Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH:22]=[C:21]([CH2:31][CH3:32])[CH:20]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:33].O1CCOCC1>C(OCC)(=O)C>[ClH:33].[CH2:31]([C:21]1[CH:20]=[C:19]([NH:18][C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[CH:24]=[C:23]([C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)[CH:22]=1)[CH3:32]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)NC[C@H]2CCCNC2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of (S)-3-{3-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureidomethyl}-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in ethyl acetate (5 mL) was treated with a solution of hydrogen chloride in dioxane (4.0 N, 2 mL, 8 mmol) and stirred at room temperature for 6 hours. The mixture was concentrated, and the residue was triturated twice in diethyl ether and dried under vacuum to provide a white powder (165 mg, 97%). 1H NMR (300 MHz, DMSO-d6) δ9.24 (s, 1H), 8.89 (bm, 1H), 8.68 (bm, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 6.79 (t, J=6 Hz, 1H), 4.16 (s, 3H), 3.40 (m, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 2.9-2.5 (m, 4H), 2.0-1.6 (m, 4H), 1.21 (t, J=8 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[Br:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:15])=[O:14])[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)N3CCCC3)cc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
A mixture of 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride (0.25 g, 0.74 mmol), pyrrolidine (0.156 g, 2.2 mmol) and THF (10 mL) was stirred at 20° C. for 18 h then was partitioned between water (50 mL) and EtOAc (2×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid. Chromatography (SiO2; gradient elution with 50-100% EtOAc in petrol) gave the title compound (0.206 g) as a colourless solid. MS: [M+H]+=373.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1.[C:11]([O:19]CC)(=O)[CH2:12][C:13]([O:15]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>>[OH:19][C:11]1[C:12]2[C:13](=[O:15])[N:9]([CH3:10])[CH:5]=[N:4][C:3]=2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1cc(=O)n(C)cn1
Solvent: CN1CCCC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reaction time: 0.5 h

Procedure:
3-Methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B; 400 mg, 2.88 mmol, 1 eq), diethyl malonate (873 μl, 5.76 mmol, 2 eq) and phenyl ether (915 μl, 5.76 mmol, 2 eq) were dissolved in 1-methyl-2-pyrrolidinone (2 ml, 20 mmol). The mixture was placed in a microwave reactor at 240° C. for 30 minutes to yield 5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C). The product was confirmed by LC-MS and isolated by HPLC to give 125 mg (21%) of compound 1C. [M+H] calc'd for C9H9N3O3, 208; found, 208.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was added dropwise to a stirred solution of 2.55 g of 3-chloroaniline in 35 ml of ether. The mixture was stirred for one hour at room temperature and then filtered. The filtrate was evaporated and the residue crystallized from hexane to yield phenyl N-(3-chlorophenyl)-carbamate.
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2Cl)[NH:11][N:10]=1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:28].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:28])[NH:11][N:10]=1)[CH3:3]
Reactant: CCN(CC)CCCNc1n[nH]c2cccc(Cl)c12
Reactant: O=C=O
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CC(C)Br
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCCNc1n[nH]c2cccc(O)c12
Reaction time: 12 h
Yield: 41 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 2.81 g of the 3-(3-diethylaminopropylamino)-4-chloroindazole, 2.06 g of isopropyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.08 g of 3-(3-diethylaminopropylamino)-4-hydroxyindazole having the following analytical values in a yield of 41%.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][N:7]1[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCSc1ccncc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.153g (4.0 mmol) of 4-[2-(2-hydroxymethylbenzoyl)aminoethylthio]pyridine and 1.68 ml (12.1 mmol) of triethylamine in 50 ml of methylene chloride, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 623 mg of the desired compound (57.6% yield, colorless crystals), mp. 86°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][OH:37])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(N[C@H](CO)c1ccccc1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@H](CO)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (S)-2-bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide. MS (ESI): mass calcd. for C24H21FN4O3S, 464.13; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.30 (m, 2H), 8.05-8.01 (m, 1H), 7.85 (t, J=8.2, 1H), 7.61-7.56 (m, 1H), 7.50-7.44 (m, 1H), 7.26-7.19 (m, 4H), 7.10-6.97 (m, 4H), 4.20 (t, J=6.6, 1H), 3.69-3.58 (m, 2H).
Reaction SMILES: [C:1](O)(=O)CC(O)=O.[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]2=[CH:14][CH:13]=1)=[O:18].C(N(CC)CC)C.C(OCC)(=O)C>O>[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:22]=[C:16]2[C:15](=[CH:14][CH:13]=1)[C:20](=[O:21])[O:19][C:17]2([OH:18])[CH3:1]
Reactant: O=C1OC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Reactant: O=C(O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Dried malonic acid (156 g, 1.5 mol) and 5-(2-chloro-4-trifluoromethylphenoxy)phthalic anhydride (342 g, 1.0 mol) were stirred with triethylamine (200 ml) under a nitrogen atmosphere and warmed slowly to 80° C. After 5 hours at 80° C., the reaction mixture was allowed to cool to room temperature and ethyl acetate (750 ml) and water (500 ml) were added. The organic phase was separated and washed with dilute hydrochloric acid then water. Ethyl acetate was distilled from the solution and the crude product purified by chromatography over silica gel. Finally, crystallisation from 40°-60° petroleum spirit/diethyl ether afforded the product as a white solid, m.p. 106°-108° C. Yield=154 g (43%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:36]=[CH:35][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[N:11]=[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][O:25][CH2:24]4)[CH:18]=3)[CH:9]=2)=[CH:5][CH:4]=1.Cl.[CH3:40][NH:41][CH3:42].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:36]=[CH:35][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]([N:41]([CH3:42])[CH3:40])=[O:15])[N:11]=[C:10]([C:17]3[CH:18]=[C:19]([C:23]4([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:24][O:25][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(CC(=O)O)n3)c2)COC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1nc(-c2cccc(C3(NC(=O)OC(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[5-(4-Trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetic acid (85 mg, 0.16 mmol), dimethylamine hydrochloride (26 mg, 0.32 mmol), EDC (46 mg, 0.24 mmol), HOBT (37 mg, 0.24 mmol), and diisopropylethylamine (0.11 mL, 0.64 mmol) were combined in 0.5 mL of DMF and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g silica gel column using 0-5% MeOH:CHCl3 over 15 min at 30 mL/min. Product-containing fractions were combined and the solvents were evaporated under reduced pressure to give tert-butyl [3-(3-{5-(4-trifluoromethylphenoxy)-1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]carbamate as a foam. Calcd (M+1)+: 561.6. Found: 561.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5](=[CH:9][C:10]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:6]([OH:8])=[O:7].O.[C:17](=O)([O-])[O-].[K+].[K+]>CO.S(=O)(=O)(O)O>[NH2:15][C:4]1[CH:3]=[C:2]([F:1])[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(F)c(S(N)(=O)=O)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S(N)(=O)=O)c(F)cc1N

