Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:14]([C:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH:10]=2)[C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
0.49 g of 1-t-Butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-3,6-dihydro-2H-pyridine was dissolved in 5 ml of methanol, and 20 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with 1M aqueous sodium hydroxide solution and a saturated aqueous sodium solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 5 ml of acetonitrile, and 340 μl of 37% formalin, 200 μl of acetic acid and 90 mg of sodium cyanoborohydride were added, followed by stirring at room temperature for an hour. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 0.25 g of 4-{1-(4-fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methyl-3,6-dihydro-2H-pyridine as an oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.CO>O1CCCC1>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(N)n3)[C@H]2SC1
Yield: 86 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.95 g), conc.hydrochloric acid (0.324 g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.78 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=1[I:29]>O1CCCC1>[I:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(F)c(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc([N+](=O)[O-])cc2I)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A solution of sodium hydride (0.16 g, 3.9 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (0.82 mL, 3.7 mmol) in tetrahydrofuran (5 mL) and stirred at 0° C. for 30 minutes. The reaction mixture was treated with a solution of 1-fluoro-2-iodo-4-nitrobenzene (1.0 g, 3.7 mmol) in tetrahydrofuran (5 mL) and heated at 70° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude brown oil. Purification by flash column chromatography gave the desired product (1.4 g, 81%) as a yellow oil. LCMS for C18H251N2O5Na (M+Na)+: m/z=499.0.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+].Cl>CO>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1cccc(Cl)c1
Yield: 93.8 %

Procedure:
A mixture of 109 mg (0.228 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 10 mL of methanol was treated with 0.17 mL of 2 M sodium hydroxide and stirred at reflux for 3 hours. The reaction was cooled to ambient temperature and neutralized to pH 1 with 1 M HCl then concentrated to a solid. The solids were triturated with water and dried in vacuo to provide 99 mg (94%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a solid. nmr (300 MHz, dmso-d6) δ1.00 (t, 3H), 2.46 (s, 3H), 2.90 (q, 2H), 4.85 (s, 2H), 5.49 (s, 2H), 7.01 (m, 1H), 7.32 (m, 3H), 7.60 (s, 1H), 8.00 (s, 1H)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CSc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve 4-(methylmercapto) aniline (1.39 g, 10 mmol) in anhydrous pyridine (25 mL) and cool to 5° C. Add, by dropwise addition, p-toluenesulfonyl chloride (2.1 g, 11 mmol) and stir overnight. Partition between water and ethyl acetate and separate the organic phase. Wash the organic phase with cold 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[S:24][C:23]([C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][SiH3])[CH:40]=2)[C:32]3=[O:37])=[O:26])=[CH:22][CH:21]=1.[O:47]1CCCC1>>[Cl:19][C:20]1[S:24][C:23]([C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][OH:47])[CH:40]=2)[C:32]3=[O:37])=[O:26])=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1cccc2c1CN(Cc1cccc(C[SiH3])c1)C2=O)c1ccc(Cl)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(Nc1cccc2c1CN(Cc1cccc(CO)c1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under argon and at room temperature, a solution of tetra-n-butylammonium fluoride (1 M in THF, 4.6 ml, 4.6 mmol) is added to a solution of 5-chloro-N-{1-oxo-2-[3-(silylmethyl)benzyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide (2.0 g, 3.8 mmol) in tetrahydrofuran (38 ml). The reaction mixture is stirred at room temperature for 14 h and concentrated under reduced pressure. The crude product is used without further purification for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][NH2:14])=[O:12])=[O:6].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[S:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][NH:14][C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21])=[S:30])=[O:12])=[O:6]
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Product: O=C(NNC(=S)Nc1ccccc1Cl)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To 200 mg (0.69 mmol) of 3-(3-chlorobenzamido)benzhydrazide in 2.5 mL of tetrahydrofuran was added 175 mg (135 μL, 1.04 mmol) of 2-chlorophenyl isothiocyanate. The reaction was stirred at room temperature overnight. After concentration by rotoevaporation, the residue was purified by preparative HPLC to give 243 mg (0.53 mmol, 77% yield) of 1-[3-(3-chlorobenzamido)benzoyl]-4-(2-chlorophenyl)thiosemicarbazide. 1H NMR (CDCl3): δ7.28 (d of t, 1H), 7.35 (d of t, 1H), 7.99 (t, 1H), 8.34 (br s, 1H), and 8.98 ppm (br s, 1H). MS m/z: 459.0 (M+H).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=S.[Br:12]Br>>[Br:12][C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Reactant: BrBr
Product: O=c1[nH]c(Br)nc2nc[nH]c12

