 7-bromo-2-(3,4-difluorobenzyl)-2H-5,8-diazaisoquinolin-3-one (0.80 g, 2.28 mmol) with 3-phenyl-1-propyne (0.71 mL, 5.74 mmol) using triethylamine (0.64 mL, 4.59 mmol), CuI (0.031 g, 0.16 mmol), and Pd(Ph3P)4 (0.106 g, 0.092 mmol) in dimethylformamide (6 mL) is carried out as described in Example 1, Step (2). The resulting red oil is evaporated onto silica gel and purified on a 3.5×20 cm silica gel column eluted with hexanes/ethyl acetate 3:1. The resulting red solid is triturated with ethyl ether and dried. This will afford the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28]>CN(C=O)C>[CH2:31]([O:30][C:27]([CH2:28][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:29])[CH3:32]
Reactant: CC(=O)OCCBr
Reactant: O=C(OCc1ccccc1)c1cc2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCc2ccccc2)cc2cc(F)ccc21
Reaction time: 5 h

Procedure:
Benzyl 5-fluoroindole-2-carboxylate (9.4 g) was dissolved in DMF (94 ml). Potassium carbonate (9.7 g) and bromoethyl acetate (4.0 ml) were added and the mixture was stirred for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from isopropyl alcohol to give 9.59 g of benzyl 1-ethoxycarbonylmethyl-5-fluoroindole-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=O)[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=[S:24])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 159.8 %

Procedure:
To a suspension of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (1.00 g, 4.99 mmol) in 6 mL of THF was added Lawesson's reagent (1.01 g, 2.50 mmol). The pale yellow cloudy reaction mixture was stirred at room temperature for 6 h and then partitioned between 40 mL of ethyl acetate and 15 mL of 0.5 M NaOH solution. The organic phase was washed with 15 mL each of water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel, eluting with 20-60% EtOAc/hexanes, to give 864 mg (80%) of (1-thiocarbamoyl-cyclopropyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].F[C:16]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=1[CH:18]=[O:19]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:16]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=2[CH:18]=[O:19])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
(4-Chloro-3-hydroxy-phenyl)-acetic acid ethyl ester was reacted with 2-fluoro-5-nitrobenzaldehyde as outlined in Example 21, Step 5, to provide [4-chloro-3-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][N:8]2[C:4]3[C:3]([O:21][CH2:22][CH:23]4[CH2:26][CH2:25][CH2:24]4)=[C:2]([Br:1])[CH:20]=[CH:19][C:5]=3[N:6]([CH3:18])[C:7]2=[O:17])[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (49.4 μL, 0.283 mmol) followed by the addition of acetyl chloride (10.1 μL, 0.142 mmol), and the resultant reaction mixture was stirred at RT for 1 h. Purification by flash column chromatography (5% MeOH/EtOAc) gave the desired product (46 mg, 94%). LCMS calculated for C21H30BrN4O3 (M+H)+: m/z=465.1, 467.1. found: 465.1, 467.1.