Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[C:15]([NH:18][CH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]([F:33])=[CH:31][C:27](C(Cl)=O)=[C:26]([F:34])[CH:25]=2)[CH2:20]1)(=[O:17])[CH3:16].Cl>CCCCCC.O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1.O>[C:15]([NH:18][CH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]([F:33])=[CH:31][C:27]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[C:26]([F:34])[CH:25]=2)[CH2:20]1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(=O)NC1CCC(c2cc(F)c(C(=O)Cl)cc2F)C1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of 26.4 g (0.2 mol) of monoethyl malonate, 0.1 g of 2,2'-bipyridyl and 350 ml of dry tetrahydrofuran was cooled to -35° under a nitrogen atmosphere and treated dropwise with 80 ml (0.2 mol) of a 2.5 M solution of n-butyl lithium in hexane. After the addition was complete, the reaction mixture was allowed to warm to -5° where it was treated dropwise with 80 ml (0.2 mol) of 2.5 M n-butyl lithium in hexane, titrating the final addition to a pale pink color which persisted for 5 minutes. The mixture was cooled to -78° and treated with a solution of 30.2 g (0.1 mol) of 4-[3-(acetylamino) cyclopentyl]-2,5 difluorobenzoyl chloride in 150 ml of dry tetrahydrofuran. The suspension was stirred at -78° for 45 minutes, then allowed to warm to -35° and poured into a mixture of ice, water, and concentrated hydrochloric acid (17 ml-0.20 mol). The organic phase was separated, washed with water, 5% sodium bicarbonate, dilute hydrochloric acid and water. After drying over magnesium sulfate, the solvent was removed in vacuo to give 31.8 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[N:4][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccc(CBr)nc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(F)(F)F)cn1)OCC

Procedure:
To a solution of 2-(bromomethyl)-5-(trifluoromethyl)pyridine (3.0 g, 12.5 mmol) in toluene (100 ml) was added triethyl phosphite (6.2 g, 37.0 mmol). The reaction was refluxed for 17 hours and was then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-50% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1>>[CH2:30]([O:29][C:27]([CH:26]1[CH2:32][CH2:33][N:23]([CH2:22][CH2:21][C:17]2[N:16]=[C:15]3[CH2:14][O:13][C:12](=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][C:6]4=[O:11])[C:20]3=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)=[O:28])[CH3:31]
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(CCc2ccc3c(n2)COC3=C2C(=O)Nc3ccc(F)cc32)CC1
Yield: 26.1 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) and ethyl isonipecotate (300 mg, 1.96 mmol) are reacted to provide the title compound (20 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[C:4]([F:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-:25].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(Br)cc1F
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (2.0 g, 8.3 mmol) in tetrahydrofuran (20 mL) under nitrogen was added 1 N solution of DIBAL-H in tetrahydrofuran (19 mL, 19 mmol) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N hydrochloric acid aqueous solution (10 mL) at 0° C. After stirred at ambient temperature for 10 minutes, the solution was basified with saturated aqueous sodium bicarbonate solution to pH 8-9, and then extracted with ethyl acetate (3×50 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-2% ethyl acetate in hexane to afford the title compound as a colorless oil. MS ESI: [M+H]+ m/z 245; 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.32-7.21 (m, 1H), 7.18-7.03 (m, 2H), 1.41 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]#N)[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CC[O:32]CC>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]=[O:32])[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Cc1ccc(C2(C#N)C3CC4CC(C3)CC2C4)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1ccc(C2(C=O)C3CC4CC(C3)CC2C4)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A flame dried flask under argon was charged with 2-(4-methylphenyl)adamantane-2-carbonitrile (5.90 g, 23.5 mmol) and anhydrous ether (120 mL) and the solution was cooled to 0° C. Diisobutylaluminium hydride (47 mL, 46.9 mmol, 1-M in heptane) was added dropwise and the reaction left to warm to room temperature. After stirring for 1 h the reaction mixture was quenched with dilute HCl (20 mL) and then filtered through celite. The filtrate was partitioned between EtOAc (100 mL) and water (100 mL), separated, dried (MgSO4) and concentrated in vacuo to afford the title compound (5.11 g, 86%) as a white solid: mp 93-97° C.: NMR δH(400 MHz, CDCl3) 1.61-1.64 (2H, d, J 12.8 Hz), 1.71 (2H, br s), 1.78-1.97 (8H, m), 2.33 (3H, s), 2.86 (2H, br s), 7.18-7.20 (2H, d, J 8.4 Hz), 7.25-7.27 (2H, dd, J 2, 8.4 Hz) and 9.27 (1H, s); Retention time 7.99 min (λ=220 nm).