Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P(Cl)(Cl)(Cl)=O.S[C:20]1[CH:25]=[CH:24]N=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].Cl.[C:31]([OH:36])(=O)[C:32](O)=O>O.C(O)C>[CH:32]1([CH:31]([OH:36])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH2:3][N:2]([CH3:13])[CH3:1])[CH2:24][CH2:25][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C(=O)O
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: Sc1ccncc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 35, but starting from 3-dimethylaminoacrylophenone (10 g), phosphorus oxychloride (5 cc), 4-mercaptopyridine (6.35 g) and sodium cyanoborohydride (2 g), a chestnut-coloured residue is obtained which is taken up in water (100 cc). The solution is acidified to pH 2 by adding an aqueous solution of concentrated hydrochloric acid and then washed with ethyl ether (2×50 cc). The aqueous phase is adjusted to pH 10 by adding a concentrated aqueous solution of sodium hydroxide and then extracted with methylene chloride. The resultant organic phase is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C. to give a red residue which is chromatographed on silica gel [eluent: methylene chloride/methanol (95/5 by volume)], 200 cc fractions being collected. Fractions 13 to 25 are concentrated under reduced pressure (2.7 kPa) at 30° C. A residue is obtained which is dissolved in ethanol (15 cc). A 1.2N ethanolic solution (20 cc) of oxalic acid is added to this solution; the solid which precipitates is separated off by filtration and recrystallised from a mixture (110 cc) of acetonitrile and ethanol (20/80 by volume). In this way 1-dimethylamino-3-phenyl-3-(4-pyridylthio)-2-propene (Z) sesquioxalate (3 g) is obtained in the form of white crystals melting at 173° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#[N:14])[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1.C#C.[C:18]1(C)[CH:23]=CC=[CH:20][CH:19]=1>[Co+].C1(C2CCC=CCCC=2)C=CC=C1>[CH3:15][N:2]([CH3:1])[C:3]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:23][N:14]=2)[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cc1ccccc1
Agent: [Co+]
Agent: C#C
Agent: C1=CC(C2=CCCC=CCC2)C=C1
Product: CN(C)C1(c2ccccn2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.5 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, 50 mg cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and 100 ml toluene were transferred into the reaction vessel in a protective gas/acetylene counterflow. After saturation with acetylene the reaction solution was irradiated for a period of 6 hours at a temperature of 25° C. with vigorous stirring. The reaction was interrupted by switching off the lamps and air supply, and the reaction solution was concentrated to low volume. The resulting crude product (5.47 g) was taken up in a mixture of water (8.7 ml) and concentrated hydrochloric acid (15 ml) and stirred overnight at room temperature. To recover the product it was washed with diethyl ether (3×100 ml), the phases separated, the aqueous phase alkalified with 32 percent by mass of sodium hydroxide solution, extracted with dichloromethane (3×100 ml), the combined extracts dried (Na2SO4), filtered and concentrated to low volume. 3.72 g 4-dimethylamino-4-pyridin-2-yl cyclohexanone were obtained.