Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1C=CC=CC=1.O>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:25])=[CH:22][CH:21]=1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]-hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 6.3 g. portion of p-fluorobenzoyl chloride in 40 ml. of benzene is added and the mixture is stirred overnight. The solid in the aqueous layer is recovered by filtration, washed with water and slurried in ether giving the product as white crystals, mp 101°-103° C.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCCCCC.C([O:20][CH2:21][CH3:22])(=O)C.C1C[O:26][CH2:25][CH2:24]1>>[C:4]1([CH2:3][O:26][CH2:25][CH2:24][CH2:22][CH2:21][OH:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: OCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
To a solution of diol compound (4.51 g, 50 mmol) in dry THF (50 ml) was added 60% NaH (1.6 g, 43 mmol) at 0° C. After stirring for 2 hours, benzyl bromide (5.7 g, 33 mmol) was added dropwise and stirred for 15 hours. After the reaction was completed, ice-water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (936 mg, yield: 16%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C[OH:6].[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10]C(O)=O>N1C=CC=CC=1>[CH3:2][C:1]([O:3][CH2:10][CH2:9][C@H:8]([NH2:7])[C:14]([OH:16])=[O:15])=[O:6]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)Cl
Reactant: CO
Solvent: c1ccncc1
Product: CC(=O)OCC[C@H](N)C(=O)O
Reaction time: 48 h

Procedure:
A cold solution of 300 ml of acetyl chloride was slowly added to a flask containing 3 liters of methanol. To this mixture was added 442 g of L-glutamic acid. The flask was stoppered and shaken for several minutes to effect solution. The flask was then allowed to stand at room temperature with intermittent shaking for 24 hours. 300 ml of pyridine was added causing a precipitate to form. Upon standing for an additional 48 hours, the precipitate was collected on sintered glass and washed with two 600 ml portions of ethanol and a 250 ml portion of ether. The precipitate was dried in vacuo at room temperature for 3 hours and then in a vacuum desiccator over Drierite® for 5 hours. Pyridine vapors were still perceptible from the precipitate which was further triturated with ether and dried again yielding 201.5 g of the desired γ-methyl L-glutamate as white, shiny plates, m.p. 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH2:22].C(N(CC)CC)C.[C:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42])#[N:31].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH:22][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:30]#[N:31])=[C:33]([N+:41]([O-:43])=[O:42])[CH:34]=1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a suspension of 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)phenylamine (Example 3.3) (70 g, 165 mmol) in 1,2-dichloroethane (660 ml) was added triethylamine (50.09 g, 495 mmol), followed by 4-cyano-3-nitrobenzoic acid (made as in WO 2008/074427) (63.4 g, 330 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (84 g, 330 mmol). The reaction mixture was stirred at 90° C. for 6 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) (500 ml) and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine. The aqueous phase was extracted twice with 1,2-dichloroethane. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-4-cyano-3-nitrobenzamide (89 g, 90% yield). 1H NMR (400 MHz, CDCl3): 8.89 (s, 1H), 8.40 (d, 1H), 8.12 (d, 1H), 7.88 (m, 2H), 7.72 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Cl)[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12].C(OCC(P(OCC)(OCC)=O)OCC)(=O)C>>[C:1]([O:4][CH:5]([P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])[CH2:6][O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(Cl)COC(C)=O
Agent: CCOC(COC(C)=O)P(=O)(OCC)OCC
Product: CCOCC(OC(C)=O)P(=O)(OCC)OCC
Temperature: 150 °C

Procedure:
18.5 g (112 mmol) of chloro-ethoxy-ethyl acetate and 19.2 ml (112 mmol) of triethylphosphite are put in a flask and heated at 150° C. for 5 hours. The progress of the reaction is monitored with NMR. 34 g (100%) of (diethoxy-phosphoryl)-ethoxy-ethyl acetate is obtained directly in the form of a colorless liquid.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Br[CH2:31][C:32]#[N:33]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:31][C:32]#[N:33])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1

