Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.[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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(-c3ccsc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 170 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (20 mg, 0.038 mmol), 3-thiophene boronic acid (9.7 mg, 0.076 mmol) and tetrakis(triphenylphosphine) palladium (4.4 mg, 0.0038 mmol) in 1 mL of toluene is added 2.0 M Na2CO3 solution (200 μL). The reaction mixture is heated at 170° C. on the microwave oven for 20 min. After cooled down, the resulting solution is concentrated and purified with HPLC. 1H NMR (CDCl3) δ(ppm) 8.12 (s, 1H), 7.71 (d, 2H), 7.57 (t, 2H), 7.47 (m, 4H), 7.38 (m, 1H), 7.33 (m, 5H), 7.14 (d, 2H); HPLC-MS calculated for C27H17ClN4OS (M+H+): 481.0. Found 481.0.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]2[S:14][CH:15]=[C:16]([CH3:17])[C:5]=12.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](OC)=[O:26].[Cl-].[NH4+]>C(N1CCCC1=O)C>[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25]([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]2[S:14][CH:15]=[C:16]([CH3:17])[C:5]=12)=[O:26]
Reactant: Cc1csc2nc3c(c(N)c12)CCCC3
Reactant: COC(=O)CN1CCCC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCN1CCCC1=O
Product: Cc1csc2nc3c(c(NC(=O)CN4CCCC4=O)c12)CCCC3
Reaction time: 0.67 h
Yield: 83.5 %

Procedure:
Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-ethylpyrrolidone, was added 3.28 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50.degree. C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50.degree. C. over a period of 30 minutes. After the stirring at 50.degree. C. for 20 minutes, the mixture was cooled to 15.degree. C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride. After extraction of the solution with 100 ml of chloroform, the extract was dried over anhydrous sodium sulfate, followed by evaporation to dryness. The resultant product was added with ethyl acetate, pulverized and filtered. The crude crystals were recrystallized from chloroform-ethyl acetate to obtain 4.31 g of the titled compound having the melting point of 244.degree. to 246.degree. C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:20]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: C1=CCCCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CC1(C)CC(O)CC(C)(C)N1OC1C=CCCCCC1
Temperature: 87.5 °C
Yield: 17.4 %

Procedure:
A mixture of 15.0 g (0.09 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 126.6 g (1.15 mol) of cyclooctene is heated under a nitrogen atmosphere at 87-88° C. for 40 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 5% ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is crystallized from heptane to give 4.40 g (36% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:14]([CH3:15])[C@H:13]([O:16][Si](C(C)(C)C)(C)C)[C:12]([CH3:25])([CH3:24])[C:11]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:14]([CH3:15])[C@H:13]([OH:16])[C:12]([CH3:25])([CH3:24])[C:11]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 55 %

Procedure:
To a solution of rac-2-chloro-4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]benzonitrile (121 mg) in THF (5.5 mL) was added tetrabutylammonium fluoride-THF solution (0.5 mL, 1 mol/L), and the mixture was stirred at room temperature for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/2) to give the title compound as a colorless solid (yield: 47.2 mg, 55%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:25]([CH3:26])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:5]([C:10]2[N:25]([CH3:26])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:35])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccnc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
To a mixture of 2-(3-ethylsulfanyl-pyridin-2-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (254 mg) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (266 mg) while ice-cooling. The mixture was heated to room temperature and then stirred for 0.5 hours. To the mixture were poured saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethane sulfinyl-pyridin-2-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (8 mg), which is hereinafter referred to as “the present compound 7”), and 2-(3-ethanesulfonyl-pyridin-2-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (235 mg), which is hereinafter referred to as “the present compound 8”.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35]([CH2:36][CH3:37])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CCC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, propanoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.[K+].[Br-]>O1CCCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)cc1

Procedure:
The operation is carried out in a fashion similar to that described in Example 2, but starting from 1.12 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate and 1.3 cm3 of para-chlorophenyl isocyanate in 50 cm3 of tetrahydrofuran. After treatment, 1.2 g of tert-butyl (2RS,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylprolinate are obtained in the form of an amorphous solid [proton NMR (250 MHz, DMSO D6, δ in ppm), 1.50 (s, 9H, (CH3)3); 1.85 (m, 2H, CH2); 2.2 and 2.4 (2m, 2H, CH2); 3.25 and 3.85 (ABX, 2H, CH2N); 4.30 (dd, 1H, CHN); 5.20 (dd, 1H, CHN); 6.3 (t, 1H exchangeable, NH); 7.2 to 7.6 (m, 9H, aromatic); 9 (s, 1H exchangeable, NH)], [infrared spectrum (KBr), characteristic bands in cm-1 3370, 3065, 3030, 2980, 2930, 287, 1735, 1595, 1490, 1450, 1545, 1365, 1150, 830, 760, 700].
Reaction SMILES: Cl[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:28]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\OC1CCCCC1)c1csc(N)n1
Yield: 90 %

