Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5.0 g (16.3 mmoles) of (4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole of Example 3 dissolved in 75 ml of chloroform, chilled in an ice bath, was added dropwise a solution of 3.30 g (16.3 mmoles) of 85% 3-chloroperbenzoic acid in chloroform. After stirring at 25° C. overnight, the reaction mixture was washed with 5% sodium carbonate, dried over anhydrous potassium carbonate, and stripped in vacuo. The residue was flash chromatographed on silica eluting with 5 to 10% methanol in methylene chloride: 2-propanol (9:1). The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to give the desired titled compound, mp 163.5°-165.5° C. 1H NMR (360 MHz, CDCl3) δ 8.62 (2H,d), 7.68 (2H,d), 7.57 (2H,d), 7.25 (2H,d), 4.05 (2H,t), 3.02 (2H,t), 2.72 (s) superimposed upon 2.69 (m) (5H total). Mass Spec. ##STR25## (M+H) 324 (MW=323).
Reaction SMILES: C([S:14][C:15]1[N:19]([CH2:20][C:21]#[CH:22])[N:18]=[N:17][N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:20]([N:19]1[C:15]([SH:14])=[N:16][N:17]=[N:18]1)[C:21]#[CH:22]
Reactant: C#CCn1nnnc1SC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C#CCn1nnnc1S
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 5-benzhydrylthio-1-(2-propynyl)-1H-tetrazole (0.35 g), anisole (0.6 g) and trifluoroacetic acid (3.4 ml) was stirred for 30 minutes at 20° C. and then allowed to stand for 45 minutes. The reaction mixture was filtered and the filter cake was washed with isopropyl ether. The filtrate and the washing were combined and evaporated under reduced pressure. After the addition of the residue to a saturated aqueous solution of sodium bicarbonate precooled to 10° C., the resulting mixture was adjusted to pH 8.5 with 2N aqueous solution of sodium hydroxide and washed with ethyl acetate. The washed aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 1-(2-propynyl)-1H-tetrazole-5-thiol (95 mg), which is decomposed from 60° to 71° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]1.CC1C=CC(S([O-])(=O)=O)=CC=1>[I-].[K+].C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:27]3[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@H](O)C1
Yield: 97.1 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole), anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium iodide (0.007 g, 0.04 mmol) and (3S)-pyrrolidin-3-ol 4-methylbenzenesulfonate (salt) (See Intermediate 53) (0.21 g, 0.80 mmol) to give the title compound as a pale orange oil (0.15 g): MS (m/e) (79Br/81Br): 351, 353(M+1)
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:59])[CH2:21][C:22]1([CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:50])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:36][CH2:35]2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:50])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:38][CH2:39]3)=[C:27]([C:24]3[CH2:23][C:22]([CH2:51][C:52]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:58])([CH2:21][C:20](=[O:59])[O:19][C:15]([CH3:17])([CH3:18])[CH3:16])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(OC(=O)c3ccc(NC(=N)N)cc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added to a mixture of tert-butyl 4-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)-4-oxobutanoate (35.0 mg), pyridine (0.1 mL), and NMP (0.1 mL) at 50 C, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added, and the obtained mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (29.2 mg).
