Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=C[C:8]=1C#CC1SC(C=O)=CC=1.[CH3:22][C:23]([N+:30]#[C-:31])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:24].Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:22][C:23]([NH:30][C:31]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][CH:8]=1)([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:24]
Reactant: O=Cc1ccc(C#Cc2ccccn2)s1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Nc1cnc2sccn12
Reaction time: 120 h

Procedure:
A solution of 5.0 g (50.0 mmol) 2-amino-thiazole, 10.7 g (50.0 mmol) 5-(pyridine-2-yl-ethynyl)-thiophene-2-carbaldehyde, 7.0 g (50.0 mmol) (2,4,4-trimethylpentane-2-yl)-isocyanide and 1.0 ml of a 70% aq. perchloric acid in chloroform (25 ml) was heated to 50° C. while being stirred for 5 d. Dilution with DCM was subsequently performed and a 1 molar aq. Na2CO3 sol. was added. After 10 min of stirring at RT, the phases were separated. The aqueous phase was extracted with DCM. The collected organic phases were dried over Na2SO4, filtered and concentrated in a vacuum. 11.86 g (27.3 mmol, 55%) 6-(5-pyridine-2-ylethynyl)thiophene-2-yl)-N-(2,4,4-trimethylpentane-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained by multiple crystallisation of the residue from AE.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][C@H:7]([NH:11][C:12]([CH2:14][CH2:15][NH2:16])=[O:13])[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[Br:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CN(C)C=O.C(OCC)(=O)C>[Br:24][CH2:25][CH2:26][CH2:27][C:28]([NH:16][CH2:15][CH2:14][C:12]([NH:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:2]1[N:3]=[CH:4][NH:5][CH:1]=1)=[O:13])=[O:29]
Reactant: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Reactant: O=C(Cl)CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCCBr)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of carnosine (5 g, 22.1 mmoles) in N,N-dimethylformamide (80 ml), triethylamine (4.62 ml, 33.1 mmoles) and 4-bromobutyrylchloride (chloride of 4-bromobutyric acid-83.85 ml, 33.1 mmoles) are added. The solution is left under stirring for 24 hours at room temperature, then it is diluted with ethyl acetate and the organic phase is washed with water. The organic phase is then anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel eluting with ethyl acetate, obtaining the final product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=O)[N:24]([CH3:26])[CH3:25])[N:20]=[C:15]2[CH:14]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:23]([N:24]([CH3:26])[CH3:25])=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)N(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(N(C)C)n43)n1COCC[Si](C)(C)C)cn2C
Temperature: 85 °C
Yield: 427.6 %

Procedure:
A flask was charged with 3-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-1,1-dimethylurea (0.114 g, 0.224 mmol, Preparation #X.1) and DCE (5 mL). A solution of POCl3 (0.063 mL, 0.672 mmol) in DCE (2 mL) was added and mixture was heated to about 85° C. for about 3 h. The mixture was concentrated under reduced pressure and then diluted with EtOAc (15 mL) and washed with saturated aqueous NaCl (10 mL). The organic layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified using silica gel chromatography with an elution gradient of 0 to 100% EtOAc/heptane to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-amine (0.47 g, 43%): LC/MS (Table 2, Method b) Rt=3.14 min; MS m/z: 491 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[CH2:18]([I:21])[CH2:19][CH3:20]>CC(=O)C(C)(C)C>[I-:21].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N+:11]([CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Reactant: CCCI
Solvent: CC(=O)C(C)(C)C
Product: CCC[n+]1cccc(-c2ccc(OC)c([N+](=O)[O-])c2)c1
Product: [I-]
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To pinacolone (50 mL, Aldrich) was added 3-[4-(methyloxy)-3-nitrophenyl]pyridine (3.5 g, 15.22 mmol) and propyliodide (10.46 g, 61.52 mmol, Fluke). The reaction was stirred at 95° C. overnight. The solvent was decanted and the remaining solids were dried under reduced pressure overnight to provide 3-[4-(methyloxy)-3-nitrophenyl]-1-propylpyridinium iodide, which was use for the next reaction without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[N:15]1([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:25]2[C:24]3[C:28](=[CH:29][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)[NH:27][C:26]2=[O:30])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2ccc(N3CCOCC3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(N4CCOCC4)ccc32)c(C)c1CCC(=O)O
Yield: 41.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (3.3 g), 4 g 6-(morpholin-4-yl)-2-oxindole and 1.8 mL piperidine in 60 mL of ethanol were heated at 90° C. for 7 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The resulting solid was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 2.78 g (38% yield) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClCCl.CN(S(F)(F)[F:38])C.Cl>[OH-].[Na+].O1CCCC1>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:38])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Reactant: CN(C)S(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Temperature: -78 °C
Yield: 69.7 %

