Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:40])/[CH:24]=[CH:25]/[CH2:26][N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:40])/[CH:24]=[CH:25]/[CH2:26][N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C/C=C/C(=O)N2CCc3c(sc4ncnc(Nc5ccc(F)c(Cl)c5)c34)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C/CN1CCNCC1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-[(2E)-4-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-4-oxobut-2-en-1-yl]piperazine-1-carboxylate from Example 3 (150 mg, 0.255 mmol) in dichloromethane (15 mL) was added TFA (1.0 mL, 13 mmol), and the mixture was stirred at rt for 5 h. The solvent was removed in vacuo. 1 M aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was crystallized from dichloromethane/diethyl ether to yield 108 mg (87%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH:8](O)[CH2:7][CH2:6][NH:5]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH:8]([N:58]=[N+:59]=[N-:60])[CH2:7][CH2:6][NH:5]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1NCCC1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)[C@H]1NCCC1N=[N+]=[N-]

Procedure:
Reaction of 3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([N+:24]([O-:26])=[O:25])[C:22]=1[CH3:23])[N:19]=[CH:18][N:17]=[C:16]2Cl>CC(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([N+:24]([O-:26])=[O:25])[C:22]=1[CH3:23])[N:19]=[CH:18][N:17]=[C:16]2[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1c(Br)cc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1[N+](=O)[O-]
Temperature: 140 °C
Yield: 48 %

Procedure:
To a microwave vial were added 3-(trifluoromethyl)aniline (343 μl, 2777 μmol), 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (840 mg, 2777 μmol) and IPA (5 mL). The reaction mixture was heated to 140° C. for 20 min. On cooling a ppt was observed to form which was then washed with hexane, filtered and air-dried to afford 6-bromo-7-methyl-8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (569 mg, 48.0% yield) as an amorphous yellow solid. MS (M+H)+ 427, 429.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:14])[CH2:9]2
Reactant: COc1ccc2c(OC)cccc2c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1CCC(=O)C2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
1.6-Dihydroxynapthalene (44 g (0.247 mole)) was mixed with 245 mL of 2N NaOH and 55 mL of methyl sulfate. The mixture was stirred at room temperature. When the pH of the mixture was 6, 124 mL of 2N NaOH and 26.4 mL of methyl sulfate were added and stirred until 1,6-dihyroxynapthalene was disappeared. Excess of methyl sulfate was destroyed by heating for 30 minutes at 100° C. The warm liquid was acidified and extracted with CH2Cl2. The CH2Cl2 layer was washed twice with 2N NaOH and evaporated. A yield of 47.73 g(92%) of 1,6-dimethoxynaphthanene was obtained. Sodium (19 g) was added to a solution of 22.5 of crude 1,6-dimethoxynaphthalene in 190 mL of boiling ethanol. Ethanol (40 mL) was then added and heating continued under reflux until the Na had disappeared (about 40 minutes). Water (60 mL) was added cautiously and then most of the ethanol was removed under reduced pressure. The residue was mixed with 30 mL of water and the lower aqueous layer was separated and extracted twice with dioxane, which was then combined with the oily upper layer. Water (25 mL) and then hydrochloric acid (density of 1.18 g/mL) until the mixture was acidic (pH 2-3). Then, 3 mL more of HCl was added and the liquid was stirred at about 70° C. for 30 minutes. The lower oily layer was separated, the aqueous layer was diluted with 100 mL of water, separated from more oil, and extracted thrice with methylene chloride. The combined oil and methylene chloride extracts were stirred with 50 mL of saturated aqueous sodium bisulfite until crystallization began. The solid was triturated with ether, then washed with ether and dried. Free 5-methoxy-2-tetralone was obtained by treating the bisulfite addition compound with excess 10% Na2CO3 and extracting the resulting mixture with methylene chloride. The extract was washed with 10% HCl and then with water and dried with Na2SO4. Volatiles were removed under reduced pressure to leave 17 g (81% yield) of liquid. On keeping, the 3,4-Dihydro-5-methoxy-2-(1H)-naphthalenone (hereinafter, “Compound 20”) solidified in massive prisms with a melting point of 25-36° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[C:11]([CH2:12]O)=[C:10]([CH3:14])[NH:9][C:8](=[O:15])[C:7]=1[I:16].O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH2:12][C:11]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=2)=[C:7]([I:16])[C:8](=[O:15])[NH:9][C:10]=1[CH3:14]
Reactant: Cc1cc(C)cc(Oc2c(CO)c(C)[nH]c(=O)c2I)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2c(CCl)c(C)[nH]c(=O)c2I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The heterogeneous solution of compound 257 (450 mg; 1.2 mmol) in CH2Cl2 (30 ml) became homogeneous mixture by addition at room temperature of SOCl2 (2.6 ml). After 2 hours on stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected compound 125 in quantitative yield (470 mg); m.p.=256–258° C. This compound was used for the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1(C)[CH:11]=[C:10]([CH3:12])[C:9]2[C:5]([CH:6]=[C:7]([C:13]([O:15]CC)=[O:14])[N:8]=2)=[C:4]1[CH3:18].[OH-].[K+].[C:22](O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:9](=[C:10]([CH3:12])[C:11]=1[CH3:22])[NH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2
Reactant: CCOC(=O)C1=CC2=C(C)C(C)(OC)C=C(C)C2=N1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)c(C)c2[nH]c(C(=O)O)cc2c1C