Procedure:
A reaction flask, containing 7.2 g (0.0307 molecule) of 4-fluoro-5-sulphamylanthranilic acid (6) in 125 ml of methanol and 10 ml of concentrated sulphuric acid, was attached to a Soxhlet apparatus, containing molecular sieves 4A, immersed in methanol (25 ml). After 48 hours' reflux, the solution was poured into cold water (500 ml), containing 25 g of potassium carbonate. The solid, which separated out, was recovered on a filter and dried in vacuo at 80°; yield: 5.6 g (73.7%); m.p.: 209°-211°.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>C1COCC1>[NH2:34][C:33]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: N#Cc1ccncc1N
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cccnc3[nH]2)c(=O)[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20 minutes, a solution of 3-aminopyridine-4-carbonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred 3 hours, and then refluxed overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. A precipitate formed, was filtered off, and was washed repeatedly with ether to yield the desired compound as a brown solid. Purification by reverse phase chromatography afforded the desired product as a yellow solid. LC/MS m/z 279.0 (MH+), Rt 1.29 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=3)[NH:13][C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[C:36]1C=C(C2C3C(=CC=C(C(C4C=NC(Cl)=CC=4)(O)C4N(C)C=NC=4)C=3)NC(=O)C=2)C=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Product: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 13 %

Procedure:
The same procedure was used as that in example 2, except that 4-(3-ethoxy-phenyl)-6-(hydroxy-di-pyridin-3-yl-methyl)-1H-quinolin-2-one (91 mg, 0.202 mmol) was used in the place 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one to give the title compound of example 37C as a white solid (12 mg, 13% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:14]2[NH:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-]>C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[C:10]([C:14]2[N:19]=[CH:18][C:17](=[O:20])[N:16]([CH2:21][C:22]([F:25])([F:23])[F:24])[N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(c2cccc(Cc3ccccc3)c2)=NN1CC(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1cnc(-c2cccc(Cc3ccccc3)c2)nn1CC(F)(F)F