Procedure:
A suspension of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (100 mg, 0.246 mmol) and dichloromethane (5 mL) is stirred at −78° C. Dimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added and the mixture is warmed to room temperature. An additional portion of dimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added and suspension becomes a solution. The reaction mixture is diluted with aqueous 2N sodium hydroxide (5 mL) and tetrahydrofuran (2 mL) and stirred 10 min. The pH is adjusted to 2 with aqueous 5N hydrochloric acid and extracted with ethyl acetate (2×20 mL). The combined extracts are concentrated and the resulting residue is purified via silica chromatography eluting with hexanes to 1:1 hexanes:ethyl acetate to give the title compound (70 mg, 70%) as a white solid. 1H NMR (DMSO-d6) δ 13.12 (s, 1H), 12.86 (s, 1H), 7.93-7.95 (m, 2H), 7.82 (d, 1H), 7.68 (d, 1H), 7.44-7.59 (m, 5H), 6.75-6.90 (d, 1H), 6.72 (d, 1H), 5.29 (s, 2H), 2.59 (s, 3H), 2.06 (s, 3H). LCMS M−1 407.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][N:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][N+:14]=1[O-:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(Cl)c(C)c1
Solvent: ClCCl
Product: COc1cc(C)c(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloroperoxybenzoic acid (70%, 695 mg, 2.82 mmol) was added to a solution of 2-chloro-5-methoxy-3-methylpyridine (370 mg, 2.35 mmol) in dichloromethane (10 mL). After stirring for 18 hours at room temperature, the reaction mixture was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) to afford the product as a white solid. Yield: 370 mg, 2.13 mmol, 91%. 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J=2.5 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC1CCCCN(CC2(c3ccc(Cl)cc3)CCC2)C1
Yield: 36.2 %

