Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[C:3]1=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl.[O:24]1CCCC1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:3]2[C:2]([CH3:12])([CH3:1])[CH2:7][CH2:6][N:5]3[CH:8]=[N:9][C:10]([OH:24])=[C:4]23)=[CH:17][CH:16]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Reactant: CC1(C)CCn2cncc2C1=O
Agent: Cl
Product: COc1ccc(C2c3c(O)ncn3CCC2(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.90 mmol of 7,7-dimethyl-6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one in 50 ml of tetrahydrofuran is admixed at 0-5° C. with 15.8 mmol of 4-methoxyphenylmagnesium bromide (0.5M solution in tetrahydrofuran). The reaction solution is subsequently stirred at 0° C. for 1 hour and then at room temperature for 16 hours. The reaction solution is hydrolysed with 0.5N HCl and extracted with tert-butyl methyl ether. The aqueous phase is rendered basic with saturated aqueous sodium hydrogen carbonate solution and the precipitated solid is isolated by filtration and dried. The title compound is obtained as a grey solid and used without further-purification for the next stage. Rt=5.42 (Gradient I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](OC)(OC)(OC)[CH2:11][CH3:12].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][CH3:12])[N:8]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCC(OC)(OC)OC
Reactant: C[Si](C)(C)CCOCCl
Product: CCc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C

Procedure:
Synthesized according to the method of reagent preparation 19 by using 5-bromo-2,3-diaminopyridine and trimethyl orthopropionate in step 2 and 2-(trimethylsilyl)ethoxymethyl chloride in step 3. MS (EI) for C14H22BrN3OSi: 357 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF was added allyl tributyltin (0.26 ml, 0.86 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate/Hexane (60:40) as the eluent to provide the title compound (0.10 g, 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:21]([CH2:33][CH:34]=O)[CH2:22][N:23]([CH3:32])[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([C@H:21]([CH2:33][CH2:34][N:10]2[CH2:11][CH2:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)[CH2:22][N:23]([CH3:32])[C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: CN(C[C@@H](CCN1CCC(c2ccccn2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(2-pyridyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Conversion to the hydrochloride salt Gave a white solid; mp 200°-202° C.; MS: 496; NMR: 2.14 (b, 8), 2.7 (s, 3), 3.4-3.9 (m, 8), 6.9-7.7 (m, 12), 8.16 (m, 1), 8.68 (m, 1), 10.4 (br, 1). Analysis for C28H31Cl2N3O·2.0 HCl·0.5 H2O: Calculated: C, 58.14; H, 5.92; N, 7.26 Found: C, 58.00; H, 5.90; N, 7.56.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8](O)[CH3:9].N1(CC[OH:19])C=CC=CC1.CN1CCN(C)C1=O.C([Li])CCC.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42](Cl)=[O:43])=[CH:34]1>C1COCC1.CCCCCC>[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]([O:43][CH2:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:19])=[CH:34]1
Reactant: CC(O)C1CCCCN1C
Reactant: OCCN1C=CC=CC1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CN1CCCCC1CCOC(=O)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of (1-methyl-2-piperidyl)-1-ethanol (19.4 g, 140 mmol), obtained according to the procedures in Reference Example 4 starting with pyridine-1-ethanol, and 1,3-dimethyl-2-imidazolidinone (30 ml, 270 mmol) in THF (300 ml) was dropwise added 1.6M hexane solution of n-butyllithium (85 ml, 140 mmol) over a period of 25 min. After stirring for 30 min., a THF (100 ml) solution of indole-3-carboxylic acid chloride (17.0 g, 95 mmol) and 1,3-dimethyl-2-imidazolidinone (10 ml, 90 mmol) was added at a temperature of -5° C. or below over a period of 50 min. The mixture was stirred under cooling for 30 min. followed by removal of the ice bath and stirring for additional one hour. A reaction mixture was poured onto water (500 ml) followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and then transferred to diluted hydrochloric acid (500 ml). The acid layer was washed with ethyl acetate, adjusted with sodium carbonate to a pH >10 and extracted with ethyl acetate (3×200 ml). The organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give a crude product (9.5 g) as a yellow oil, which was found by NMR to be an approximately 5:1 diastereomeric mixture. Thus, the oil was crystallized from a chloroform-isopropyl ether to afford a less polar major product as colorless crystals, which were a single diastereoisomer of the title compound (6.10 g). m.p. (HCl salt): 185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)(Cl)=O.COC1C=CC(C(Cl)=O)=CC=1[N+]([O-])=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:9])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-methoxy-3-nitrobenzoic acid (10.0 g, 0.051 mol), and thionyl chloride (25 g, 0.212 mol), were refluxed together for 24 hours. The reaction mixture was cooled to room temperature and concentrated. The off-white solid was carried onto the next step. Step 2: 4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in dichloromethane (10 mL) for 48 hours to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% ethyl acetate in hexane. Step 3: Into a 100 mL round bottom flask was placed 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide (0.735 g, 2.69 mmol), 10% Palladium on carbon (250 mg), ethanol (50 mL), and acetic acid (10 mL) under inert atmosphere. Atmosphere then exchanged with hydrogen (via balloon) and allowed to stir 24 hours at room temperature. Reaction mixture was filtered through celite, concentrated under reduced pressure, then purified via silica column chromatography using 0 to 100% ethyl acetate in hexane. MS m/z=244 [M+H]+. Calc'd for C13H13N3O2: 243.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(C)c(C(=O)O)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
5-Bromo-2,4-dimethylbenzoic acid (12 g, 52.17 mmol) was added to cooled conc. H2SO4 (48 mL) at −10° C. lot wise. After 10 minutes nitrating mixture {prepared as mixing Conc. HNO3 (6 mL) with conc.H2SO4 (24 mL)} was added drop wise at −10° C. Resulting reaction mass was stirred at −10° C. for 30 minutes. On completion, reaction mixture was poured on ice cold water, solid precipitated was filtered, washed with water and dried under vacuum giving desired compound (13 g, 91%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:57][CH3:58])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][N:48](C([O-])=O)[CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]>>[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:57][CH3:58])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][NH:48][CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]
Reactant: CCO[C@H]1CN(C(=O)[O-])C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting (3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.15, 1.22-1.34, 2.45, 2.71, 2.89, 3.06, 3.22, 3.41, 3.51, 3.65, 3.85, 4.51, 5.32, 6.88, 7.02, 7.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:33][CH2:32][CH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:23])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: NCCC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl (2-piperidin-3-ylethyl)carbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 3.01 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:32]([CH3:33])[CH3:31])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.25 mmol) obtained in Example 12 in methylene chloride (3 ml), dimethylamine hydrochloride (23 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.061 ml, 0.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 3 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elusion with hexane:ethyl acetate=3:2 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (77 mg, 0.17 mmol, 69%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=S(=O)=O)[N:10]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:6]=[CH:5]1)([CH3:3])[CH3:2].[CH:25]1([N:31]2C(C3C=CNC(=S(=O)=O)N=3)=C(C3C=CC(F)=CC=3)N=C2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:10]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc(-c2ccc(F)cc2)c1-c1cc[nH]c(=S(=O)=O)n1
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)cc[nH]1
Product: CC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccnc(Nc2ccccc2)n1