Procedure:
A solution of ethyl 5-methoxy-4,5,7 trimethylindole-2-carboxylate (PREPARATION 19, 1.04 g) in ethanol (30 ml) containing potassium hydroxide (45%, 2.5 ml) is heated under reflux for 1.5 hr. The mixture is acidified with acetic acid (2 ml) and concentrated under reduced pressure. The residue is mixed with water (200 ml) and filtered. The filter cake is washed with water and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.Cl[C:15]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[F:24][C:22]1[C:21]([F:25])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:7][C:5]2[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:23]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Under an argon atmosphere, a solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.01 g, 34.5 mmol), 2-chloro-4,5-difluorobenzoic acid (6.64 g, 34.5 mmol), copper acetate (II) (0.718 g, 3.95 mmol) and potassium carbonate (4.77 g, 34.5 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux for 2 hours. The solution was cooled to room temperature, and poured into water. The solution was made weakly acidic by the addition of acetic acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give the title compound (9.21 g, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[NH:25]1[CH:26]=[C:22]([CH2:21][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]#[N:10])[N:23]=[CH:24]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
As described in Example 1, 3.0 g. of 2-(4-fluorophenyl)-2-phenylacetonitrile, 1.36 g. of 50% sodium hydride and 2.17 g. of 4-chloromethylimidazole hydrochloride were mixed, and the reaction mixture was stirred at 60° C. for 3 hours and then at ambient temperature for 65 hours. The reaction mixture was then worked up as described in Example 1 to obtain 2.60 g. of the free base of the product named above, which was identified by 60 mHz nuclear magnetic resonance analysis in CDCl3 : δ10.65 (broad m, 1H); 7.37 (m, 8H); 6.88 (d, 2H, J=9 Hz); 6.65 (s, 1H), 3.70 (s, 2H).
Reaction SMILES: [Li+].[OH-].[C:3]([NH:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl>O1CCOCC1>[C:3]([NH:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
Aqueous LiOH (1M, 3.12 mL) is added to a suspension of the product of Step C (445 mg, 1.6 mmol) in dioxane (6 mL). The reaction is stirred for 90 minutes at room temperature. Concentrated HCl (1.5 mL) is added to lower the pH to less than 6 and the resulting precipitate is collected by filtration. The filter cake is washed with water then dried to give the desired product (337 mg, 80%). MS for C15H13NO4 (ESI) (M−H)− m/z 270.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1ccc(OC)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The obtained ester compound was dissolved in 0.5 ml of methanol and 0.5 ml of tetrahydrofuran, and 0.52 ml of aqueous 1 N sodium hydroxide solution was added to it, and stirred at room temperature for 2 hours. This was neutralized with aqueous 10% citric acid solution, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure to obtain 17.2 mg of the entitled compound as a white crystal.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2)=O.[OH-].[Na+].O>CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reaction time: 18 h

Procedure:
A mixture of 25.8 g. of 6-methoxycarbonyl-2-naphthyl-α-methylacetic acid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanol are heated to 50° C., cooled, and evaporated. The residue is taken up in 500 ml. of diethylene glycol dimethyl ether and diborane is bubbled through. The resulting mixture is saturated with diborane and then is allowed to stand for 18 hours. The reaction mixture is acidified by the addition of aqueous 1 N hydrochloric acid. The mixture is extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-hydroxymethyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10](COCC[Si](C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[NH:10][CH:9]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccccc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 53.5 %

Procedure:
(S)-2-(1-((5-(2-Hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (52 mg, 0.09 mmol) was treated with trifluoroacetic acid (1.04 mL, 13.50 mmol) and a solution of ammonia (7N in methanol, 1.04 mL, 7.28 mmol) according to the method described in Example 27 to give 23 mg (56% yield) of the title compound. Purity 98%.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([C:32]#[N:33])=[C:30]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:29]=[C:28]([S:39][CH2:40][C:41]3[N:42]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=4)[S:44][CH:45]=3)[C:27]=2[C:53]#[N:54])=[CH:22][CH:21]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>ClCCl>[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58].[NH2:8][C@H:9]([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:31]([C:32]#[N:33])=[C:30]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:29]=[C:28]([S:39][CH2:40][C:41]3[N:42]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=4)[S:44][CH:45]=3)[C:27]=2[C:53]#[N:54])=[CH:24][CH:25]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.37 g (1.74 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-leucinate were initially charged in 15 ml of dichloromethane, and 15.00 ml (194.70 mmol) of trifluoroacetic acid were added. The mixture was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was dissolved in 5.00 ml of dichloromethane and 10.00 ml of diethyl ether were added. The residue formed was filtered off with suction. Drying gave 1.09 g (76.1% of theory) of the desired target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1>C(O)(=O)C.C1COCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([NH:22][CH3:23])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
2-Chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (220 mg, 0.640 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (215 mg, 0.960 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (92 mg, 0.172 mmol, 26.8% yield). LC-MS (M+H)+=531.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.93 (1H, s), 7.66 (1H, br s), 7.50 (1H, s), 7.10-7.23 (4H, m), 7.02 (2H, d, J=15.3 Hz), 6.83 (1H, d, J=8.2 Hz), 4.70-4.83 (1H, m), 4.13-4.28 (1H, m), 3.12 (3H, d, J=4.9 Hz), 2.74 (1H, br. s.), 2.65 (2H, d, J=8.2 Hz), 1.97-2.08 (1H, m), 1.25 (3H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1>CN(C=O)C>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: Brc1nccs1
Reactant: COc1ccccc1S
Solvent: CN(C)C=O
Product: Oc1ccccc1Sc1nccs1
Temperature: 100 °C
Yield: 81 %