Procedure:
Ethyl 4-chloro-(Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (0.68 g) was dissolved in ethanol (6 ml) and N,N-dimethylaniline (0.30 g) and thiourea (0.19 g) added with stirring. After 18 h the mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography eluting with ethyl acetate/hexane gave the title compound as a cream solid (0.66 g, 90%). A sample was crystallised from cyclohexane, m.p. 133°-4° C.; νmax (CHCl3) 2940, 1730, 1605 cm-1 ; δH (CDCl3) 1.34 (3H, t), 1.3-2.0 (10H, br m), 4.3 (1H, br m), 4.36 (2H, q), 5.4 (2H, br s, exch D2O), and 6.68 (1H, s).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][C@H:36]([CH2:38][NH:39][C:40]([C:42]4[S:43][C:44]([Cl:47])=[CH:45][CH:46]=4)=[O:41])[O:35][C:34]3=[O:48])=[CH:29][C:28]=2[O:49][CH3:50])[CH:24]=[CH:25][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>Cl.CO>[Cl:47][C:44]1[S:43][C:42]([C:40]([NH:39][CH2:38][C@@H:36]2[O:35][C:34](=[O:48])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([N:23]4[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][OH:18])[C:22]4=[O:51])=[C:28]([O:49][CH3:50])[CH:29]=3)[CH2:37]2)=[O:41])=[CH:46][CH:45]=1
Reactant: COc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: Cl
Solvent: CO
Product: COc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO)c1=O
Reaction time: 1 h

Procedure:
At 0° C., 37 g (49 mmol) of the compound from Example 24A are dissolved in 313 ml of 1.25N hydrochloric acid in methanol. After 1 h, the solution is evaporated under reduced pressure and diluted with dichloromethane. The organic phase is washed twice with water, dried over magnesium sulphate and, after filtration, evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of dichloromethane and methanol. The product fractions are combined and evaporated to dryness under reduced pressure. This gives 19 g (78% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:4].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:12]([CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1CCCCCC1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude cis-2-(2-cyclopropyl-ethylamino)-cycloheptanecarboxylic acid methyl ester (260.5 mg, 1.09 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 399 mg, 1.2 mmol) and dissolved in N,N-dimethylformamide (9 mL). N-Methylmorpholine (264 μL, 2.4 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol). The resulting mixture was shaken at 25° C. overnight. A 1.0 M aqueous hydrochloric acid solution (11 mL) was added (pH=2) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further dried in vacuo for 5.5 h to afford the crude product, 2-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cycloheptanecarboxylic acid methyl ester, containing 2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetylamino]-cycloheptanecarboxylic acid methyl ester as a side product, as a brown oil. This crude product was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H34N4O7S2 554.19, found 555.3 [M+H+] and LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.3 [M+H+]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.ClC(N(C)C)=C(C)C.[NH2:32][C:33]([C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1)([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:32][C:33]([C:40]3[CH:45]=[N:44][CH:43]=[N:42][CH:41]=3)([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CCOC(=O)C(C)(N)c1cncnc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a mixture of 167 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid and 1.5 ml of dichloromethane was added 90 μl of 1-chloro-N,N,2-trimethylprop-1-en-1-amine under ice-cooling, followed by stirring at room temperature for 30 minutes. A solution of 93 mg of ethyl 2-amino-2-(pyrimidin-5-yl)propanoate in 1.5 ml of dichloromethane and 0.15 ml of triethylamine were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 56 mg of ethyl 2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-(pyrimidin-5-yl)propanoate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8].COC1C=C(O)C=CC=1O>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CCNCC
Reactant: C=CC(=O)OC
Agent: COc1cc(O)ccc1O
Product: CCN(CC)CCC(=O)OC
Yield: 98.9 %