Procedure:
This compound is prepared from 2-thioxanthine** through oxidation of the mercapto group by bromine and in situ displacement by hydrobromine. For reference on the oxidation and displacement, see Beaman, A. G.; Gerster, J. F.; Robins, R. K, J. Org. Chem, 1962, 27, 986.1.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[CH3:7][C:8]([CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=[O:12])=O.C(O)(=O)C.[OH-].[Na+]>[Zn].O>[CH3:7][C:8]1[NH:5][CH:4]=[C:2]([CH3:1])[C:10]=1[C:11](=[O:12])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(=O)/C=N/O
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c[nH]c(C)c1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 14.6 %

Procedure:
According to the literature procedure (Chiswell, B. Inorganica Chimica Acta. 1972, 629), a mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15 mmol), 1,1,1-trifluoro-2,4-pentadione (1.85 mL, 15 mmol), glacial acetic acid (12 mL) and H2O (3.0 mL) was stirred vigorously at room temperature. To this flask, zinc dust (3 g) was added slowly keeping the temperature below 60° C. After addition, the resulting brown solution was heated under reflux condition for 2 hours. After cooling down to room temperature, the reaction mixture was basified by an addition of 2 M aqueous NaOH, then filtered. The filtrate was extracted with CH2Cl2 (20 mL×3), the combined organic layer dried over MgSO4, and concentrated iii vacito. The residue was purified by flash chromatography (1-3:1 CH2Cl2-Hexane) to afford the subtitle compound (0.42 g, 15% yield) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23](C)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: Cc1cc2c(-c3ccccc3F)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1cncnc1
Product: Fc1ccccc1-c1n[nH]c2cnc(-c3cncnc3)cc12
Yield: 25 %

Procedure:
Following the procedures as described in Example 136, pyrimidin-5-ylboronic acid and 3-(2-fluorophenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 138 as a white solid (25 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 14.2 (s, 1H), 9.51 (s, 2H), 9.28 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 7.92 (mt, 2H), 7.59 (t, 2H), 7.41 (t, 1H). ESI MS m/z=292 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>CN(C)C=O>[Cl:39][CH2:38][CH2:37][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (30 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (107 mg) and 1-bromo-2-chloroethane (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine 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 chloroform-methanol to give the title compound (37 mg, yield 100%).
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(N(C)C(NCCCCCCC)=O)C=2)=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:92])[C:80]([NH:82][C:83]3[CH:88]=[CH:87][C:86]([N:89]([CH3:91])[CH3:90])=[CH:85][CH:84]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([O:63]CC)=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Li+]>>[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:92])[C:80]([NH:82][C:83]3[CH:84]=[CH:85][C:86]([N:89]([CH3:91])[CH3:90])=[CH:87][CH:88]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([OH:63])=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc(N(C)C)cc3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CN(C)c1ccc(NC(=O)N(C)c2cccc(-c3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)O)cc3)c2)cc1
Yield: 74.4 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 0.60 g (0.9 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionate (Example 4) and 43 mg (1.02 mmol) of lithium hydroxide, 0.41 g of (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionic acid is obtained with an 89% yield.
Reaction SMILES: [OH-].[K+].N([CH2:5]NCNC(=O)OC(C)C)=O.[N+](=C)=[N-].[C:18]([OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)COCCO.O.CCOCC>[C:18]([O:26][CH3:5])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)OC(=O)NCNCN=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCOCCO
Solvent: O
Product: COC(=O)c1ccccc1
Yield: 81 %

