Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][CH:10]2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1.CS(O)(=O)=O.C(OCC)(=O)C.C(O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][C:10]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 100 g of 3-(p-Chlorophenyl)-2,3,-dihydro-3-hydroxythiazolo[3,2-a]benzimidazol-2-acetic acid, hydrobromide and 200 ml of methanesulphonic acid was stirred overnight in a 500 ml round bottom flask. Thin layer chromatography on silica plates (solvent ethyl acetate/acetic acid) indicated rapid formation of an intermediate. After 20 hours at room temperature thin layer chromatography (silica plates, ethyl acetate/acetic acid) showed the presence of a single component. The mixture was poured into water and the resulting crystals removed by filtration. The crystalline product was suspended in 5 volumes of hot water for 1/2 hour, filtered and the procedure repeated. After a final aqueous wash the material was dried in vacuo to yield the title compound (75 g, 91%) m.p. 242°-3° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][CH2:15][C:16]3[N:20]4[N:21]=[C:22]([C:25]5[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=5)[CH:23]=[CH:24][C:19]4=[N:18][N:17]=3)=[CH:9][CH:10]=[N:11]2)=[N:6][CH:5]=1.Br.[OH-:35].[Na+]>>[F:33][C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]3[N:20]([C:16]([CH2:15][NH:14][C:8]4[CH:9]=[CH:10][N:11]=[C:12]5[C:7]=4[N:6]=[CH:5][C:4]([OH:3])=[CH:13]5)=[N:17][N:18]=3)[N:21]=2)[CH:30]=[C:29]([F:31])[C:28]=1[F:32].[CH:2]([O-:3])=[O:35]
Reactant: [OH-]
Reactant: COc1cnc2c(NCc3nnc4ccc(-c5cc(F)c(F)c(F)c5)nn34)ccnc2c1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: O=C[O-]
Product: Oc1cnc2c(NCc3nnc4ccc(-c5cc(F)c(F)c(F)c5)nn34)ccnc2c1
Temperature: 25 °C

Procedure:
A sealed tube was charged with 7-methoxy-N-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine hydrochloride (238 mg, 502 μmol) and HBr (5966 μl, 52740 μmol), sealed, then placed in a 120° C. oil bath for 48 h. Cooled to room temperature and brought to pH˜14 with NaOH (6N). Isolated solid by filtration which was purified by RPHPLC to afford 8-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol as its formate salt. MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C20H12F3N7O: 423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]2[N:20]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:19]2[N:24]=[CH:23][C:22]3=[CH:25][CH:26]=[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]3[N:20]=2)=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)cc1N1CCOCC1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)cc1N1CCOCC1
Yield: 38.7 %

Procedure:
4-Methoxy-3-morpholin-4-yl-phenylamine (80.0 mg, 0.384 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (70.0 mg, 0.192 mmol) and N,N-Diisopropylethylamine (0.100 mL, 0.576 mmol) were dissolved in 1-Methoxy-2-propanol (0.75 mL, 7.7 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced and the crude residue was isolated and purified by Gilson prep HPLC to afford 37.80 mg of N-{2-[2-(4-Methoxy-3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=509.0. 1H NMR (400 MHz, DMSO, d6) δ 9.18 (s, 1H), 8.94 (s, 1H), 7.73 (m, 1H), 7.65 (m, 1H), 7.52 (m, 2H), 7.41 (m, 1H), 7.05 (d, 1H, J=8.80 Hz), 6.91 (m, 1H), 6.83 (m, 2H), 3.72 (s, 3H), 3.61 (m, 4H), 3.06 (s, 3H), 2.79 (s, 3H), 2.60 (m, 4H).
Reaction SMILES: COC([C@@H]1CC2C=C3OC[C@@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1C(OC(C)(C)C)=O)=O.[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59]([OH:61])=O)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].[CH3:82][O:83][C:84](=[O:102])[C@@H:85]([NH2:101])[CH2:86][C:87]1[CH:92]=[CH:91][C:90]([C:93]2[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=2)=[CH:89][CH:88]=1>>[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59](=[O:61])[NH:101][C@H:85]([C:84]([O:83][CH3:82])=[O:102])[CH2:86][C:87]2[CH:88]=[CH:89][C:90]([C:93]3[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=3)=[CH:91][CH:92]=2)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:43])([CH3:44])[CH3:45]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 76.7 %