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C1C(=O)N([Br:16])C(=O)C1>C1(C)C=CC=CC=1>[Br:16][C:5]1[S:1][C:2]([CH2:6][CH2:7][OH:8])=[CH:3][CH:4]=1
Reactant: OCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Product: OCCc1ccc(Br)s1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2-(2-thienyl)ethanol (Aldrich, 5.0 g, 39 mmol) was diluted in toluene (50 mL) and cooled to −20° C. using an ice/NaCl bath. NBS (6.95 g, 39 mmol, 1 eq) was added portionwise over 15 minutes and the mixture was stirred at rt overnight. After quenching with 10% aq potassium hydroxide (20 mL), the layers were separated and the aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by Isco Combiflash, eluting with 0-80% ethyl acetate in hexanes (120 g column), afforded the desired as a slightly yellow oil (6.72 g, 83%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13]C(=O)OC(C)(C)C)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[ClH:1].[NH2:13][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)[CH:10]([OH:12])[CH3:11]
Reactant: CC(O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(O)[C@H](N)Cc1ccncc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
a solution of 20 cm3 of 4N hydrochloric acid in dioxane is added with stirring, at a temperature in the region of 20° C., to a solution of 1.85 g of tert-butyl N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxypropyl]carbamate. The mixture is stirred at a temperature in the region of 20° C. for 5 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.8 g of (3R,2RS)-3-amino-4-(4-pyridyl)-2-butanol dihydrochloride are obtained in the form of a yellow solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm). We observe a mixture of two diastereoisomers A and B in respective proportions of 70/30; δ=1.18 and 1.20 (2 d, J=6.5 Hz: 3H in total); 3.13 (dd, J=10.5 and 6 Hz: 0.7H); from 3.20 to 3.35 (mt: 1.3H); from 3.45 to 3.65 (mt: 0.6H); 3.72 (mt: 0.7H); 3.96 (mt: 0.7H); from 8.05 to 8.15 (mt: 2H); 8.88 (broad d, J=6 Hz: 2H)].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:36](OCC)=[O:37])=[C:14]([CH2:33][CH2:34][CH3:35])[N:15]2[C:20]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:16]2)=O)C.CCOCC>C1COCC1>[OH:9][CH2:10][C:12]1[C:13]([CH2:36][OH:37])=[C:14]([CH2:33][CH2:34][CH3:35])[N:15]2[C:20]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:18][C:17]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:16]2
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1c(CO)c(CO)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (118 mg, 3.11 mmol) in THF (10 mL) was added 2-morpholino-4-yl-4-phenyl-7-propyl-pyrrolo [1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (15) (242 mg, 0.52 mmol). The reaction mixture was heated at reflux for 1 h. After cooling to 0° C., Et2O (10 mL) was added and an excess reagent in the reaction mixture was quenched by brine. The resulting precipitate was removed by filtration. The filtrate was dried over Na2SO4 and concentrated in vacuo to provide the title compound. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H), 1.63-1.71 (m, 2H), 2.91 (t, J=7.2 Hz, 2H), 3.40 (br t, J=5.0 Hz, 4H), 3.72 (br t, J=5.0 Hz, 4H), 4.05 (d, J=5.0 Hz, 2H), 4.22 (t, J=5.0 Hz, 1H), 4.55 (d, J=5.1 Hz, 2H), 4.61 (t, J=5.1 Hz, 1H), 6.34 (s, 1H), 7.46-7.48 (m, 3H), 7.53-7.56 (m, 2H). Mass Spectrum (ESI+) m/e=364 (M−OH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH:31]=[C:30]([CH:32]=O)[C:29]([CH3:34])=[N:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:30]3[C:29]([CH3:34])=[N:28][N:27]([CH3:26])[CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: Cc1nn(C)cc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1-c1nc2c(N3CCN(Cc4ccc(Cl)cc4)CC3)c(Cl)cnc2[nH]1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.076 