Procedure:
The reaction was conducted in a manner analogous to Example 2d except substituting polymer-bound 1-isopropyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole for polymer-bound 1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole: ESMS m/z=374 (MH)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:28][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: Clc1nc(N2CCOCC2)c2nc(-c3ccc(N4CCOCC4)nc3)sc2n1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine via General Procedure A to give crude 5-chloro-7-morpholino-2-(6-morpholinopyridin-3-yl)thiazolo[5,4-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 123 after purification by reverse HPLC. MS (Q1) 478 (M+)
Reaction SMILES: [OH-:1].[C:2]1(/[CH:8]=[CH:9]/B(O)O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>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.O>[CH:9](/[C:4]1[CH:5]=[CH:6][C:7]2[O:1][C:9]3[CH:4]=[CH:3][C:2](/[CH:9]=[CH:8]/[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:7][C:8]=3[C:2]=2[CH:3]=1)=[CH:8]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: [OH-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C(=C/c1ccc2oc3ccc(/C=C/c4ccccc4)cc3c2c1)\c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Tetrethylamine hydroxide (13.6 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium(0) (142 mg) and trans-2-phenylvinylboronic acid (2.3 g, 15.3 mmol) are added to a solution of the product from example 1a) (2.00 g, 6.14 mmol) in N,N′-Dimethylacetamide (DMA) (30 ml). The mixture is then stirred at 110° C. for 24 hours. The reaction mixture is cooled to room temperature and poured into H2O. A gray crude product is obtained after filtration and washing with n-hexane. The crude product is purified by silicagel column chromatography with CH2Cl2, which result in a white solid (71% yield, mp.: 226° C.).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=O)[CH:6]=1)([CH3:4])[CH3:3].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>C(O)C>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=O)no1
Reactant: N#CCC#N
Solvent: CCO
Product: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
4.63 g of 5-(1-hydroxy-1-methylethyl)isoxazole-3-carbaldehyde was dissolved in 50 ml of ethanol, and 1.98 g of malononitrile was then added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 5.35 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:18]([C:12]2[CH:11]=[C:10]3[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:8](=[O:21])[NH:9]3)=[CH:14][CH:13]=2)=[O:20])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: NCCCN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
30 mg (25%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-morpholine-4-yl-propylamine (87 mL, 0.598 mmol).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH:11]=[CH2:12]
Reactant: C=CCOc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 100 °C
Yield: 47 %

Procedure:
4-Fluorobenzaldehyde (3.8 mL, 35.1 mmoles) was added to a solution of the product from Example 60A (4.39 g, 29.3 mmoles) and K2CO3 (8.90 g, 64.4 mmoles) in DMF (29.3 mL). The resulting mixture was heated to 100° C. for 2.5 days and then cooled to room temperature. The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage column (hexane→9:1 hexane:ethyl acetate) on silica gel to provide the title compound (3.50 g, 81%) as a clear colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C[Si](C)(C)[O:14][K].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:10])=[O:14])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(CC#N)ccc1F
Reactant: C[Si](C)(C)O[K]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC(N)=O)ccc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in toluene (35 ml), and trimethylsiloxypotassium (3.7 g) was added. After stirring at 110° C. for 2.5 hours, saturated sodium bicarbonate water was added, followed by separation with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 863 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@@H:9]2[CH2:12][C@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)[CH:8]=1)([O-])=O.CCN(CC)CC.[C:31]1([CH2:41][C:42](O)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.[Pd]>[C:31]1([CH2:41][C:42]([NH:1][C:4]2[N:5]=[CH:6][N:7]([C@H:9]3[CH2:12][C@H:11]([O:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH2:10]3)[CH:8]=2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-Toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg) in ethyl acetate (30 mL). The mixture was then reacted under 50 psi H2 at room temperature for 6 h. The mixture was filtered through celite into a flame-dried flask which was kept under a nitrogen atmosphere. Et3N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 h and was then diluted with ethyl acetate and was washed with water and brine. The organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester; 1H NMR (400 MHz, CDCl3) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/CI): 476.2 (M+H)+.