Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([N:58]3[CH2:59][CH2:60][CH:61]([NH:64][C:65]4[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=4)[CH2:62][CH2:63]3)=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: N#Cc1ccc(NC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (26 mg; 0.08 mmol, prepared in accordance with Example 3), diisopropylethyl amine (26 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (28 mg; 0.08 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(piperidin-4-ylamino)-benzonitrile hydrochloride (18 mg; 0.08 mmol, prepared in accordance with Example 82) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 4 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (21 mg; 0.04 mmol). The structure was confirmed using Protocol I-B. Calculated mass=500; observed mass=500; HPLC retention time=4.90 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][C:17]=3[CH3:28])[O:13][N:12]=2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][C:17]=3[CH3:28])[O:13][N:12]=2)=[CH:7][C:6]=1[C:29]([F:30])([F:31])[F:32])([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(-c2nc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)no2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CCC(=O)O)ccc1-c1nc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 33 mg (0.07 mmol) of methyl 3-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-methylphenyl)propanoate (from Step D) in 2.0 mL of EtOH was added 200 μL (1.0 mmol) of 5.0 N NaOH. The mixture was stirred at rt overnight. Purification by HPLC B gave 22 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.40 (d, J=6.0, 6H), 2.66 (t, J=7.7, 2H), 2.74 (s, 3H), 2.99 (t, J=7.6, 2H), 4.87 (m, 1H), 7.28-7.37 (m, 3H), 8.06 (d, J=8.0, 1H), 8.30-8.31 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:23](OC)(OC)OC>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[CH:23]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 200 mg of N-(1-benzyl-piperidin-4-yl)-benzene-1,2-diamine (from Step A) in 6 mL of trimethyl orthoformate was added 0.2 mL concentrated HCl. After stirring at 80° C. for 16 hours, the reaction mixture was diluted with 30 ml of EtOAc. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 198 mg yellow solid. 1H NMR (400 MHz, CDCl3): δ2.11-2.22 (m, 6H), 3.06 (m, 2H), 3.58(s, 2H), 4.20 (s, 1H), 7.24-7.34(m, 7H),7.42(m, 1H), 7.81 (m, 1H), 8.04(s, 1H). ESI-MS 292 (M+H); HPLC A: 1.80 min.
Reaction SMILES: [ClH:1].[N:2]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]=1[NH2:16])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]([NH2:16])=[C:4]([NH2:2])[CH:8]=[N:7]2)=[CH:11][CH:12]=1
Reactant: Nc1c(N=O)cnn1Cc1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cnn(Cc2ccncc2)c1N

Procedure:
In an autoclave, 38.1 g (158 mmol) of the crude product from Step 2.2 was suspended in 800 mL of ethanol and hydrogenated at 9 bar of hydrogen pressure for 2 hours using 3.8 g of Pd/C (10%). The catalyst was then filtered off through diatomaceous earth, to the filtrate was added 200 mL of 3M ethanolic hydrochloric acid, and the solution was concentrated to incipient crystallization in a rotary evaporator at 40° C. To complete the crystallization, the mixture was cooled in an ice bath, after which the solid was filtered off. The product was then washed with a small amount of ethyl acetate and dried at 40° C. under vacuum. This gave 19.5 g (41% of the theoretical) of a slightly pink-colored powder.
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[N:11][C:10]=1[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>C1(C)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]=[N:11][C:10]3[C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25](=[O:27])[O:26][C:9]=3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2cc(O)c(-c3ccccc3C(=O)O)nn2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2cc3oc(=O)c4ccccc4c3nn2)cc1
Yield: 92 %