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[C:24]([OH:26])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27](N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:8]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To methanol (500 ml) was added conc. sulfuric acid (10 ml) below 30° C. To this solution was added (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (100 g) and the resulting mixture was heated under reflux for 4 hours. To the mixture was added triethylamine (63 ml) below 10° C. and the mixture was evaporated in vacuo keeping a bath temperature of rotary evaporator below 40° C. to give a syrup. To this syrup were added tetrahydrofuran (100 ml) and toluene (200 ml) successively, and then evaporated in vacuo keeping the bath temperature below 40° C. This procedure was performed once more to give (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine. The compound obtained above was dissolved in a mixture of ethyl acetate (1000 ml) and triethylamine (63 ml). To this solution was added dropwise a solution of methanesulfonyl chloride (35 ml) in ethyl acetate (100 ml) at 0°-5° C. over a period of 1.5 hours. This mixture was stirred at the same temprature for additional 30 minutes. This mixture was poured into ice-cold water (1000 ml) with stirring. The organic layer was separated, and washed with 1N hydrochloric acid (1000 ml), saturated aqueous sodium hydrogen carbonate (1000 ml) and brine (1000 ml) successively. This organic layer was evaporated in vacuo keeping the bath temperature below 40° C. to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine. The compound obtained above was dissolved in a of tetrahydrofuran (200 ml) and ethanol (300 ml). To this solution was added sodium borohydride(28.5 g) by three portions below 10° C. and then this mixture was stirred at 25°-30° C. for 2 hours. This mixture was poured into ice-cold water (5000 ml) containing conc. sulfuric acid (92 ml) with vigorous stirring, and the stirring was continued for additional 1 hour to give a white crystal. This crystal was collected by filtration and washed with ice-cold water (500 ml) to give (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (95.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=1
Reactant: CC(C)(C)CNc1cc(Cl)nc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(N2CCCC2)n1
Yield: 76 %

Procedure:
The reaction of 4-chloro-6-(2,2-dimethylpropylamino)-2-pyrrolidinopyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 76.0%, m.p.: 140°-145° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][C:16]1=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.O.Cl>C(O)C.[Fe]>[CH2:19]1[C:20]2[N:15]([C:14]3[C:4]([N:1]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=3)[CH2:16][CH2:17][S:18]1
Reactant: CCOC(=O)c1ccc(N2CCSCC2=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCSC1
Yield: 53.3 %

Procedure:
Ethyl 3-nitro-4-(3-oxothiomorpholin-4-yl)benzoate (2.00 g, 6.44 mmol) prepared in the Step 40-1-2 was dissolved in ethanol (120 ml). Purified water (12 ml), iron powder (2.62 g, 47.04 mmol) and hydrochloric acid (0.5 ml) was added to the solution, and the mixture was heated under reflux for 4 hours. The mixture was concentrated, and a saturated sodium bicarbonate solution was added thereto, and the resulting mixture was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give the title compound (0.90 g, 53%) as a light-yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=2)O1.C([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)#N>>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:36]4[CH:41]=[CH:40][C:39]([C:25]5[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=5)=[CH:38][CH:37]=4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5ccc(C#N)nc5)cc4)cc3)[C@H]2C1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile for 4-cyanophenylboronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.99 (d, J=2.14 Hz, 1H) 8.03 (dd, J=8.09, 2.29 Hz, 1H) 7.76 (d, J=7.93 Hz, 1H) 7.68-7.73 (m, 2H) 7.59-7.67 (m, 2H) 7.52-7.58 (m, 2H) 6.67 (d, J=8.85 Hz, 2H) 4.12-4.23 (m, 3.05 Hz, 1H) 3.53-3.62 (m, 1H) 3.26-3.35 (m, 1H) 2.92-3.03 (m, 1H) 2.69-2.78 (m, 1H) 2.48-2.67 (m, 3H) 2.33 (s, 3H) 2.13-2.25 (m, 1H) 1.91-2.03 (m, 1H).