Procedure:
In analogy to the procedure described for the synthesis of Example 1, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and bromoacetonitrile. The title compound was obtained in 38% yield as light green foam. MS (m/e): 445.2 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)c(F)cc4Cl)nc3s2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (171 μL, 1.25 mmol) and 1-methylpiperazine (138 μL, 1.25 mmol) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (193 mg, 75%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][Mg]Cl>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])([CH3:17])[C:12]([F:13])([F:14])[F:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Product: CC(O)(c1c[nH]c2cc(Br)ccc12)C(F)(F)F

Procedure:
1-(6-Bromo-1H-indol-3-yl)-2,2,2-trifluoro-ethanone is treated with methylmagnesiumchloride at −78° C. to rt to obtain 2-(6-bromo-1H-indol-3-yl)-1,1,1-trifluoro-propan-2-ol, which is coupled with 8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine following general procedure 2.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C[O:23][C:24]([CH2:26][CH2:27][C:28](Cl)=[O:29])=[O:25].O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:28](=[O:29])[CH2:27][CH2:26][C:24]([OH:25])=[O:23])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CCC(=O)c1c(-c2ccccc2)cc2ccccn12
Yield: 53.6 %

Procedure:
To a suspension of 10.2 g of 2-phenylindolizine in 150 ml of benzene were added 6 ml of pyridine and 9.6 g of β-methoxycarbonylpropionyl chloride and the mixture was refluxed overnight. After cooling, 50 ml of water was added and the whole mixture was extracted with benzene. After the extract was decolorized and concentrated, to the residue was added 30 ml of isopropyl ether and the mixture was cooled to precipitate methyl 4-(2-phenyl-3-indolizinyl)-4-oxobutyrate. The precipitate was filtered off and then this ester compound was hydrolyzed in a conventional manner to give 8.3 g of 4-(2-phenyl-3-indolizinyl)-4-oxobutyric acid, melting at 131°-133° C.
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)#[N:2].O.[NH2:32][NH2:33].O>CO>[F:23][C:18]1[CH:17]=[C:16]([N:5]([CH2:6][CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:4]2[NH:3][C:1]([NH2:2])=[N:33][N:32]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: Nc1nnc(N(CCCOC2CCCCO2)c2ccc(F)c(F)c2)[nH]1
Temperature: 25 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)-N-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)carbamimidate (73 mg, 176 μmol) in methanol (0.5 mL) was added hydrazine hydrate 25% in water (35.2 mg, 34.8 μl, 176 μmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using methylene chloride/methanol 19:1 (v/v) as eluent. The title compound was obtained as a light yellow viscous oil (46 mg, 74%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[F:18][C:19]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:20]=1[C:21]([C:23]1[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=1)=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][CH:13]([O:14][CH3:15])[O:16][CH3:17])[C:28]([C:25]1[NH:26][CH:27]=[C:23]([C:21](=[O:22])[C:20]2[C:19]([F:18])=[CH:34][C:33]([F:35])=[CH:32][C:31]=2[F:36])[CH:24]=1)=[O:29]
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Reactant: COC(CNCc1nc2ccccc2[nH]1)OC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(CN(Cc1nc2ccccc2[nH]1)C(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a DMF 5 mL solution of product obtained in step A (693 mg, 2.95 mmol) were added 4-(2,4,6-trifluoro-benzoyl)-1H-pyrrole-2-carboxylic acid (793 mg, 2.95 mmol), EDC (678 mg, 3.53 mmol), HOBt (541 mg, 3.53 mmol) and triethylamine (0.821 mL, 5.89 mmol). The reaction mixture was stirred overnight at room temperature. Resulting suspension was filtered and diluted with EtOAc. The organic layer was washed with sat. ammonium chloride aq., sat. sodium bicarbonate aq. and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as oil (930 mg). LC/MS: m/z 487(M+H). 1H-NMR (500 MHz, CDCl3): δ 3.39 (s, 6H), 3.86 (br.s, 2H), 4.69 (d, 1H), 5.21 (s, 2H), 6.74 (t, 2H), 7.01 (br.s, 1H), 7.28 (s, 1H), 7.45 (dd, 2H), 7.65 (dd, 2H), 11.23 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13](Cl)[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:37][NH2:38]>C1COCC1.