Procedure:
Acetic acid anhydride (100 ml), 2-[4-hydroxy-6-(4-methoxyphenyl)-3-pyridaziny]benzoic acid (11 g, 0.0342 mol) and toluene (100 ml) are reacted in a 250 ml flask; oil bath about 130° C. When the reaction is completed, the mixture toluene/acetic acid is distilled off at 96-108° C. (about 100 ml/1.5 hours). The acetic acid anhydride is eliminated under vacuum, the residue is taken up with methylene chloride (250 ml), washed with 5% aqueous sodium bicarbonate and then with water up to neutrality. THe organic layer is oven dried, and concentrated to dryness to give 3-(4-methoxyphenyl)-6H-[2]-benzopyrano[4,3-c]pyridazin-6-one 230°-231° C. (9,8 g; Yield 92%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CSc1ccc(C#N)cc1
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(NC(=N)c2ccc(SC)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1 g, 6.7 mmol) and 4-n-butylaniline (1 g, 6.7 mmol) by following the procedure described in preparation 10 (1.27 g, yield 63.66%). 1H-NMR (CDCl3):δ 0.91-0.95 (t, 3H), 1.33-1.39 (m, 2H), 1.56-1.63 (m, 2H), 2.52 (s, 3H), 2.56-2.6 (m, 2H), 4.8 (bs, 2H, D2O exchangeable), 6.88-6.9 (d, 2H), 7.15-7.17 (d, 2H), 7.27-7.29 (m, 2H), 7.79-7.81 (d, 2H). MS m/z:299.3 (M+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)(=O)=O>CN(C)C=O.O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 105 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Sodium azide (350 mg, 5.38 mmol) was added to a solution of methanesulfonic acid, 2-(2-benzotriazol-1-ylmethyl-benzimidazol-1-yl)-ethyl ester (200 mg, 0.54 mmol) in 5 mL of anhydrous N,N-dimethylformamide. The reaction temperature was raised to 105° C. and stirred for 4 hours. The mixture was cooled, diluted with water and extracted with diethyl ether (3×100 mL). The combined ether extracts were dried over magnesium sulfate, filtered, and evaporated under vacuum. This gave the title compound as a white solid (160 mg, 94% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:14][C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: C=CC[C@@H](O)COCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-Benzyloxy-4-penten-2-ol (3.13 g) was dissolved in DMF (32 ml), and sodium hydride (60%, 0.91 g) was added in an ice bath. After stirring at the same temperature for 30 minutes, bromoacetaldehyde diethyl acetal (3.03 ml) was added. The mixture was heated to room temperature and stirred for two hours, and then heated to 50° C. and stirred for one hour. After cooling to room temperature, ice was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. The mixture containing the recovered raw material was reacted under the same conditions. The title compound was obtained by purification by the same method (total yield: 5.00 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[H][H]>O.C(O)C.[Pd](Cl)Cl>[CH3:2][C:3]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: [H][H]
Reactant: Cc1c(C(=O)c2ccc(F)cc2)cccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(N)cccc1C(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
38 ml of hydrochloric acid, 23 g of activated carbon and 12 ml of a solution of 20% palladium chloride in water were added to a solution of 114.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in 1 liter of ethanol and then a current of hydrogen was passed therethrough for 3 hours. The reaction mixture was filtered and the filter was rinsed with ethanol. The filtrate was concentrated until crystallization began and was iced and then vacuum filtered. The precipitate was empasted with ethanol and dried under reduced pressure to obtain 59.5 g of 2-methyl-3-amino-4'-fluorobenzophenone in the form of white crystals melting at 170° C. Evaporation of the mother liquor and treatment with isopropyl ether gave another 50.5 g of product for a total of 110 g. For analysis, a sample of the product was crystallized from an aqueous solution of 5% hydrochloric acid and melted at 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 1-[4-(4-chloro-phenyl)-piperidin-4-yl]-ethanone in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.5:0.5) afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
Dissolve N-tert-butoxycarbonyl-L-tyrosine (2.42 Kg, 8.3 moles) in dry DMF (7.26 L) under argon and still till complete dissolution. Add K2CO3 (3.57 Kg, 25.81 moles), 4-fluorobenzaldeyde (5.34 Kg, 43.01 moles) and stir at 70±5° C. for 48 h under argon. Cool the reaction mixture less than 30° C. Poured the reaction mixture in water (75 L) and stir for 15 min. Add ethyl acetate (40 L) and stir for 30 min. Separate the organic layer and aqueous layer was acidified with HCl (6M) to pH 2. Solid precipitated was dissolved in ethyl acetate (40 L) and aqueous layer was separated. Organic layer was washed with brine (40 L), dried on sodium sulfate and evaporate solvent under reduced pressure. Observed HPLC purity (93.4%) and chiral purity by HPLC (100%). Dry with anhydrous MgSO4 and evaporate under reduced pressure. Pale yellow solid (3.06 Kg, 99.3%). 1H NMR (300 MHz, DMSO-d6): 9.89 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.00 (overlapped d, J=9.0 Hz, 4H), 4.63 (m, 1H), 3.2 (m, 1H), 3.06 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:29]=4[C:28]4[CH:44]=[CH:45][CH:46]=[CH:47][C:27]3=4)=[O:25])=[CH:20][C:19]=2[F:48])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:49]>CO.O1CCOCC1>[ClH:49].[ClH:49].[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:19]([F:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-fluoro-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E69.1 (110 mg, 0.17 mmol) was dissolved in methanol (5 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 20 h at room temperature then concentrated in vacuo to yield the title compound (105 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](Br)=[C:4]([Br:8])[C:3]=1[Br:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:5]1[S:6][C:2]([Br:1])=[C:3]([Br:9])[C:4]=1[Br:8])=[O:21])[CH3:20]
Reactant: Brc1sc(Br)c(Br)c1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)c1sc(Br)c(Br)c1Br
Temperature: -18 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To tetrabromothiophene (2.0 g, 5.0 mmol) in an oven dried 50 mL flask, evacuated and flushed with nitrogen, was added anhydrous diethyl ether (12 ml). The resulting solution was cooled to −18° C., then n-butyllithium (1.6 M in hexane) (3.1 ml, 5.0 mmol ) was added dropwise via a syringe. After stirring for 10 min at −18° C., diethyl oxalate (0.75 ml, 5.5 mmol) was added dropwise. Stirring was continued for 30 min, then the reaction mixture was quenched with 1N HCl. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. Purification was performed by column chromatography using hexane/ethyl acetate (20:1) to yield (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid ethyl ester as a yellow solid (1.5 g, 71%). MS (M+H)+: 422.55; 1H NMR (300 MHz, CDCl3) δ4.45 (2H, q, J=7.1 Hz), 1.44 (3H, t, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ173.89, 161.64, 133.35, 124.81, 123.05, 122.54, 63.75, 14.11.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[NH2:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(F)cc2)c(C(F)(F)F)cc1N
Temperature: 160 °C