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (200 mg) was hydrolyzed according to General Procedure B. The resulting (3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (172 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (126 mg) according to General Procedure A to give (3R,8S)-8-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (191 mg). Boc-cyano-biphenyl ester (188 mg) was treated as described in General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt (155 mg). LCMS: (m/z) 749; 1H NMR (400 MHz, Methanol-d6): 8.54 (d, 1H), 7.95 (s, 1H), 7.87 (d, 1H), 7.81-7.72 (m, 2H), 7.63-51 (m, 4H), 7.50-7.47 (m, 2H), 7.38-7.32 (m, 3H), 7.01 (d, 2H), 6.99 (d, 2H), 5.07 (s, 2H) 5.04-5.03 (m, 1H), 4.34-4.31 (m, 1H), 4.12-4.08 (m, 1H), 4.01-3.96 (m, 3H), 3.75 (s, 3H), 3.74-3.63 (m, 4H), 3.11-2.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=[O:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.[CH3:33][Li]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:30]([OH:32])([CH3:33])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:29])[CH2:12][CH2:13]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(C)(C)O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.173 mmol 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone in tetrahydrofuran (2 ml) was added dropwise 0.190 mmol 1.6M Methyllithium solution in ether at −75° C. The mixture was stirred for 2 hours and then allowed to warm to 0° C. The mixture was quenched with a 20% NH4Cl solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica, eluting with dichloromethane/MeOH to yield after evaporation the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:17]2[C:18](=[O:21])[CH2:19][O:20][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC1CCCC1
Reactant: BrCc1ccc(Br)cc1
Product: COc1ccc(C2CN(Cc3ccc(Br)cc3)C(=O)CO2)cc1OC1CCCC1
Yield: 96.5 %

Procedure:
According to the same procedure as used in Example 12, using the 2-(3-cyclopentyloxy-4-methoxyphenyl)morpholin-5-one produced in Example 2 instead of 2-(3,4-dimethoxyphenyl)morpholin-5-one, and using 4-bromobenzyl bromide instead of methyl iodide, the above-described compound (yield 96.5%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:18]1([S:24]([CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:5][N:6]([CH2:30][CH2:29][CH2:28][CH2:27][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:26])[CH2:7][CH2:8]1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCNCC1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Yield: 100.1 %

Procedure:
4-Methoxy-4-tert-butoxycarbonylaminomethylpiperidine (1.43 g), 4-phenylsulfonylbutyl bromide (1.7 g) and potassium carbonate (1.6 g) were reacted and treated in the same manner as in Preparation Example 138(1) to give 2.58 g of 4-methoxy-1-(4-phenylsulfonylbutyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1F
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3F)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 2-fluorophenylisocyanate to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].O>O1CCCC1>[F:28][C:17]([F:29])([C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:23])[F:22])[CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Anhydrous tetrahydrofuran (200 ml) was added to 60% sodium hydride (2.78 g, 69.52 mmol) and the resulting mixture was cooled to 0° C. Diethyl malonate (12.18 ml, 80.22 mmol) was slowly added dropwise to this mixture, which was then stirred for 1 hour at room temperature. A solution of 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane (20.0 g, 53.48 mmol) in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (19.4 g, Yield 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:9]1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 686 mg of Azetidin-3-yl-carbamic acid tert-butyl ester in 10 ml of DCM, 403 mg of triethylamine was added and the mixture was cooled to 0° C. Then, 598 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 2 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 910 mg.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([O:17]CC)=[O:16].Cl.N(OCCC(C)C)=O>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1nnn(-c2cccc(Cl)c2F)c1Cl
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1nnn(-c2cccc(Cl)c2F)c1Cl
Reaction time: 48 h

Procedure:
Ethyl 5-chloro-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate: (Can. J. Chem., 37:118-119 (1959)). To a solution of Intermediate 27A (1.1 g, 3.86 mmol) in EtOH (30 mL) at 0° C. was passed HCl gas until all of the solid dissolved. To the solution was added isoamyl nitrite (0.520 mL, 3.86 mmol) in one portion and the resulting solution was kept at 0-5° C. for 48 h. The reaction mixture was diluted in EtOAc and washed with aq NaHCO3 and brine. The organic layer was concentrated and purified by reverse phase HPLC to yield the desired product. MS(ESI) m/z: 304.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]2[NH:6][CH2:7][CH2:8][CH:2]12.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:5][CH2:4][CH:3]3[NH:6][CH2:7][CH2:8][CH:2]23)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CC2NCCC2N1
Product: O=[N+]([O-])c1ccc(N2CCC3NCCC32)cc1

Procedure:
Octahydropyrrolo[3,2-b]pyrrole (0.50 g) was reacted by method C with 4-fluoronitrobenzene (0.53 g). The product with the molecular weight of 233.27 (C12H15N3O2); MS (ESI): 234 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CC([O-])=O.[Na+].[Br:21]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:21][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([CH3:9])[CH:7]=1
Reactant: COc1ccc(C)cc1CCCC(=O)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(Br)cc(C)cc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.5 %