Reaction SMILES: [Na].C(O)C.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1.[C:18]1([CH2:24][C:25](OCC)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:5][C:6]([F:16])([F:17])[C:7]1[CH:8]=[C:9]([CH:13]([C:25]([CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(C(=O)Cc1ccccc1)c1cccc(C(F)(F)F)c1
Yield: 73.5 %

Procedure:
In this example, 4.91 g of metallic sodium was added to 110 ml of anhydrous ethanol at room temperature and stirred until all of the sodium dissolved. A mixture containing 18.76 g of (3-trifluoromethylphenyl)acetonitrile and 21.73 g of ethyl phenylacetate was then added dropwise and the resulting mixture was stirred at reflux for about 18 hours. The mixture was then poured into 300 ml water and extracted three times with ethyl ether. The pH of the extracted aqueous layer was adjusted to a pH of about 1 with aqueous 10 wt. % hydrochloric acid and again extracted three times with ethyl ether. The organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under vacuum affording 22.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:12](/[C:14](=O)[CH3:15])\[CH3:13].[N:17]([O-])=O.[NH2:20][C:21]([CH:25]([F:27])[F:26])=[CH:22][C:23]#[N:24]>CC(O)C>[F:26][CH:25]([F:27])[C:21]1[NH:20][C:14]([CH3:15])=[C:12]([C:13]#[N:17])[CH:11]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[CH:6]3)[C:22]=1[C:23]#[N:24]
Reactant: CC(=O)/C(C)=C/c1cc2cn[nH]c2cc1F
Reactant: N#CC=C(N)C(F)F
Reactant: O=N[O-]
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc3cn[nH]c3cc2F)C(C#N)=C(C(F)F)N1

Procedure:
A suspension of 200 mg (0.87 mmol) (2E)-2-[(6-fluoro-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrite (Example 6A) and 419 mg (3.49 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux temperature overnight. After cooling, the mixture was concentrated under reduced pressure, and the residue was suspended in p-xylene (3 ml). Small amounts of p-toluenesulfonic acid and powdered 4 Å molecular sieve were added, and the mixture was stirred at reflux temperature for 16 h. Upon cooling, the mixture was diluted with aceto-nitrile and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 9:1 v/v) to yield 81 mg (28% of th.) of the racemic title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:33]([F:36])=[CH:34][CH:35]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]([NH:14]C2C=CN(CC(O)(C)C)N=2)=[O:13])[C:8](=[O:32])[CH:7]=1.[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44](N)=[N:43][CH:42]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([NH:14][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]([O:5][C:4]3[C:33]([F:36])=[CH:34][CH:35]=[C:2]([Cl:1])[C:3]=3[F:37])=[CH:7][C:8]2=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:43][CH:42]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 510 mg, 1.28 mmol) in dichloromethane (20 mL) was treated with 6-amino-nicotinic acid methyl ester (252 mg, 1.67 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (1.20 g, 2.57 mmol) and N,N-diisopropylethylamine (438 mg, 2.52 mmol). The reaction mixture was stirred for 5 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 50% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (160 mg, 24%) as a tan solid: HR-ES-MS m/z calculated for C26H26ClF2N3O5 [M+H]+ 534.1602, observed 534.1606; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.36 (m, 6H) 1.37-1.93 (m, 7H) 3.86 (s, 3H) 4.33 (d, J=18.5 Hz, 1H) 4.64 (d, J=18.5 Hz, 1H) 5.04 (dd, J=11.3, 5.0 Hz, 1H) 5.27 (s, 1H) 7.45 (td, J=9.5, 2.1 Hz, 1H) 7.68 (ddd, J=9.5, 8.1, 5.6 Hz, 1H) 8.13-8.19 (m, 1H) 8.29 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (dd, J=2.4, 0.8 Hz, 1H) 11.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:35]=C[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.Br.BrCC1C=C[N:42]=CC=1.C([O:47][C:48](=[O:57])[CH2:49]SC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:2]=[CH:35][N:42]=[CH:33][CH:32]=2)[C:9](=[O:24])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:49][C:48]([OH:57])=[O:47])=[CH:14][N:15]=2)[CH2:26][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: BrCc1ccncc1
Agent: Br
Product: C[C@H]1CC[C@H](N(CCOCc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 4-bromomethylpyridine hydrobromide and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Cl:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1>C1COCC1.O.CCOC(C)=O>[Cl:10][C:11]1[N:12]=[N:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:15][CH:16]=1