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 3D) (200 mg, 0.669 mmol), 4-fluorophenylboronic acid (94 mg, 0.669 mmol) and 1,1′bis(diphenylphosphoshio)ferrocene palladium dichloride (Apollo) were suspended in THF (2 ml) and 1M Cs2CO3 (0.667 ml). The vial was flushed with N2, sealed and heated at 160° C. for 15 minutes using microwave radiation. The reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic portion was separated and washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica eluting with 0-80% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: Cl.Br[CH2:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:12][C:8]=2[CH:7]=1)=O.N1C=CC=CC=1.[NH:33]([C:35](=[S:39])[O:36]CC)[NH2:34].O>C(O)C>[CH2:21]([N:10]1[C:9]2[CH:25]=[CH:26][C:6]([C:4]3[CH2:3][S:39][C:35](=[O:36])[NH:33][N:34]=3)=[CH:7][C:8]=2[N:12]=[C:11]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: COc1cccc(-c2nc3cc(C(=O)CBr)ccc3n2CC(C)C)c1
Reactant: CCOC(=S)NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cccc(-c2nc3cc(C4=NNC(=O)SC4)ccc3n2CC(C)C)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 24 g (54.8 mM) of 2-bromo-1-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride in 500 ml of ethanol are added 6.3 ml (78.4 mM) of pyridine and then 8.2 g (78.4 mM) of O-ethyl hydrazinecarbothioate. The reaction medium is then maintained at 80° C. with stirring for 20 hours. Water is then added and the resulting mixture is extracted with ethyl acetate. The organic phase is washed with water and then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is purified on a column of silica, using a dichloromethane/methanol mixture (98/2). The residue obtained after evaporation is taken up in diethyl ether to give, after filtration, 10 g of 5-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of a light-beige solid.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].[CH3:29][O:30][C:31](=[O:37])[CH:32]([CH3:36])[C:33](O)=[O:34].CCN(CC)CC.[OH-].[Na+]>CCOC(C)=O>[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:33](=[O:34])[CH:32]([CH3:36])[C:31]([O:30][CH3:29])=[O:37]
Reactant: NCCc1ccccc1I
Reactant: COC(=O)C(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)C(=O)NCCc1ccccc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.5 %

Procedure:
A solution of T3P in AcOEt (50%, 26.2 mL, 44.0 mmol) was added dropwise at 0° C. under N2 to a clear solution of 2-(2-iodophenyl)ethanamine (9.45 g, 38.2 mmol), 3-methoxy-2-methyl-3-oxopropanoic acid (5.05 g, 38.2 mmol) and Et3N (10.7 mL, 76.0 mmol) in AcOEt (350 mL). The mixture was stirred at RT for 6 days. A 2N aqueous solution of NaOH (50 mL) was then added to the reaction and the mixture was extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The yellow oil obtained was purified by flash chromatography (SiO2, cHEx/AcOEt 100:0 to 50:50) to afford the title compound (10.83 g) as a clear oil. UPLC-MS: MS 362.2 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:6]([O:5][P:4]([C:9]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:10])[CH3:11])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(C)(C)c1ccc(N)cc1
Yield: 99.7 %

Procedure:
The diethyl[2-(4-nitrophenyl)propan-2-yl]phosphonate (103 mg) prepared as described above, was hydrogenated in the presence of 10% Pd/C (50 mg) in MeOH (5 mL) for 4 h. The mixture was filtered and the filtrate concentrated in vacuo to afford 92.5 mg of the desired diethyl[2-(4-aminophenyl)propan-2-yl]phosphonate (yield: 99%), which was used in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.20 (t, J=7.2 Hz, 6H), 1.54 (s, 3H), 1.59 (s, 3H), 3.65 (s, br, 2H), 3.80-3.94 (m, 2H), 6.66 (d, J=8.8 Hz, 2H), 7.32 (dd, J=2.4, 8.8 Hz, 2H). MS (ES+): m/z 272.02 (MH+). HPLC: tR=2.45 min (ZQ3, polar—5 min).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12][CH2:13][CH3:14])[N:8]=[C:7]([C:15]([O:17]C)=[O:16])[C:6]=1[Cl:19].O.Cl>C(O)C>[NH2:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12][CH2:13][CH3:14])[N:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]=1[Cl:19]
Reactant: CCOc1nc(C(=O)OC)c(Cl)c(N)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(C(=O)O)c(Cl)c(N)c1Cl
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Lithium hydroxide monohydrate (0.027 g) was added to a room temperature solution of the compound prepared in Example 2 (0.172 g) in ethanol (0.5 mL)-water (0.3 mL). The mixture was stirred for two hours and then brought to pH 3 via the addition of 1 N hydrochloric acid. The precipitated solids were collected by filtration to obtain the title compound (0.110 g) having the following physical data.