Reaction SMILES: C([O-])=O.[NH4+].C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH:13]=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH3:29])([C:23]([O:25]CC=C)=[O:24])[CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:32][CH3:33])C=C.[Cl-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:8][C:9]1[CH:31]=[CH:30][C:12]([CH:13]=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH3:29])([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: C=CCOC(=O)C1(C)CCN(C(=O)C=Cc2ccc(OCC=C)c(OC)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)N2CCC(C)(C(=O)O)CC2)ccc1O
Yield: 125.1 %

Procedure:
0.4 g of bis(triphenylphosphine)palladium dichloride and 5 g of ammonium formate were added to a solution of 1.1 g of allyl 1-(4-allyloxy-3-methoxycinnamoyl)-4-methylpiperidine-4-carboxylate (Example 67) in 100 ml of THF. Under an argon stream, the solution was reacted for hours, while it was refluxed. After reaction, 150 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 1.1 g of 1-(4-hydroxy-3-methoxycinnamoyl)-4-methylpiperidine-4-carboxylic acid (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([NH:7][C:8]([C:10]1[N:11]=[C:12](I)[NH:13][C:14]=1[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO>[CH2:1]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:12]2[NH:13][C:14]([CH2:15][CH2:16][CH3:17])=[C:10]([C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])[N:11]=2)[NH:13][C:14]=1[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)c1nc(I)[nH]c1CCC
Solvent: CO
Product: CCCCCCNC(=O)c1nc(-c2nc(C(=O)NCCCCCC)c(CCC)[nH]2)[nH]c1CCC
Temperature: 25 °C
Yield: 46.2 %

Procedure:
Iodide 6d (0.45 g; 1.1 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was recrystallized from CH3OH to afford 0.12 g (45%) of 1d as a white solid. mp>260 C; TLC (CH2Cl2-EtOAc, 1:1): Rf=0.51; 1H NMR (CDCl3): δ 0.88 (br t, 6H), 0.97 (t, 6H), 1.31 (br m, 12H), 1.60 (m, 4H), 1.72 (m, 4H), 3.06 (t, 4H), 3.38 (q, 4H), 7.00 (br t, 2H); 13C NMR (DMSO-d6): δ 14.2, 14.6, 22.8, 23.1, 26.9, 30.2, 31.7, 38.7, 131.3, 137.2, 163.5; UV/vis (CH3OH): max (M−1cm−1)=287 (26000), 295 (25900), 309 (14100); LRMS (CI+): m/z (%): 473 (100) [M+H]+; HRMS (CI+): calcd for C26H45N6O2 473.3604; found 473.3601; Anal. calcd for C26H44N6O2: C, 66.07; H, 9.38; N, 17.78; found: C, 66.26; H, 9.54; N, 17.83.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH2:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].[F:26][C:27]([F:40])([F:39])[C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][C:36](=O)[CH3:37])[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][CH:36]([CH3:37])[CH2:35][CH2:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:39])[F:40])[CH:29]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using [4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]acetic acid ethyl ester and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:5]=2[O:4]1.[F:22][C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].CN(C)C=O>[Cu]I.C1(C)C=CC=CC=1>[F:28][C:24]([F:29])([C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:20][F:21])([CH2:2][F:1])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:6]=2[CH:15]=1)[C:23]([F:31])([F:30])[F:22]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FCC1(CF)C=C(c2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Temperature: 160 °C
Yield: 79 %

Procedure:
A mixture of 1.11 g of 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran, 1.17 g of potassium pentafluoropropionate, 1.18 g of copper (I) iodide, 20 ml of N,N-dimethylformamide and 7 ml of toluene was stirred at 160° C. under nitrogen gas atmosphere with heating for 3 hours while toluene was distilled off. Ether and water were added thereto and the mixture was filtered using Celite. The mother liquor was extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.86 g of oily 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[NH2-].[Na+].ClC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)(Cl)Cl.O>O1CCCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: C1=Cc2ccccc2N(CC2CNCCO2)c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)CN1CCOC(CN2c3ccccc3C=Cc3ccccc32)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.23 g) in tetrahydrofuran was added sodium amide (0.063 g). The resulting mixture was stirred at 40° C for 30 minutes. To the reaction mixture was added trifluoroethyl trichloromethylsulfonate (0.265 g) in tetrahydrofuran at room temperature. The resulting mixture was stirred at 50° C for 5 hours. After cooling, the reaction mixture was admixed with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-trifluoroethyl-2-morpholinylmethyl)-5H-dibenz[b,f]azepine. M.P. 97°-98° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O.[CH2:8]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH2:8]([O:15][C:16]([CH2:17][CH2:18][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCC(=O)O
Reactant: C=CC(=O)OCc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(O)CCNCCC(=O)OCc1ccccc1

Procedure:
3-Aminopropionic acid (5 g, 56 mmol) was added to ethanol (50 mL), and TEA (7.8 ml, 56 mmol) and water (50 mL) were added and the mixture was refluxed under nitrogen. Acrylic acid benzyl ester ((9.1 g, 56 mmol) and more ethanol (50 mL) were added, and the mixture was refluxed for 16 h. The sample was concentrated under vacuum, adding toluene and reevaporating twice to yield 17.5 grams (product plus TEA).
