Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:30][CH2:31][CH3:32])=[CH:19][C:18]=1[N+:33]([O-:35])=[O:34])[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7](O)=[O:8])#[N:2].[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][NH2:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][NH:40][C:7](=[O:8])[CH2:6][CH2:5][CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([C:1]#[N:2])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:30][CH2:31][CH3:32])=[CH:19][C:18]=1[N+:33]([O-:35])=[O:34]
Reactant: CC(C)(C)CCN
Reactant: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)O)C2CCOCC2)cc1Oc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)NCCC(C)(C)C)C2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-cyano-6-(4-ethoxy-2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (160 mg, 0.33 mmol), 3,3-dimethylbutylamine (40 mg, 0.4 mmol), HBTU (155 mg, 0.4 mmol) and DIEA (150 μL) in DMF (10 mL) was stirred at room temperature overnight. Water was then added, and the resulting mixture was extracted with methylene chloride (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 20-50% ethyl acetate in heptane) to yield a yellow oil.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[OH:26])=[O:13])[CH2:5]1.[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.CCN(C(C)C)C(C)C.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>C(Cl)(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27](=[O:32])[N:3]1[C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=2[OH:26])=[O:13])[CH2:5]1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (8.58 g, 18.74 mmol, 1 eq), phthalic anhydride (5.55 g, 37.5 mmol, 2 eq) and DIEA (11.3 mL, 55.6 mmol, 3.5 eq) in chloroform (150 mL) was heated to 70° C. for 2 hours. The solution was cooled to rt and carbonyl diimidazole (2.24 g 13.82 mmol, 3 eq) was added and the solution heated to 60° C. for 2 hours. The solution was cooled to rt, 1 N HCl was added, the aqueous extracted with DCM, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (200 g column) eluting with 30 to 60 to 80% EA/heptane afforded the product of Step C. Calculated for C24H21F3N2O5: 474.1 (M+1). found: 475.1.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:31])[CH2:23][CH2:24][C:25]([CH:29]=[CH2:30])(O)[CH:26]=[CH2:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.O>N1C=CC=CC=1>[C:1]([O:20][CH2:21][C@@H:22]1[O:31][C:25]([CH:26]=[CH2:27])([CH:29]=[CH2:30])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(O)(C=C)CC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=CC1(C=C)CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
13.0 g of (2S)-1-(trityloxy)-5-vinyl-6-heptene-2,5-diol and 57.2 g of toluenesulfonyl chloride were dissolved in 200 ml pyridine, and stirred at 80° C. overnight. After the reaction was completed, water was added thereto, and it was stirred at room temperature for 10 min. After extracting twice with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was dissolved in toluene. After the solvent was removed again, the resulting residue was purified by silica gel column chromatography to give 5.88 g of (5R)-5-[(trityloxy)methyl]-2,2-divinyltetrahydrofuran.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1[OH:34].[O-]O.C1(C(C)C)C=CC=CC=1>CN(C=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:34])=[N:15][CH:16]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CN(C)C=O
Solvent: CC(C)c1ccccc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 22 °C

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) is solubilised in anhydrous DMF (0.65 mL). Titanium isopropoxide (IV) (22 μl, 0.076 mmol) and (1R,2S)-(+)-1-amino-2-indanol (22.8 mg, 0.151 mmol) in anhydrous DMF are added under stirring at 22° C., followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[S:13]1[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[N:15]=[C:14]1[NH2:22].[SH:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][N:25]=1>>[CH3:29][N:28]1[CH:27]=[N:26][N:25]=[C:24]1[S:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:13][C:17]2[C:16]([N:15]=1)=[N:21][CH:20]=[CH:19][N:18]=2
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1nc2nccnc2s1
Reactant: Cn1cnnc1S
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nc4nccnc4s3)c2c1

Procedure:
The compound of Example 14 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]-pyrazin-2-yl-amine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][C:23]=2[CH2:31][OH:32])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CI.[CH2:37](Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH3:37][O:32][CH2:31][C:23]1[CH:24]=[C:25]([CH2:28][O:29][CH3:30])[CH:26]=[CH:27][C:22]=1[CH2:21][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: ClCCl
Reactant: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(CO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(COC)c1
Yield: 64 %