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13]([NH:38][CH3:37])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1nn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(trifluoromethyl)benzyl)-6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (50 mg, 0.091 mmol), prepared as described in Example 3, and 2.0 M methyl amine in THF (0.4 mL) was stirred at reflux for 12 h. After this time, the reaction mixture was cooled to RT and diluted with water (5 mL). The resultant solution was extracted with EtOAc (5 mL×3). The combined organic layers were washed with water (5 mL×2) followed by saturated aqueous NaCl (5 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative reverse phase HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl-7,8-bis(4-chlorophenyl)-6-(methylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (31.5 mg, 64%) as pale yellow solid. HPLC: 4.17 min; MS: M+H=544; 1H NMR (CDCl3), ppm: 7.55 (2H, d, J=10.0 Hz), 7.47 (2H, d, J=10.0 Hz), 7.34 (2H, d, J=10.0 Hz), 7.21 (2H, d, J=10.0 Hz), 7.09 (2H, d, J=10.0 Hz), 7.05 (2H, d, J=10.0 Hz), 5.18 (2H, s), 4.19-4-21 (1H, br), 2.95 (3H, d, J=5.0 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1)=[O:20].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:10]([N:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:19]([O:18][CH3:17])=[O:20])=[CH:30][CH:29]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCNCCc1ccccc1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
N-(2-Phenylethyl)heptan-1-amine (0.080 g, 0.366 mmol) was dissolved in DMF (5 ml), (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.146 g of methyl 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}phenoxy)methyl]-benzoate (yield 87.4%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([OH:29])=[O:28].[CH3:30][CH:31]([S-:33])[CH3:32].[Na+].I[CH3:36]>CS(C)=O.O>[CH3:26][C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)=[N:10][C:11]2[C:6]([C:7]=1[C:27]([O:29][CH3:36])=[O:28])=[CH:5][C:4]([S:33][CH:31]([CH3:32])[CH3:30])=[C:13]([O:14][CH3:15])[CH:12]=2
Reactant: CI
Reactant: CC(C)[S-]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(SC(C)C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Sodium hydride (1.265 g, 31.6 mmol) was added to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred for 20 min. Sodium 2-propanethiolate (2.53 g, 23.20 mmol) was added, and the resulting mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with NaH (1.27 g of 60% dispersion in mineral oil, 31.6 mmol) and sodium 2-propanethiolate (2.53 g, 23.20 mmol), and heated at 100° C. for an additional 4 hours. The reaction mixture was cooled to room temperature. Iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 58% yield). This material was used in the next step without further purification. MS (m/z) 450.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[CH2:21][N:15]2[CH:14]=[CH:13][CH:12]=[C:16]2[CH2:17]1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 75.4 %

Procedure:
The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)=[N:7][C:6]=1[CH3:23])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:23][C:6]1[N:7]=[C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(CCc2conc2-c2ccccn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a suspension of 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (647 mg, 2.0 mmol) in THF (6.5 mL) was added a solution of lithium hydroxide monohydrate (165 mg, 3.9 mmol) in water (6.5 mL) followed by methanol (4 mL) and the resulting mixture stirred at room temperature for 4 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (578 mg, 93%) which was obtained as a light brown solid. MS: m/e=314.1 [M−H]−.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.NN>C(O)C.[OH-].[Na+].O>[NH2:3][CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 82.5 %

Procedure:
To a solution of Example 32B (12.9 g) in ethanol (400 mL) was added hydrazine hydrate (11.2 mL). The solution was then heated to 70° C. for 2 hrs. After cooling to 25° C., the resulting solid was dissolved in 1N NaOH solution (200 mL) and water (200 mL). The solution was then extracted with dichloromethane (3×200 mL), the organic extracts combined, dried and evaporated to provide 6.8 g of the title compound.