Procedure:
To 2-methoxybenzenethiol (2.8 g, 20 mmol), and 2-bromothiazole (3.29 g, 20 mmol) in dry DMF (30 mL) under N2 (g) was added Me4N+OH-.5H2O (3.62 g, 20 mmol). The stirred mixture was heated to about 100° C. for 16 hours. Isolation of the methoxyphenyl intermediate, and its subsequent deprotection to the desired product with BBr3 was accomplished according to the method described in Preparation 16 (yield 81%; GC-MS m/z 209).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of n-butyllithium in hexanes (1.65M, 4.92 mL) was added dropwise to a solution of 1,4-dibromobenzene (2.05 g) in THF (25 mL) dropwise over the course of 30 min at −78° C. The resulting mixture was stirred at the same temperature for 1 h. To the mixture was added a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (1.02 g) in THF (5 mL) dropwise over the course of 30 min at −78° C. The reaction mixture was stirred for an additional 30 min. at −78° C. then allowed to warm to room temperature. After being stirred for 1 h at room temperature, the reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes then 5% methanol in ethyl acetate) gave the product (1.85 g, 96%). 1HNMR (CDCl3) 400 MHz δ: 7.55 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.16 (d, J=6.9 Hz, 1H), 5.06 (d, J=6.9 Hz, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.94 (d, J=6.9 Hz, 1H), 4.05 (br s, 1H), 1.22 (s, 9H). LCMS: 332, 334 [M+H].
Reaction SMILES: [C:1]1([CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.P([O-])(O)(O)=O.[Na+].[BH4-].[Na+]>C(O)C>[C:1]1([CH:7]([CH2:8][OH:9])[CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC(CO)c1ccccc1
Yield: 69.1 %

Procedure:
A mixture of 20 g of diethyl phenylmalonate, 6.6 g of sodium dihydrogen phosphate monohydrate and 140 ml of absolute ethanol was cooled to 15° C. after which 7.1 g of solid sodium borohydride was added. The reaction was completed by quenching the excess of sodium borohydride with 10% HCl solution and distilling the residual ethanol. 8 ml of NaOH 50% were added in order to obtain a pH of between about 8.0 to about 9.0. The obtained 2-phenyl-1,3-propanediol was then extracted into 400 ml of ethyl acetate. The organic layer was washed with 40 ml of water and filtered through alumina. The precipitate was crystallized from toluene following solvent removal, to obtain 8.9 g of 2-phenyl-1,3-propanediol with a yield of 69%.
Reaction SMILES: C([N:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:7][CH2:6][C@@H:5]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)C=C.O>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)[NH:4]2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: C=CCN1[C@@H](c2ccc(Cl)c([N+](=O)[O-])c2)CC[C@@H]1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2)ccc1Cl
Temperature: 100 °C
Yield: 73.4 %

Procedure:
The product from Example 115A (2.0 g, 4.74 mmol) was dissolved in acetonitrile (40 mL) and water (4 mL) and treated with Tris(triphenylphosphine)rhodium(I) chloride (0.219 g, 0.237 mmol). The mixture was heated at 100° C. and nitrogen was bubbled through the solution for 3 hours. The mixture was partitioned between 5% sodium bicarbonate solution and ethyl acetate, then the organics were concentrated and the product purified by combiflash 80 g silica column eluting with dichloromethane to give 1.33 g (74%) of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH2:13]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]2[O:23][CH2:24][C:25](=O)[C:17]=12)[CH3:14]>>[CH3:1][O:2][N:3]=[C:25]1[C:17]2[C:18](=[N:19][C:20]([CH3:22])=[CH:21][C:16]=2[O:15][CH2:13][CH3:14])[O:23][CH2:24]1
Reactant: CON=C1COc2nnccc21
Reactant: CCOc1cc(C)nc2c1C(=O)CO2
Product: CCOc1cc(C)nc2c1C(=NOC)CO2

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-ethoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;