Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=[O:38])[C:6]([CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])([NH2:29])[CH:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1)(C)C.C(N(C(C1C=CC=CC=1)C)C(=O)C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Li+]>CO.O>[CH2:22]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:12][CH:13]=1)[C:6]([CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])([NH2:29])[C:5]([OH:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)OC(=O)C(N)(C(C)c1ccccc1)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CC(c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(c1ccccc1)C(N)(C(=O)O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)cc1
Yield: 85 %

Procedure:
To the above mixture of crude product 15 and N-benzyl-N-(1-phenyl-ethyl)-benzamide in methanol (30 mL) and water (15 mL) was added lithium hydroxide (831 mg, 34.7 mmol). The resulting suspension was heated to reflux for 48 hours. After cooled downed, the mixture was concentrated to remove methanol. The water layer was taken up with CH2Cl2 (30 mL×3). The organic layer was dried and concentrated. The residue was purified by silica gel column using hexane and ethyl acetate (2:1) as eluent to give 1.406 g white solid, in 85% yield for two steps. 1H NMR (400 MHz, CDCl3): δ7.44 (d, J=8.52 Hz, 2H), 7.37-7.22 (m, 12H), 6.55 (brs, 1H), 4.43 (dd, J1=4.46 Hz, J2=11.32 Hz, 1H), 4.15 (q, J=6.87 Hz, 1H), 3.98 (d, J=13.68 Hz, 1H), 3.64 (d, J=13.68 Hz, 1H), 2.92 (dd, J1=11.34 Hz, J2=16.94 Hz, 1H), 2.41 (dd, J1=4.48 Hz, J2=16.96 Hz, 1H), 1.54 (s, 9H), 1.28 (d, J=6.88 Hz, 3H); 13C NMR (100 MHz, CDCl3): 174.39, 152.82, 141.25, 138.44, 137.70, 132.56, 129.22, 128.80, 128.62, 128.60, 128.19, 127.81, 127.53, 118.52, 80.86, 57.96, 57.82, 50.61, 36.29, 28.34, 15.68. mp 93-95° C. IR v (Diamond, cm−1): 3307, 1699, 1594, 1081, 698. MS (ESI) m/z found 475.6 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:20]([O-])=O)=[CH:4][CH:3]=1.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])[C:7]=1[NH:6][C:5]1[CH:23]=[CH:24][C:2]([OH:1])=[CH:3][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(O)cc1

Procedure:
By substituting 4-(p-hydroxyanilino)-3-nitro-5-sulphamyl-benzoic acid (10 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 296°C (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:59]1([CH2:65][NH2:66])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:65]([NH:66][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)=[O:25])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 48 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.263 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (76 mg, 0.394 mmol), and 1-Hydroxybenzotriazole (53 mg, 0.394 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (68.9 μL, 0.504 mmol) and phenylmethanamine (43.1 μL, 0.394 mmol) were added. The reaction was allowed to stir for 48 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in methanol, filtered and dried under vacuum to obtain pure product as a white solid. Yield: 60 mg (White solid)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.S(=O)(=O)=O.N1C=CC=CC=1>ClCCl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H](CO)N1C(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H](C=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Add pyridine sulfur trioxide complex (0.42 g) to (2R,3S,5S)-2-(2,2-dimethylpropoxy)-5-hydroxymethyl-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.46 g, 1.45 mmol) and N,N-diisopropylethylamine (0.66 g, 5.07 mmol) in dichloromethane (1 mL) and dimethylsulfoxide (4 mL) at −2° C. and stir 30 minutes. TLC shows some alcohol remaining. Add more pyridine sulfur trioxide (100 mg) and stir 30 minutes. Pour into ice-cold saturated aqueous sodium chloride and extract with ethyl acetate. Wash the ethyl acetate layer with 1 N aqueous citric acid, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate to give the title compound as an oil (456 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].O>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)[CH3:16]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Sodium hydride (60%/mineral oil: 81 mg) was dissolved in dimethylformamide (5 mL), and the solution was cooled to 0° C. After addition of 4-nitroindole (300 mg), the mixture was stirred for one hour, and bromoacetic acid ethyl ester (340 mg) was added thereto, followed by stirring at 0° C. for 4 hours. Water was added thereto and the mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, then concentrated to give the title compound (367 mg)