Procedure:
To a solution obtained by dissolving 4.2 g of potassium hydroxide in a mixed solvent of 15 ml of diethylene glycol (DEG) and 3 ml of water, 50 ml of ether was added. The temperature of a water bath was maintained at 45°-50° C. and when the ether began to be distilled out, a solution prepared by dissolving 8.8 g of isopropyl N-[(N-nitrosomethylamino)methyl]carbamate in 70 ml of ether was added dropwise thereto. The ether fraction rapidly changed to yellow. After adding dropwise for 15-20 minutes, ether was added dropwise in order to make the amount of ether in the flask constant. When about 70 ml of ether was added dropwise for 20 minutes, the distillate became colorless and the reaction was completed. To the distilled ether solution containing diazomethane, benzoic acid was added to produce methyl benzoate, and an excess of benzoic acid was back-titrated with 0.2 N NaOH. The amount of the diazomethane was 1.7 g (81% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Br[C:14]1[CH:19]=[N:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:21][O:20][C:17]1[N:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=2)=[N:15][CH:16]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COc1cnc(Br)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(Oc2cc(C)c(C(C)=O)c(C)c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 3.50 g, 21.3 mmol), 2-bromo-5-methoxypyrazine (6.04 g, 32.0 mmol), copper (271 mg, 4.26 mmol), and potassium carbonate (8.84 g, 64.0 mmol) in 35.5 mL of DMF was stirred at 100° C. overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (20% EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (15-1, 2.90 g) as yellow oils: 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1 H), 7.87 (s, 1 H), 6.72 (s, 2 H), 3.96 (s, 3 H), 2.47 (s, 3 H), 2.24 (s, 6 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=O)[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(Cl)Cl>C(#N)C>[CH2:12]([O:11][C:9]1[O:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCCCOc1cnc(C(=O)OCC)o1
Temperature: 60 °C

Procedure:
Butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) was dissolved in 8 L of acetonitrile in a 50 L Chemglass reactor with overhead stirrer and P2O5 (415 g, 2.92 mol) was added in large portions, watching for exotherm. The reaction was heated to 60° C. for 1 hour and LCMS showed the reaction done. After cooling, water (8 L) was added at 20° C. and the reaction was transferred to a 50 L flask. Methylene chloride (8 L) was added, the layers split and the aqueous layer was extracted with three 2 L volumes of methylene chloride. The combined organic layers were washed with two 4 L portions of saturated aqueous NaHCO3, then dried with MgSO4 and evaporated to give an oil that was purified on silica eluting with 0-30% EtOAc/heptane to give the product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([F:38])[CH:37]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:29][CH2:30][O:31][C:32]3[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([F:38])[CH:37]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCNCC1
Reactant: Fc1cc(OCCBr)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)c(F)c(F)c2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
A mixture of 0.62 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.505 g of 5-(2-bromoethoxy)-1,2,3-trifluorobenzene, 0.34 g of potassium iodide and 1.14 g of potassium carbonate in 80 cm3 of acetonitrile was stirred under an inert atmosphere for 18 hours at a temperature in the region of 70° C. After cooling to about 20° C., the suspension was filtered and the insoluble material was washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height 21 cm), eluting with ethyl acetate and collecting 40-cm3 fractions. Fractions 9 to 24 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylate was obtained in the form of a pale yellow viscous oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55](CC3C=CC(OC)=CC=3)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:87][C@H:88]([CH3:92])[C:89](O)=[O:90])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:87][C@@H:88]([C:89]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:90])[CH3:92]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (68.4 mg, 0.155 mmol) was added to a solution of 62B (30.0 mg, 0.052 mmol), DIEA (0.036 mL, 0.206 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (19.52 mg, 0.103 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. TFA (0.238 mL, 3.09 mmol) was added and the reaction solution was stirred at 70° C. for 1 h. The reaction mixture was then concentrated and diluted with MeOH. The crude product was purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 90% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-N-(2-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11.5 mg, 0.022 mmol, 41.9% yield) as a white solid. HPLC Rt=1.613 (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=533.17.