Reaction SMILES: P([C:9]#[N:10])(=O)(OCC)OCC.CN(C=O)C.[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=O)=[CH:45][CH:44]=3)[CH2:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]1=[O:52].[ClH:53].CN>C(OCC)(=O)C.C(N(CC)CC)C>[ClH:53].[ClH:53].[CH3:9][NH:10][C:47](=[O:49])[C:46]1[CH:50]=[CH:51][C:43]([CH2:42][N:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:17]([CH3:16])[C:18](=[O:52])[CH:19]=[CH:20]3)[CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[CH:44][CH:45]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)Cc3ccc(C(=O)O)cc3)ccc21
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(CN(CCCCCOc2ccc3c(ccc(=O)n3C)c2)CCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Diethyl phosphorocyanidate (39.1 mg) was added to a DMF solution (1 ml) of 4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid (0.10 g), methylamine hydrochloride (27 mg), and triethylamine (0.07 ml), and the mixture was stirred at room temperature overnight. Ice water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (81.3 mg) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Reactant: Sc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1CCCCCCCSc1ccc(Br)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (0.6 g., 2.01 mm), was reacted with 4-bromothiophenol (0.60 g., 3 mm), and triethylamine (1.12 ml, 8.05 mm) in DMF (35 ml) as in Example 14(b) to afford the desired product. This was further purified by flash chromatography over silica gel with ethyl acetate in hexane.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC)=[O:19]>C1COCC1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:19])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCCl)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 5-chloropentanoate (1.50 g, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98) to give the product (1.60 g) with colorless oil in 17% yield. 1HNMR (CDCl3, ppm) δ 1.76 (m, 6H), 2.67 (t, J=6.6 Hz, 2H), 3.01 (d, J=21.7 Hz, 2H), 3.35 (t, J=6.2 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Product: CCOC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Yield: 28.6 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:24]#[N:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:38].[Na+]>COCCO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:9]([C:24](=[O:38])[NH2:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 125 °C
Yield: 100.5 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (290 mg, 0.58 mmol) and NaOH (290 mg, 7 mmol) in 2-methoxyethanol/H2O (8 mL/2 mL) was sealed in a microwave tube. The reaction mixture was purged with N2 (3×) and heated at 125° C. in a microwave reactor for 45 min. After cooling down to r.t., the reaction was diluted with water, and the resulting solid was filtered, washed with water, dried under vacuum. (R)-tert-Butyl 3-(4-amino-6-carbamoyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (125) (300 mg, quant.) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 515.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(c1ccccc1)c1nc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C(=O)c3ccccc3)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
(3-Hydroxy-quinolin-2-yl)-phenyl-methanone (27 mg), 4-chloro-6,7-dimethoxyquinoline (120 mg), and 4-dimethylaminopyridine (147 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 42%).
Reaction SMILES: O=[C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6]>S(=O)(=O)(O)O>[F:26][C:24]1[CH:23]=[CH:22][C:21]([C:27]([F:29])([F:28])[F:30])=[C:20]([C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[N:9]=[N:8][C:7]([C:5]4[O:6][C:2]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:3][N:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)=[O:31])[CH:25]=1
Reactant: O=C(CNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(c1cc(F)ccc1C(F)(F)F)N1CCN(c2ccc(-c3ncc(-c4ccccc4)o3)nn2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
A few drops of concentrated sulfuric acid was added to 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-oxo-2-phenylethyl) amide (0.100 g, 0.194 mmol). This mixture was stirred at ambient temperature over night. The reaction was quenched with ice water, followed by the addition of 2 mL of 5% ammonia solution. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulphate, then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid in 82% yield (0.079 g). m.p. 122-125° C. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=9.6 Hz, 1H), 7.80-7.71 (m, 3H), 7.49-7.37 (m, 3H), 7.36-7.29 (m, 1H), 7.28-7.19 (m, 1H), 7.1-7.04 (m, 1H), 7.01 (d, J=9.6 Hz, 1H), 4.08-3.96 (1H), 3.93-3.71 (m, 5H), 3.4-3.32 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.1 158.8, 158.4, 152.5, 142.3, 129.8, 129.6, 128.9, 128.8, 127.6, 126.8, 125.1, 124.6, 123.4, 122.9, 116.8, 116.6, 114.9, 114.7, 112.4, 46.4, 44.7, 44.4, 41.4. MS (ES+) m/z 498.1 (M+1).