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CN(C)C=O.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15 g), N,N-dimethylformamide (30 mL), potassium acetate (0.26 g) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40 mg) was heated at 90° C. over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 mL), dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1M hydrochloric acid and extracted with ethyl acetate (3×25 mL). The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50 mg). LC/MS System C: Rt=4.18 mins, m/z (ES−)=349 (M− for C21H18O5).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([O:17]C(=O)C)[C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:17])[C:12]([CH3:15])([CH3:16])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CCOCc1ccccc1)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C#N)[C@@H](O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (17.5 mmol) of 5-benzyloxy-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile from the second fraction is dissolved in 50 ml of methanol and mixed with 1.4 g (35 mmol) of NaOH. It is stirred for 3 hours at 25° C., added to 200 ml of water, extracted with 2×200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:23][C:24]2[C:25]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=3[S:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH:17]C(OC)=O)=[CH:13][C:12]([F:22])=[CH:11][CH:10]=2)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:23][C:24]2[C:25]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=3[S:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH2:17])=[CH:13][C:12]([F:22])=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(CNC(=O)OC)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
salt with hydrogen chloride (from Example 119.2.) was converted to 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methoxycarbonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 429.3 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25].C(OCC(Cl)=O)C1C=CC=CC=1>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:29](=[O:30])[CH2:28][O:27][C:24](=[O:26])[CH3:25])[CH2:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Agent: O=C(Cl)COCc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)cc2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 18, and making non-critical variations but substituting (S)-(−)-N-[[2-oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 58) for (S)-(−)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide and acetoxyacetyl chloride for benzyloxyacetyl chloride, the title compound is obtained, HRMS calcd for C21H25N3O6: 415.1743. Found: 415.1752.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH:16][C:17](=O)[CH3:18])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:18][C:17]1[N:8]2[C:7]3[C:2]([CH3:1])([O:3][CH2:4][CH2:5][C:6]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:15][N:16]=1
Reactant: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCC2(C)OCCc3c2n1c1ccccc31

Procedure:
A mixture of N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide (2.7 g, described in Example 1), phosphorus oxychloride (1.8 ml) and dry benzene (150 ml) is stirred and refluxed for 2 hours, cooled and washed with water (10° C.). The aqueouslayer is separated, basified with 5N sodium hydroxide, and extracted with chloroform. The combined organic extracts are dried over magnesium sulfate, filtered and evaporated to give a residue of the title compound. The residue is dissolved in diethyl ether and hydrogen chloride is added until precipitation is completed. The precipitate is collected and crystallized from ethanol-diethyl ether to obtain the hydrochloride salt of the title compound (1.45 g); mp 226°-227° C.; ir(CHCl3) 2500, 1815, 1623, 1536, 1662 and 1575 cm-1 ; mr (CDCI3) δ 1.66 (s), 2.90 (m), 3.32 (s), 3,48 (d), 4.30 (m) and 7.51 (m).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)n(Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A mixture of ethyl 3-[4-({4-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]benzyl}oxy)-2-fluorophenyl]propanoate (0.73 g, 1.6 mmol), 1 N aqueous sodium hydroxide solution (3.0 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 1 hr. 1 N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (0.61 g, yield 81%) as colorless crystals. melting point 152-153° C., 1H NMR (CDCl3) δ: 1.26 (9H, s), 1.31 (9H, s), 2.55-2.66 (2H, m), 2.83-2.95 (2H, m), 4.96 (2H, s), 5.48 (2H, s), 5.92 (1H, s), 6.56-6.67 (2H, m), 6.84-6.94 (2H, m), 7.00-7.14 (1H, m), 7.26-7.34 (2H, m).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=2[C:16]=1[CH3:17].C(N(CC)CC)C.O>O1CCCC1.C(Cl)(Cl)Cl.CO>[C:1]([NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Acetyl chloride (460 mg, 5.84 mmol) was added dropwise with ice cooling to a solution of 5-amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (100g, 4.87 mmol) and triethylamine (640 mg, 6.33 mmol) in tetrahydrofuran (20 ml). After the addition was completed, the mixture was stirred for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and saturated saline, dried and concentrated. The residue was purified by column chromatography on silica gel. (chloroform-methanol, 97:3) to obtain the desired compound (920 mg, yield: 76.4%). A part of it was recrystallized from dichloromethane-isopropyl ether, m.p. 190° C. (dichloromethane-isopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:3]=1.Cl>CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Agent: Cl
Solvent: CO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCNCC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
tert-Butyl 4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate (0.04 g, 0.1 mmol) was dissolved in methanol and treated with concentrated hydrogen chloride. This mixture was stirred at ambient temperature for 2 hours before concentrating and drying under high vacuum overnight to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (38 mg). MS (APCI), positive scan, m/z=539.1 (M+).