g, 0.20 mmol) and EtOH (4.0 mL) was added 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (0.027 g, 0.22 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.85 mL, 0.85 mmol). The reaction mixture was stirred at 80° C. for 24 h, it was then allowed to cool to room temperature, concentrated in vacuo, and the residue was absorbed on silica gel and placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v/v; 1:1), and then 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1) afforded the title compound as a white solid after trituration with diethyl ether (0.023 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][C:11](=O)[C@@H:10]3[C:4]=2[CH:3]=1.Cl.[OH-].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[C:4]=2[CH:3]=1
Reactant: O=C1NC[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)[C@H]1CNC[C@@H]1c1ccccc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.55 g (5.4 mmol) of trans-11-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (compound trans-XVIIa) was dissolved in 32.5 mL of anhydrous tetrahydrofuran. 2.1 mL of N,N-diethylaniline-borane complex (11.5 mmol) were added dropwise and the obtained solution was stirred at room temperature for 30 min before heating to reflux. The reaction mixture was stirred for 8 h then it was allowed to cool to room temperature overnight. The mixture was reheated to reflux and stirred for 5 h before allowing to cool down to room temperature. 3 mL of a 6 M hydrochloric acid were added and the mixture refluxed for 1 h and overnight at room temperature. The mixture was then basified with 95 mL of 0.25 M potassium hydroxide and extracted with diethyl ether (50 mL), three times. The organic layers were combined and dried with anhydrous sodium sulfate, filtered and rotary evaporated.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30](Cl)=[O:31])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:20])[F:21])[CH:5]=3)(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[O:31])[CH:23]=1
Reactant: O=C(Cl)C=Cc1cccnc1
Reactant: Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C=Cc1cccnc1)Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 50 °C
Yield: 49.6 %

Procedure:
To a solution of 4-((3-(trifluoromethoxy)phenyl)sulfonyl)aniline (86, 0.27 mmol) in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (58 mg, 0.28 mmol) and K2CO3 (138 mg, 1 mmol). The mixture is heated at 50° C. for 2 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. Purification of the residue by preparative TLC with 100:5:0.5 CH2Cl2/MeOH/NH4OH gives the titled compounds as a white solid (60 mg, 50%). (LC_MS: M+1 449.14; 1HNMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.82 (d, 1H), 8.57 (dd, 1H), 7.89-8.06 (m, 7H), 7.76 (t, 1H), 7.74 (m, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 6.91 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[C:19](OC)=[O:20])=[O:12].C[Al](C)C.C1(C)C=CC=CC=1>C(Cl)CCl>[O:20]=[C:19]1[NH:8][CH2:9][C@H:10]([NH:23][C:24](=[O:25])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11](=[O:12])[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]12
Reactant: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 72 h
Yield: 16.7 %

Procedure:
To a solution of (R)-methyl 1-((S)-3-amino-2-(benzyloxycarbonylamino)propanoyl)piperidine-2-carboxylate trifluoroacetate (601 mg, 1.26 mmol) in ClCH2CH2Cl (10 mL) at rt was added trimethylaluminum in toluene (1.89 mL, 3.78 mmol). The reaction was stirred in a sealed bottle at 75° C. for 3 days. After cooling to rt, the reaction was quenched with water and then aqueous 1 N HCl solution until the solution became clear. The aqueous solution was extracted with DCM (2×30 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex to give benzyl (4S,10aR)-1,5-dioxodecahydropyrido[1,2-a][1,4]diazepin-4-ylcarbamate (71 mg, 0.21 mmol, 17% yield) as a white solid. Anal. Calcd. for C17H21N3O4 m/z 331.4. found: 332.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.65-7.02 (m, 5H), 6.20 (d, J=5.5 Hz, 1H), 5.59 (s, 1H), 5.35-4.96 (m, 2H), 4.58 (s, 1H), 4.15 (d, J=13.3 Hz, 1H), 3.99-3.70 (m, 1H), 3.26-2.82 (m, 2H), 2.46-2.14 (m, 1H), 1.93-1.37 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C(NC(C)C)(C)C.[Li].CN(C)[CH:20]=[O:21].C(O)(=O)C>O1CCCC1.O>[F:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH3:8])[C:4]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1ccc(F)c(F)c1