Procedure:
To a cold (0° C.) solution of [2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-methoxymethyl-phenyl]-methanol (0.085 g, 0.20 mmol) in THF (2 mL) was added a slurry of NaH (95% dry, 0.100 g, 4.17 mmol) in THF (2 mL) followed by neat MeI (0.25 mL, 4.02 mmol). The resultant mixture was stirred for 2.5 hours and treated with brine (5 mL) and CH2Cl2 (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2—CH3OH—NH4OH) gave COMPOUND 55 (60 mg, 64%) as a colorless oil. 1H NMR (CDCl3) δ 1.65-1.73 (m, 3H), 2.00-2.07 (m, 1H), 2.20-2.41 (m, 8H), 3.21 (s, 6H), 3.56 (s, 2H), 3.97 (m, 2H), 4.18 (s, 2H), 4.22 (s, 2H), 6.77 (s,1H), 6.83-6.89 (m, 3H), 7.14-7.20 (m, 3H), 8.31 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 19.22, 25.72, 28.37, 48.62, 57.85, 58.50, 66.60, 72.27, 74.68, 122.14, 125.94, 126.81, 129.51, 132.43, 135.29, 135.36, 138.11, 138.62, 146.56, 160.00; ES-MS m/z 446 (M+H). Anal. Calcd. For C28H35N3O2.0.3CH2Cl2: C, 72.16; H, 7.62; N, 8.92. Found: C, 71.88; H, 7.61; N, 8.95.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:9]#[N:10])=[C:4]([O:18][CH3:19])[CH:3]=1.Cl.[N:21]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:30]([CH2:32][C:33]([NH:35][C:36](=[O:40])[O:37][CH2:38][CH3:39])=[O:34])#[N:31]>O.C(O)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([NH:1][N:21]=[C:32]([C:30]#[N:31])[C:33]([NH:35][C:36](=[O:40])[O:37][CH2:38][CH3:39])=[O:34])=[CH:3][C:4]=2[O:18][CH3:19])=[CH:12][CH:13]=1
Reactant: COc1cc(N)ccc1C(C#N)c1ccc(Cl)cc1
Reactant: O=N[O-]
Reactant: CCOC(=O)NC(=O)CC#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(C(C#N)c2ccc(Cl)cc2)c(OC)c1
Reaction time: 2 h

Procedure:
To a stirred and cooled (5°-10° C.) mixture of 5.6 parts of 4-amino-α-(4-chlorophenyl)-2-methoxybenzeneacetonitrile, 6.2 parts of concentrated hydrochloric acid and 50 parts of acetic acid is added dropwise, during a 15 minutes period, a solution of 1.25 parts of sodium nitrite in 10 parts of water at about 10° C. Upon completion, the whole is stirred for 60 minutes and then 3.6 parts of anhydrous sodium acetate and 2.8 parts of ethyl (2-cyanoacetyl)carbamate are added and stirring is continued for 2 hours at room temperature. The reaction mixture is poured into 250 parts of water. The product is filtered off, washed with water and dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo, yielding ethyl [2-[[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]hydrazono]-2-cyanoacetyl]carbamate.
Reaction SMILES: C1(P(=[O:20])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][S:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[N:63]([CH2:73][CH:74]1[CH2:76][CH2:75]1)[S:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:74]1([CH2:73][N:63]([C:52]2[CH:53]=[C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])[CH:55]=[C:56]3[C:51]=2[NH:50][C:49]([C:47]2[S:43][CH:44]([CH2:77][N:78]4[CH2:83][CH2:82][S:81](=[O:20])[CH2:80][CH2:79]4)[CH2:45][N:46]=2)=[CH:57]3)[S:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)(=[O:65])=[O:66])[CH2:75][CH2:76]1
Reactant: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a mixture of triphenylphosphine oxide (557 mg) and dichloromethane (1 mL) was added trifluoromethanesulfonic anhydride (0.17 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min, followed by an addition of dichloromethane (3 mL). A mixture of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxamide (355 mg), thioanisole (0.12 mL) and dichloromethane (3 mL) was added thereto at 0° C., and the mixture was stirring at 0° C. for 10 min. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was extracted with concentrated hydrochloric acid, and after basified with the aqueous layer with potassium carbonate, the whole mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the amorphous solid from a fraction eluted with ethyl acetate. To the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 369 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the resulting mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give amorphous solid, which was crystallized from diisopropyl ether to give the title compound (146 mg, yield 47%) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=O)[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[O:31][CH3:32].[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([C:4]1[C:5]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([OH:11])=[CH:8][C:9]=1[O:10][C:30]([O:31][CH3:32])=[O:33])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1c(C(C)=O)c(O)cc(O)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c(OC(=O)OC)cc(O)c(-c2ccccc2)c1CC(=O)OC
Temperature: 4 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Compound 69 (0.12 g, 0.41 mmol) obtained in Example 69 was dissolved in tetrahydrofuran (10 mL), triethylamine (0.15 mL, 1.1 mmol) was added thereto, and the solution was cooled to 4° C. Then, methyl chlorocarbonate (0.081 mL, 1.1 mmol) was added thereto, and the mixture was stirred for 2 hours with heating up to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting methyl 2-acetyl-3,5-bis(methoxycarbonyloxy)-6-phenylphenylacetate was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL) and water (5.0 mL), then the solution was cooled to 4° C., and sodium borohydride (73 mg, 1.9 mmol) was added thereto, taking 5 minutes, and then stirred for 1 hour. Water (10 mL) was added to the reaction mixture, and stirred for 10 minutes, and then extracted twice with ethyl acetate (0.10 L). The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (ethyl acetate/n-hexane=1/2) to obtain methyl 6-ethyl-3-hydroxy-5-(methoxycarbonyloxy)-2-phenylphenylacetate (89 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:5][CH:1]([CH3:3])[CH3:2])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Solvent: CC(C)O
Product: CC(C)Oc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 2-propanol. White solid. MS (m/e): 222.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.ClC1C=CC(S[CH2:14][N:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]2=[O:22])=CC=1.C1CCCCC=1>ClCCl>[Cl:4][CH2:14][N:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]1=[O:22]
Reactant: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=c1ncc(Cl)cn1CCl
Reaction time: 0.25 h