Reaction SMILES: [CH2:1]([C@:3]([OH:15])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1F)[C:4]([OH:6])=[O:5])[CH3:2].[CH3:16]N(C=O)C.C1(C)C=CC=CC=1.[H-].[Na+]>O>[CH2:1]([C@@:3]1([C:4]([O:6][CH3:16])=[O:5])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:15]1)[CH3:2]
Reactant: CC[C@](O)(Cc1ccccc1F)C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@]1(C(=O)OC)Cc2ccccc2O1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of the product from Step 3 (4.0 g, 20 mmol) in 1:4 DMF/toluene (100 mL) was added 60% NaH in mineral oil (1.76 g, 44 mmol) in 3 portions. The reaction mixture was stirred at 110° C. under N2 for 4 hrs. The reaction was cooled to room temperature and poured into cold water (100 mL). The aqueous layer was washed with hexane (50 mL), acidified with 2 N aqueous HCl and extracted with ethyl acetate (3×50 mL). The extracts were washed with brine (50 mL), dried and concentrated. The residue was dissolved in 7:1 benzene/MeOH (80 mL) and treated with TMSCHN2 (1M in hexane) until gas evolution ceased. The reaction was concentrated and the residue was chromatographed on silica gel eluting with 85:15 hexane:ethylacetate to give the title compound
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:31][CH:32]=1.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]=2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@@H]3CO)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@@H]3CO)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of (R)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (55 mg, 0.14 mmol), 5-methyl-2-(tributylstannyl)pyridine (65 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0068 mmol) and Toluene (1.5 mL, 14 mmol) under argon was subjected to microwave irradiation at 160° C. for 1 hour. The mixture was cooled to room temperature. Solvent was removed in vacuo and the residue was rinsed with hexane and then dissolved in MeOH and filtered. The filtrate was purified by preparative HPLC (100×21.2 mm C18 column, 20-70% CH3CN/water [10 mM Et2NH]) to afford a white foam. LC-MS: 1.64 min, 417.3 [M+1]+; HPLC: 6.76 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:27][C:26]4[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-c1ccc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn12
Temperature: 140 °C
Yield: 28.4 %

Procedure:
7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 3,4,5-Trimethoxyaniline (51 mg, 0.00028 mol) were dissolved in N-Methylpyrrolidinone (5.00 mL) and the reaction was heated at 140° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 29.22 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine as a lyophilated powder. (M+H)=441.09. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H), 7.45 (m, 1H), 7.22 (d, 1H, J=8.84 Hz), 7.02 (s, 2H), 6.92 (m, 2H), 3.76 (s, 3H), 3.57 (s, 3H), 3.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[Cl:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[C:26]([N:31]2[CH2:32][CH2:33][N:34]([C:14]([CH:13]3[CH2:12][N:11]([S:17]([CH:20]([CH3:21])[CH3:22])(=[O:18])=[O:19])[C:10](=[O:23])[N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[O:16])[CH2:35][CH2:36]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Reactant: Clc1cccnc1N1CCNCC1
Product: CC(C)S(=O)(=O)N1CC(C(=O)N2CCN(c3ncccc3Cl)CC2)N(c2ccc(F)cc2F)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 82, step 3) was coupled with 1-(3-chloropyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 527.8 ([M+H]+)