Agent: [Li]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)c(F)c1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of 1,2-difluoro-4-methyl-benzene (5.0 g, 39 mmol) in tetrahydrofuran (200 mL) at −78° C. was added lithium diisopropyl amine (24 mL, 1.8 M in THF, 43 mmol) dropwise during a period of 15 mins. The mixture was stirred at −78° C. for another 20 min. Then N,N-dimethyl-formamide (3.6 mL, 47 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (9.4 g, 1.56 mmol) and followed by the addition of water (37.6 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give 2,3-difluoro-6-methyl-benzaldehyde as colorless oil (Yield: 3.5 g, 57.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:51]>O1CCCC1.CO>[ClH:51].[ClH:51].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
185 mg 4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}-1-benzene sulfonamide obtained in Example 11 was dissolved in 3.5 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.5 mL of 5 N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with 4 mL diethyl ether, and the aqueous layer was evaporated into dryness under reduced pressure (azeotropic evaporation with ethanol). The residue was recrystallized from ethanol and diethyl ether to give 123 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:39][C:40]2[NH:44][N:43]=[N:42][N:41]=2)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3nnn[nH]3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(4-tert-butyl-benzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-benzoic acid with 5-aminotetrazole there was obtained 3-(4-tert-butybenzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-N-(1H-tetrazol-5-yl)-benzamide as a white solid.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[O:43]1[C:47]2([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1>C(#N)C>[O:43]1[C:47]2([CH2:52][CH2:51][N:50]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC2(CC1)OCCO2
Yield: 83.5 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (254 mg, 0.67 mmol, 1.0 eq), N-methylmorpholine (96 uL, 0.88 mmol, 1.30 eq) in acetonitrile (7 mL) was treated with isobutyl chloroformate (96 uL, 0.74 mmol, 1.1 eq) followed by 1,4-dioxa-8-aza-spiro[4.5] decane (0.193 g, 1.35 mmol, 2.0 eq). Purification by flash chromatography provided 280 mg (83%) of L-isoleucine, N-[1-(2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxoethyl)-L-Prolyl] benzylamide as a colorless oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[CH3:13][O-:14].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,2,4-Trifluoro-5-nitrobenzene (10 g, 56.5 mmol) was dissolved in methanol, cooled in ice and treated with 25% sodium methoxide in methanol. After being stirred at room temperature for 6 hours the mixture was diluted with water and extracted with ethyl acetate to give 1,4-difluoro-2-methoxy-5-nitrobenzene (10.1 g). This was dissolved in ethanol (400 ml) and hydrogenated over 10% palladium on carbon to give the title compound (7.8 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[F:11][C:12]([F:17])([F:16])[C:13](O)=O>>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:13]([C:12]([F:17])([F:16])[F:11])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CNc1ncc(I)cc1N
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)nc2cc(I)cnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of 5-iodo-N2-methylpyridine-2,3-diamine and 6 ml of trifluoroacetic acid was stirred at room temperature for 1 hour, and then stirred under heat-reflux for 9 hours. The cooled reaction mixture was concentrated under reduced pressure, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.57 g of 6-iodo-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:6][CH2:5]1)=[O:3].[CH3:17][O:18]C1C=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:17])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)Cl)CC1
Yield: 57 %

Procedure:
Compound 39A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(o-methoxyphenyl)piperazine (441 mg, 2.3 mmol); triphosgene (210 mg, 0.7 mmol); triethylamine (315 ml, 2.3 mmol); tetrahydrofuran (30 ml).