Reactant: CN(C)CCCO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-dimethylamino-propanol (95 μL) in 5 mL of THF at 0° C. was added NaH (20 mg). The mixture was stirred for 5 min; then 3,6-dichloropyridazine (100 mg) was added and the mixture was allowed to warm to room temperature and stirred overnight at this temperature. The mixture was diluted with 5 mL of water and 5 mL of EtOAc, the phases were separated, and the aqueous phase was extracted with 2×5 mL of EtOAc. The combined organics were washed with 5 mL of brine, dried over Na2SO4 and concentrated to a colorless oil (128 mg) that was used without further purification. Mass spectrum (ESI) 215.9 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:22][NH:24][C:4]2=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1N
Reactant: NC=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (7.36 g, 0.025 mol), formamide (25 mL) and acetic acid (6.25 mL) was heated at 130° C. for 24 hr. After letting cooling down to room temperature, water was added and the resulting solid was filtered and washed with plenty of cold water. The solid was dried under vacuum at 120° C. for 3 hr to yield 6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one. Yield: 7.45 g (100%). 1HNMR (DMSO-d6): δ 12.15 (1H, s), 8.05 (1H, s), 7.66 (1H, s), 7.44 (5H, m), 7.23 (1H, s), 5.28 (2H, s), 3.92 (3H, s). LC-MS (ESI) m/z 207 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[O:20][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: Cc1nc2c(Cl)c(O)ccc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Cl)c(Oc3cc(Cl)ncn3)ccc2[nH]1

Procedure:
270 mg (1.81 mmol) 4,6-dichloropyrimidine, 330 mg (1.81 mmol) 4-chloro-5-hydroxy-2-methyl-1H-benzo[d]imidazole and 270 mg (1.95 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].C(N(CC)C(C)C)(C)C.[C:56]1([S:62](Cl)(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([S:62]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)(=[O:64])=[O:63])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(S(=O)(=O)c2ccccc2)CC1
Yield: 18 %

Procedure:
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) was stirred in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (16 μL, 0.089 mmol), and benzenesulfonyl chloride (2.5 μL, 0.020 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (18%). LCMS for C30H30ClN6O3S (M+H)+: m/z=589.2.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:22])[CH:10]=2)=[CH:5][CH:4]=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].CCN(CC)CC.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenylamine, (Example 26), (0.33 g, 1.0 mmol), butyryl chloride (0.15 mL, 1.5 mmol, Aldrich), and 4-dimethylaminopyridine (0.006 g, 0.05 mmol, Aldrich) in CH2Cl2 (5 mL) was added Et3N (0.21 mL, 1.5 mmol, Aldrich). The mixture was stirred for 30 min, diluted with hexanes (10 ml) and treated with H2O (2 mL). The resulting solids were filtered, washed with H2O and hexanes, and dried in vacuum for 16 h at room temperature to give the title compound as a white powder. Mp: 112° C., MS (ESI, pos. ion) m/z: 402 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.[C:37](#[N:40])[CH:38]=[CH2:39].CC([O-])(C)C.[K+].CCOC(C)=O>C1COCC1.C(Cl)Cl>[C:37]([CH2:38][CH2:39][CH:26]([C:13]1[N:9]2[CH:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:3]=3[O:2][CH3:1])[C:8]2=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[N:14]=1)[C:27]([O:29][CH3:30])=[O:28])#[N:40]
Reactant: C=CC#N
Reactant: COC(=O)Cc1nc(-c2ccc(C(=O)OC)cc2)c2c(NCc3ccc(OC)cc3OC)nccn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(C(CCC#N)C(=O)OC)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-methoxy-2-oxoethyl) imidazo[1,5-a]pyrazin-1-yl)benzoate (11.4 g, 23.3 mmol) in THF (100 mL) was added acrylonitrile (1.4 g, 25.6 mmol) and t-BuOK (2.3 mL, 1M in THF). The mixture was stirred at RT for 2 hrs. The reaction was complete detected by TLC (PE/EtOAc 1:1). The mixture was extracted with EA and water, the organic layer was dried and concentrated, the residue was purified by column chromatography on silica gel eluted with PE:EA:DCM=2:1:1 to give methyl 4-(3-(4-cyano-1-methoxy-1-oxobutan-2-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (12 g, yield 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1)#[N:2].[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
2-Cyano-5-hydroxy pyridine (200 mg, 1.66 mmol), DMF (10 mL) and K2CO3 (253 mg, 1.83 mmol), and Mel (354 mg, 2.49 mmol) were combined at rt and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water, dried and concentrated to give 2-cyano-5-methoxy pyridine (175mg, 78%).