Procedure:
A solution of 4-(2-methoxy-5-methylphenyl)-butyric acid (74 g, 0.36 mole), NaOAc (29.8 g, anhydrous), and glacial acetic acid (710 mL) was stirred under N2 at room temperature. as a solution of bromine (22 mL, 0.43 mole) and glacial acetic acid (185 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 hours. 10% aqueous sodium bisulfite (400 mL) was added and the solution was extracted with CH2Cl2. The combined extracts were washed with water, 10% aqueous sodium thiosulfate, water, saturated aqueous. NaCl, dried (MgSO4), filtered, and evaporated to yield 108 g brown solid which was recrystallized from hexane to yield 76 g white solid, (74%); m+ 286.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:10]3=[C:9]([C:23]([O:25]C)=[O:24])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].C(O)C>C1COCC1>[C:19]([O:18][C:16]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]([C:23]([OH:25])=[O:24])=[C:10]2[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 7-tert-butyl 1-methyl 3-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (3A) (1.6 g, 4.47 mmol) in THF (50 mL) was added aqueous LiOH (0.7 g in 18.5 mL water) and ethanol (13 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified to pH 4 with 1N aqueous HCl solution. The aqueous suspension was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give Intermediate 3B as a white solid in quantitative yield. The material was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.81 (m, 2H), 4:14 (m, 2H), 5.02 (s, 2H), 7.46-7.51 (m, 3H), 7.62-7.68 (m, 2H). LCMS (+ESI) m/z 344.23 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([C:35]([O:37]C)=[O:36])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[OH-].[Na+].Cl.O>CO>[C:35]([C:12]1[CH:11]=[C:10]([N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][C:7]([OH:9])=[O:8])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)([OH:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 80 %

Procedure:
A solution of 1.0 g (1.87 mmol) of N-(carboxymethyl)-N-[3(methoxycarbonyl)-5-(octadecyloxy)phenyl]glycine and 3.1 ml (9.35 mmol) of 3N NaOH in 100 ml of methanol was stirred at reflux under argon for 48 hours. The warm solution was acidified with 3N HCl to pH 2 and the methanol was removed at reduced pressure. Water was added and the product was filtered and recrystallized from methanol-water to give 0.78 g (80% yield, mp 149°-155°) of N-[3-carboxy-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine as a hydrate with 0.75 mole of water.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4]I.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]2=[CH:18][CH:19]=1.C(=O)([O-])[O-:21].[K+].[K+].Cl>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]([NH:15][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[O:17])[C:12](=[CH:18][CH:19]=1)[C:13]([OH:21])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: FC(F)(F)CCI
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)cc1C(=O)NCCC(F)(F)F
Temperature: 20 °C
Yield: 105.2 %

Procedure:
3.6 g of 1,1,1-trifluoro-3-iodopropane are added dropwise to a mixture of 7.5 g of 4-chlorophthalimide and 4.6 g of potassium carbonate in 40 cm3 of dimethylformamide at a temperature in the region of 110° C. with stirring. After stirring for 11 hours at a temperature in the region of 120° C., the reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 200 cm3 of water. The mixture is acidified with dilute aqueous hydrochloric acid solution to a pH of about 3, and is then extracted 3 times with 100 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated to dryness. 5.0 g of 4-chloro-N-(3,3,3-trifluoropropyl)phthalamic acid are thus obtained, Rf=0.12 (thin layer chromatography on silica gel, eluent: ethyl acetate).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[C:10]1([CH:8]2[NH:9][C:3](=[NH:17])[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(c2ccccc2)CCCC1
Solvent: CO
Product: Cl
Product: N=C1CCCCC(c2ccccc2)N1
Yield: 90.5 %

Procedure:
The product of EXAMPLE 191 (1.4 g, 6.9 mmol) in 75 mL of MeOH was reacted with ammonium chloride (0.31 g, 5.9 mmol) by the method of EXAMPLE 27 to yield 1.2 g (77%) of the title material.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29](=[O:31])[CH3:30])[C:23]4=[N:22][C:21]=3[CH3:32])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5]>C1COCC1>[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])([CH3:1])[CH3:30])[C:23]4=[N:22][C:21]=3[CH3:32])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: C[Mg+]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)=O)cccn34)c(C)nc12
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)(C)O)cccn34)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of CeCl3 (0.37 g, 2.22 mmol) in THF (10 mL) is stirred at RT for 2 h. It is then cooled to 0° C., and treated with 3.0 M CH3MgBr (0.74 mL, 2.22 mmol). The mixture is stirred at 0° C. for 2 h. A solution of 1-{3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridin-8-yl}-ethanone (0.57 g, 1.48 mmol) in THF (5 mL) is added to the mixture at 0° C. The reaction is stirred at 0° C. for 30 min and at RT for 2 h. It is finally quenched with sat. NH4Cl (10 mL), diluted with H2O (50 mL); extracted with EtOAc (3×100 mL). The combined organic layers is dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.36 g, 0.90 mmol, 61%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.80 (s, 6H), 1.80-1.95 (m, 4H), 2.41 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H), 3.31-3.41 (m, 1H), 6.67-6.74 (m, 1H), 6.73 (s, 1H), 6.92 (bs, 1H), 7.09 (bs, 1H), 7.41 (d, J=5.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C24H31N5O (M+H)+: 406.6. found: 406.3.