Procedure:
To a stirring 0° C. solution of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone (0.075 g, 0.26 mmol) under N2 in toluene (2.6 mL, 0.1M) was added sodium bis(2-methoxyethoxy)aluminum hydride (65+weight % in toluene) (0.28 mL, 0.91 mmol) dropwise with stirring. When the reaction was complete by HPLC, the reaction was quenched with H2O. 10% NaOH and ethyl acetate were added, and the organic was removed, dried with Na2SO4, and concentrated. The crude reaction mixture was purified by silica gel chromatography (90:8:2 Hexanes:methylene chloride: 2N NH3 in ethyl alcohol). A 39% yield (0.0290 g) of pure material was obtained as well as other impure fractions. 1H NMR (CDCl3, 300 MHz) 7.28-7.25 (2H, m), 7.15-7.09 (2H, m), 3.44 (1H, dd, J=10.5, 4.5 Hz), 3.27 (1H, dd, J=10.3, 5.5 Hz), 2.89 (1H, d, J=13.9 Hz), 2.83 (H, d, J=13.9 Hz), 2.72-2.60 (1H, m), 2.50-1.10 (16H, m) ppm. 13C NMR (CDCl3, 75 MHz) 146.5, 131.22, 128.10, 127.93, 70.95, 67.49, 61.85, 59.10, 47.62, 40.59, 32.12, 31.90, 29.92, 25.41, 16.20 ppm. LRMS: 308.24.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCc1ccccc1
Product: CCc1cc(-c2cncc(C(=O)NCc3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and benzyl amine to afford the title compound. MS: m/e=348 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3](=O)[CH3:4].CC(C)([O-])C.[K+].[NH2:12][C@@H:13]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)[CH2:14][NH:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=C[C:24](F)=[C:25]([CH:28]=2)C#N)=[CH:19][N:20]=1.C[N:42](C=O)C>CCOC(C)=O>[NH2:12][C@@H:13]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=1)[CH2:14][NH:15][C:16]1[S:17][C:18]([C:21]2[CH:28]=[CH:25][C:24]3[O:1][N:2]=[C:3]([NH2:42])[C:4]=3[CH:22]=2)=[CH:19][N:20]=1
Reactant: N#Cc1cc(-c2cnc(NC[C@@H](N)Cc3ccc(C(F)(F)F)cc3)s2)ccc1F
Reactant: CC(=O)NO
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nc1noc2ccc(-c3cnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc12
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of N-hydroxyacetamide (0.02 g, 0.3 mmol) in 1.5 mL of DMF, was added potassium tert-butoxide (1.0 M in THF (0.3 mL, 0.3 mmol)). The mixture was stirred for 30 minutes and then 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)-2-fluorobenzonitrile (0.086 g, 0.2 mmol) was added in 1.5 mL of DMF. The mixture was stirred for 12 hours and was then diluted with 20 mL of EtOAc. The organic layer was washed with 10 mL of brine and was then dried over MgSO4. Filtration and concentration under reduced pressure, followed by HPLC purification (95:5 to 70:30 water:MeCN over 50 minutes) afforded 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amine (0.018 g, 0.04 mmol, 20% yield) as an amorphous solid. 1H NMR (400 MHz DMSO-d6) δ ppm 7.84 (s, 1H), 7.63-7.67 (m, 1H), 7.65 (d, 9.1 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.7 Hz, 1H), 7.25 (s, 1H), 5.51 (s, 2H), 3.52-3.43 (m, 2H), 3.38-3.32 (m, 1H), 3.03 (dd, J=5.3, 13.7 Hz, 1H), 2.82 (dd, J=7.5, 13.7 Hz, 1H). HRMS (M+H) for C20H18F3N5OS calc. 434.12569, obs. 434.12614.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[OH:20].Cl[CH2:22][C:23](Cl)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CC#N>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:23](=[O:24])[CH2:22][O:20][C:13]=2[CH:14]=1
Reactant: COc1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)OCC(=O)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
DIPEA (2.2 mL, 12.5 mmol) was added to 2-amino-5-methoxyphenol hydrochloride (1 g, 5.7 mmol) in THF (13 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (0.5 mL, 6.3 mmol) was added portionwise and then stirred at 0° C. for 5 minutes. Further DIPEA (1.1 mL, 6.3 mmol) was added and the mixture was allowed to warm to r.t. and stirred for 3 days. The majority of the THF was removed in vacuo. EtOAc (50 mL) and water (50 mL) were added. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo. To a portion of the crude material (0.250 g, 1.159 mmol) in MeCN (6 mL) was added potassium carbonate (0.449 g, 3.246 mmol) followed by THF (2 mL). The reaction mixture was stirred at r.t. for 5 h and then concentrated in vacuo. Water (5 mL) was added and the solid collected by filtration, washed with water (3×5 mL) and dried in vacuo to give the title compound (0.173 g, 17%) as a red solid. δH (DMSO-d6) 10.53 (1H, br s), 6.80 (1H, d, J 8.5 Hz), 6.58-6.51 (2H, m), 4.52 (2H, s), 3.69 (3H, s). LCMS (ES+) 180.1 (M+H)+, RT 2.27 minutes (Method 1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]C(C)C)=[CH:31][CH:30]=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)C(C)C.C(OC(=O)C(C)(C1C=CC(C)=CC=1)CCCCC(=O)CCCCC(C)(C1C=CC(C)=CC=1)C(OCC)=O)C.[OH-].[K+]>O.C(O)C>[CH3:28][C:24]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)([CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:39])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:40])([C:8]1[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[C:25]([OH:27])=[O:26]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(C)cc2)C(=O)O)cc1
Yield: 39 %