Procedure:
A solution of 3-(3-benzylphenyl)-1-(2,2,2-trifluoroethyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (0.284 g, 0.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-quinone (DDQ, 0.204 g, 0.9 mmol) in ethyl acetate (9 mL) was refluxed for 5 hours, concentrated under reduced pressure, dissolved in methylene chloride (120 mL), washed with saturated aqueous sodium carbonate (2×60 mL), brine (70 mL), dried over magnesium sulfate and eluted through a silica gel plug. The filtrates were concentrated under reduced pressure to leave an amorphous yellow solid. Yield 0.267 g (95 percent). mp 95-96° C.; 1H NMR (CDCl3) δ 8.54 (s, 1H), 8.00 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.32-7.28 (m, 3H), 7.23-7.20(m, 3H), 4.76 (q, J=7.8 Hz, 2H), 4.06 (s, 2H); ES/MS 346 m/e (M+1); IR (KBr) σ cm−1 1688.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:23])=[C:12]([N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[N:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[F:23][C:11]1[C:12]([N:16]2[CH2:17][CH2:18][CH:19]([O:22][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH2:20][CH2:21]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: Oc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(O)CC2)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cccc(N2CCC(Oc3ccncc3)CC2)c1F
Temperature: 55 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-ol (200 mg) and pyridin-4-ol (65 mg) were mixed with THF (3 ml), and triphenylphosphine (250 mg) was added thereto. A 1.9M DIAD/toluene solution (0.5 ml) was added dropwise to the reaction mixture, followed by stirring at 55° C. overnight. Then, a 1M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and diethyl ether and 1M hydrochloric acid were added thereto. The organic layer was separated by a liquid separation operation, and the aqueous layer was washed with diethyl ether twice again. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {2-fluoro-3-[4-(pyridin-4-yloxy)piperidin-1-yl]phenyl}methanol (84 mg).
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:5])=[O:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[NH:24][N:23](Cl)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[NH:24][N:23]([NH:1][CH:2]([CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([OH:5])=[O:4])[N:22]=1
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: NC(C(=O)O)C1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(NC(C(=O)O)C2c3ccccc3-c3ccccc32)N1
Temperature: 80 °C
Reaction time: 13 h
Yield: 28.9 %

Procedure:
2.29 g (9.6 mmol) of 2-amino-2-(9-fluorenyl)acetic acid, 0.70 g (4.0 mmol) of 4,6-dimethoxy-2-chlorotriazine and 0.51 g (4.8 mmol) of sodium carbonate were introduced into a mixture of 16 ml of DMF and 16 ml of water and stirred at 80° C. for 13 hours. Then ethyl acetate and water were added and the phases were separated. The aqueous phase was acidified with 6 normal HCl and extracted three times with ethyl acetate. The organic phases were dried with MgSO4 and concentrated. The crude product was chromatographed on silica gel with ethyl acetate/n-heptane (1:1). 0.44 g (29.1%) of a white powder was obtained; RF=0.135, melting point 182-186° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].Cl.[CH3:36][O:37][CH:38]1[CH2:41][NH:40][CH2:39]1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:40]4[CH2:41][CH:38]([O:37][CH3:36])[CH2:39]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Reactant: COC1CNC1
Agent: Cl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC(OC)C5)ccn34)c12

Procedure:
Prepared according to the procedure for Example 128 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Steps A-B) and 3-methoxyazetidine hydrochloride. MS (ES+APCI) m/z=524 (M+H) detected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](OCC)=[O:9])=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(OCC)C>[OH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CCOC(=O)Cc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccncc1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
Ethyl 4-pyridylacetate (20 g, 121 mmol) was added to a suspension of LiAlH4 (9.2 g, 242 mmol) in diethyl ether (600 mL). Diatomaceous earth (about 50 mL) was added to aid stirring. The mixture stirred overnight. The mixture was cooled to 0° C. and aqueous NaOH (15%) was added until degassing ceased. The mixture was allowed to stir for 1 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product was purified by chromatography (SiO2, 40:1-20:1 CH2Cl2:methanol) to provide 4-(2-hydroxyethyl)pyridine (8.1 g, 54%) as an amber liquid.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:13]1[CH2:19][C:18](=[O:20])[CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:18]2([OH:20])[CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:19]2)=[CH:8][CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1COCCOC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)COCCOC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Magnesium (1.27 g, 0.053 mol), dried in an oven for 1 hr at 75° C., was stirred with THF (125 mL) in a 500 mL three-necked flask at reflux. A crystal of iodine was added followed by a solution of 4-methoxybromobenzene in THF (50 mL), added dropwise over 15 min. After the addition of 10 mL of the solution the reaction initiated. After complete addition of the solution, the reaction mixture was heated at reflux for 2 hrs. The resulting grey solution was cooled to 0° C. and a solution of 1,4-dioxepan-6-one (prepared as described in U.S. Pat. No. 4,410,354) (5.08 g, 0.044 mol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was acidified to pH=1 with 1N HCl and extracted with ether (2×250 mL). The ether extracts were washed with water, dried (MgSO4), filtered and concentrated to give a sticky brown solid (9.45 g). This was purified by column chromatography on silica gel eluting with ethyl acetate-hexanes. The relevant fractions were concentrated to give the desired product (6.21 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=2)[C:7]=1[CH2:33][C:34]([O:36]CC)=[O:35])=[O:5])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=2)[C:7]=1[CH2:33][C:34]([OH:36])=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(N)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(N)cn3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(5-aminopyridin-2-yloxy)-2-ethoxycarbonylmethyl-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (185 mg, 0.36 mmol; see step (b) above), NaOH (aq, 2 M, 2 mL) and EtOH (15 mL) was stirred at rt for 20 h, acidified to pH 2 with HCl (aq, 1 M) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 130 mg (74%).