Procedure:
Sulphuryl chloride (3.0 mmol) in dry dichloromethane (10.0 ml) was added to 1-(4-chlorophenylsulphenyl) methyl-5-chloropyrimidin-2-one (see Example 2) (3.0 mmol) in dry dichlormethane 30.0 ml) at -30° C. for 3 mins. The mixture was stirred at -25° C. for 50 mins before cyclohexene (3.5 mmol) in dry dichloromethane (10 ml) was added. After stirring for 15 mins the mixture was filtered, evaporated and the residue washed three times with Pet. ether. Insoluble 1-chloromethyl-5-chloropyrimidin-2-one (0.45g), 84% was used in Example 31 without further purification.
Reaction SMILES: S.[CH2:2]([O:4][C:5]([C:7]1([CH2:19][O:20][C:21]2[C:30]([Cl:31])=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([C:32]#[N:33])=[CH:28]3)=[CH:23][CH:22]=2)[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[N:34]1C=CC=CC=1>C(N(CC)CC)C>[ClH:31].[ClH:31].[CH2:2]([O:4][C:5]([C:7]1([CH2:19][O:20][C:21]2[C:30]([Cl:31])=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([C:32](=[NH:34])[NH2:33])=[CH:28]3)=[CH:23][CH:22]=2)[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(COc2ccc3ccc(C#N)cc3c2Cl)CCN(c2ccncc2)CC1
Reactant: c1ccncc1
Agent: S
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc3ccc(C(=N)N)cc3c2Cl)CCN(c2ccncc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydrogen sulfide was blown into a solution of 4-(8-chloro-2-cyanonaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (124 mg) in a mixture of pyridine (2.5 ml) and triethylamine (0.5 ml) with ice-cooling, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the residue was treated with hydrogen chloride-ethanol. To the residue were added acetone (2 ml), methanol (2 ml) and methyl iodide (0.172 ml), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in ethanol (4 ml). Ammonium acetate (106 mg) was added, and the mixture was stirred at 75° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:ammonia). The obtained residue was treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (92 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:10]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.F[C:38](F)(F)[C:39]([OH:41])=[O:40].O1CC[N:47](C2C3N(C=C(/C=C/C4C=CC5C(=CC=CC=5)N=4)N=3)C(C3C=CC(C(O)=O)=CC=3)=CN=2)[CH2:46]C1.[CH3:80]OC(=O)[C@H](C)N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:47][CH2:46][CH2:38][C:39]([O:41][CH3:80])=[O:40])=[O:18])=[CH:20][CH:21]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The (E)-4-(8-morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[1,2-a]pyrazin-5-yl)benzoic acid compound 57a (100.0 mg, 0.170 mmol) was treated with β alanine methyl ester (59.1 mg, 0.420 mmol), HATU (96.4 mg, 0.250 mmol), DIEA (0.175 mL, 1.00 mmol) in DMF (2 mL), and the mixture was stirred at rt for 3 h. The reaction was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH, filtered and dried to give (E)-methyl 3-(4-(8-morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[1,2-a]pyrazin-5-yl)benzamido)propanoate which was subjected to saponification with LiOH, using the methods described in Example 15, Step C, to afford the title compound 39. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.54-2.57 (m, 1H), 3.46-3.57 (m, 3H), 3.77-3.88 (m, 4H), 4.26-4.36 (m, 4H), 7.46-7.51 (m, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 7.70-7.91 (m, 5H), 7.96 (t, J=9.3 Hz, 2H), 8.00-8.11 (m, 2H), 8.25-8.30 (m, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.75 (s, 1H). Mass Spectrum LCMS, ESI (pos.) Calcd. for C31H28N6O4: 572.2 [M+H]. found 572.5.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]1[O:18][CH2:4]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[S+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
DMSO (20 ml) was added to sodium hydride (60% NaH, 1.55 g), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and THF (20 ml) was added. The mixture was cooled to -5° C. , and thereto was dropwise added trimethylsulfonium iodide (7.90 g) in DMSO (30 ml) over 3 minutes. After stirring for 1 minute, t-butoxycarbonyl-L-prolinal (5.13 g) in THF (15 ml) was added quickly, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice water (300 ml) and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give two kinds of diastereomers of (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine, 3.12 g of its less polar compound and 1.28 g of its more polar compound. (Configuration of the epoxy moiety of the both unidentified.) The less polar compound was used in the following reactions.