Procedure:
According to the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a white solid. Mp 48-50° C. 1H NMR (CDCl3): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H, J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H), 1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly): Calcd for C29H39O5 (MH+): 467.2797, found: 467.2785. HPLC: 92.4% pure. Anal. (C29H38O5) C, H.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H](C)C(O)=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].Cl.N1CCC[C@H]1C(N)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH2:26])=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(N)=O)n21
Temperature: 25 °C
Reaction time: 18 h
Yield: 245.9 %

Procedure:
To a stirred solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (50 mg, 0.10 mmol) in anhydrous methylene chloride (1 mL) was added 4-dimethylaminopyridine (DMAP) (37 mg, 0.30 mmol). L-Proline amide hydrochloride (69 mg, 0.30 mmol) was added to the mixture and the reaction was stirred for 18 h at room temperature under nitrogen. The reaction was concentrated and the residue was purified by column chromatography over silica gel (gradient elution with 35-50% EtOAc in hexanes) to provide 141 mg of (S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide as a white solid.
Reaction SMILES: Br[C@:2]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:12]([CH2:13][C@@H:14]([CH3:31])[C@@H:15]3[C:16](=[O:25])[CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@@H:11]1[CH2:10][C@H:9]([F:32])[C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1>C(Cl)Cl>[F:32][C@@H:9]1[C:8]2[C@:3]([CH3:34])([CH:4]=[CH:5][C:6](=[O:33])[CH:7]=2)[C@@H:2]2[C@H:11]([C@H:12]3[C@:26]([CH3:30])([CH2:27][C:28]2=[O:29])[C@@H:15]([C:16](=[O:25])[CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C@H:14]([CH3:31])[CH2:13]3)[CH2:10]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@]2(C)[C@H]1C(=O)COC(=O)C(C)(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)COC(=O)C(C)(C)C
Temperature: 242 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
1.5 g of 9α-bromo-6α-fluoro-11β-hydroxy-16α-methyl-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione is introduced at 220° C. into 20 ml of "Marlotherm" S and heated to boiling for 15 minutes under a vacuum of 19 mm Hg [bp19 =242° C⟧ After cooling, the mixture is diluted with methylene chloride and chromatographed on silica gel, thus obtaining 920 mg of 6α-fluoro-16α-methyl-21-trimethylacetoxy-1,4-pregnadiene-3,11,20-trione, mp 226°-227° C.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2>>[F:34][C:35]1[CH:44]=[C:43]([C:45]([NH:27][C@@H:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(N[C@H]3CCOC3)nc2c1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(N[C@@H]4CCOC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-N-((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((R)-tetrahydrofuran-3-ylamino)quinazoline-7-carboxamide (I-62) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87e.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C@@H:17]([N:28]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C@@H:17]([N:28]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCO
Yield: 74.6 %

Procedure:
Stir a mixture of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid 2-benzyloxy-ethyl ester (69 mg, 94 μmol) and Pd/C 10% (7 mg) in MeOH (1 mL) under a hydrogen atmosphere for 1 h. Filter the mixture over a pad of Celite®. Wash the solids with dichloromethane. Concentrate the filtrate and purified by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (45 mg, 75%). MS (ES+): 642 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OCC)=[O:15])[N:6]=1.[NH4+:23].CO>O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH2:23])=[O:15])[N:6]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Reactant: [NH4+]
Solvent: O
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2F)n2ccccc12

Procedure:
560 mg (1.88 mmol) of ethyl 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxylate from example 7A are heated in 55 ml of 33% strength aqueous ammonium solution in a microwave at 130° C. for 3 h. The mixture is diluted with water, and, after addition of some methanol, extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. 229 mg (87.5% purity, 40% of theory) of the desired compound are obtained as greenish crystals which are reacted without further purification.