Procedure:
Diethylamine (350 g; 4.8 moles) was added to 344 g (4 moles) of methyl acrylate containing 500 ppm of methoxyhydroquinone and the mixture was made to react at 70°-80° C. for 15 hours, so that the addition to the double bond was completed. After completion of the reaction, the unreacted diethylamine was removed by distillation to give 630 grams of methyl beta-diethylaminopropionate. The yield was 99%.
Reaction SMILES: [F:1][C:2](I)([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:15](Br)[CH:16]=[CH2:17]>[Cu].CS(C)=O>[F:1][C:2]([F:13])([C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[CH2:17][CH:16]=[CH2:15]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CCBr
Agent: [Cu]
Solvent: CS(C)=O
Product: C=CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of perfluorobutyl iodide (103.8 g, 0.3 mol), copper powder (50 g, 0.79 mol) and dimethyl sulfoxide (150 mL) was stirred at 110°-120° C. for 2 hr, then cooled to room temperature. Allyl bromide (36.3 g, 0.3 mol) was added dropwise and then the mixture was stirred at room temperature for 2 hr and at 50° C. for 1 hr. The reaction mixture was distilled in vacuo and the crude product was collected in a cold trap (-78° C.). Redistillation produced 55.2 g (70% yield) of the desired 4,4,5,5,6,6,7,7,7-nonafluoro-1-heptene, formula above, having a boiling point of 79°-80° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:20]2[C:15](=[C:16]([O:39][CH2:40][CH2:41][CH3:42])[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:25]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH3:43])(=[O:10])[CH3:9]>ClCCl>[CH3:43][C@H:12]1[CH2:13][CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)[CH:25]=3)[C:16]=2[O:39][CH2:40][CH2:41][CH3:42])[N:11]1[C:8](=[O:10])[CH3:9]
Reactant: CCCOc1c(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1c(-c2cnn(C3CCNCC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.063 g, 0.127 mmol) in dichloromethane (2.0 mL) and the reaction mixture stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.045 g, 89%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.12 (m, 6H), 1.18-1.37 (m, 1H), 1.57-1.88 (m, 5H), 1.97 (br d, J=10.26 Hz, 2H), 2.07 (s, 3H), 2.16-2.40 (m, 2H), 2.53-2.66 (m, 2H), 2.73-2.89 (m, 1H), 3.03 (br d, J=12.61 Hz, 2H), 3.46-3.65 (m, 2H), 4.09-4.30 (m, 1H), 4.62 (br d, J=5.86 Hz, 1H), 7.11 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.21 Hz, 1H), 7.84 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 397 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][C:22](OCCC)=O)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CCC>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCOC(=O)NCCCC1(O)c2ccccc2CCc2c(C)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CNCCCC1(O)c2ccccc2CCc2c(C)cccc21

Procedure:
12.5 g. of 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, 14 g. of potassium hydroxide and 120 ml. of n-butanol are boiled at reflux for 17 hours under nitrogen and with strong stirring. The butanol is removed by distillation under reduced pressure. The residue is taken up in ether and washed with water. 1-Methyl-10,11-dihydro-5-(3-methylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene is obtained as a thick oil by evaporation of the ether.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[C:23]3[O:28][CH2:29][O:30][C:22]=13)=[CH:17][C:16]([O:31][CH3:32])=[C:15]([O:33][CH3:34])[CH:14]=2)#[N:9].[CH2:35]([CH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[NH:40][CH2:39]1)[C:36]#[CH:37]>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.C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:37]#[C:36][CH2:35][CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[NH:40][CH2:39]3)=[C:23]3[O:28][CH2:29][O:30][C:22]=13)=[CH:17][C:16]([O:31][CH3:32])=[C:15]([O:33][CH3:34])[CH:14]=2)#[N:9]
Reactant: C#CCC1CCS(=O)(=O)NC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4c3OCO4)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2ncc(C#N)c(Nc3ccc(C#CCC4CCS(=O)(=O)NC4)c4c3OCO4)c2cc1OC
Temperature: -20 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
N,N-Diisopropylamine (0.043 g) was added to a stirred mixture of 3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2 g), 4-(2-propynyl)-1,1-dioxotetrahydro-4H-thiazine (0.145 g), bis(triphenylphosphine)palladium(II) dichloride (0.071 g), cuprous iodide (0.024 g) and ethyl acetate (10 ml) that had been cooled to −20° C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with a saturated brine solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of acetonitrile and water. The resultant solid was isolated and dried. There was thus obtained the title compound as a solid (0.05 g); NMR Spectrum: (DMSOd6) 2.97–3.04 (m, 4H), 3.12–3.18 (m, 4H), 3.72 (s, 2H), 3.83 (s, 3), 3.85 (s, 3H), 6.04 (s, 2H), 6.82 (d, 1H), 6.95 (d, 1H), 7.31 (s, 1H), 7.74 (s, 1H), 8.48 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 521.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[I-:35].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>>[I:35][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:8]
Reactant: NNc1ccccc1
Reactant: [I-]
Agent: CCCC[Sn](CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Product: NN(I)c1ccccc1

Procedure:
The starting reactant is phenylhydrazine. The hydrazine group is protected, the aromatic ring is nitrated and subsequently, the nitro-product is chromatographed, reduced to amine, reacted with nitrous acid and sodium iodide to give p-iodo-substituted protected phenylhydrazine. Subsequently it is reacted with hexabutylditin and tetrakis (triphenylphosphine)palladium(0) and then with sodium iodide (NaI125) in the presence of such oxidizing agent as Chloramine-T. The final step, deprotection, gives p-I125 -iodophenylhydrazine.