Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O.[NH2:29][NH2:30].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:29][N:30]=[C:19]([CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:3]=3[C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CC1CCOCC1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CC3CCOCC3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(tetrahydro-2H-pyran-4-ylacetyl)-1,8-naphthyridin-2(1H)-one (120 mg, 0.33 mmol) produced in Synthesis Example 40 in DMF (2 mL) was added hydrazine monohydrate (purity of 80%, 53 μL), and the mixture was stirred at 110to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogen carbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 5-phenyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (66 mg, yield 55%).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[CH3:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: CC(Sc1nc(N)cc(O)n1)c1ccccc1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (5.0 g) with □-methylbenzyl bromide (5.74 g) to afford the subtitle compound which was used directly in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COC(=O)C(C)Br
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(OC)cc1[N+](=O)[O-]
Yield: 70.9 %

Procedure:
Using 4-methoxy-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a light yellow solid (5.35 g, 70.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.82 Hz, 3H) 3.67 (s, 3H) 3.78 (s, 3H) 5.12 (q, J=6.65 Hz, 1H) 7.15-7.27 (m, 2H) 7.39-7.49 (m, 1H). ESI-MS: m/z 256.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])([O-:9])=[O:8].C[N:21](C)C=O>C(Cl)Cl>[CH3:19][C:18]1[C:10]([N+:7]([O-:9])=[O:8])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:21])=[O:13]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (18.1 ml, 36.1 mmol, 1.25 eq., 2M in CH2Cl2) was added to a solution of 2-nitro-3-methyl-benzoic acid (5.237 g, 28.9 mmol, 1.0 eq.) in CH2Cl2 (57.8 ml, 0.5M) and dimethylformamide (0.14 ml, 0.25% of CH2Cl2) at 0° C. and stirred for 15 minutes. The reaction was then warmed to room temperature and stirred for 3 hours. Ammonia was bubbled through the reaction for 30 minutes. Water was then added. The product was filtered off ,and pumped on to provide the title A compound (3.81 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>CCO>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=Cc1cccc(OCC2CO2)c1
Solvent: CCO
Product: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Yield: 63 %

Procedure:
A solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.49 g, 11.22 mmol) in EtOH (20 mL) was heated at 110° C. for 3 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried and concentrated. The crude product was purified by column chromatography. (1.1 g, yield 63%.) MS (ESI+) e/z: 312.3 [M+1]+.
Reaction SMILES: [CH2:1]1[C:5]([Cl:6])=[N:4][O:3][C@@H:2]1[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].[C:12]1([CH2:25][O:26][C:27](Cl)=[O:28])[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+].Cl>O>[Cl:6][C:5]1[CH2:1][CH:2]([CH:7]([NH:11][C:27]([O:26][CH2:25][CH:12]2[C:24]3[CH:16]=[CH:17][CH:18]=[CH:19][C:23]=3[C:22]3[C:13]2=[CH:14][CH:15]=[CH:20][CH:21]=3)=[O:28])[C:8]([OH:10])=[O:9])[O:3][N:4]=1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C(NC(C(=O)O)C1CC(Cl)=NO1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of AT-125 (178 mg; 1 mmole), 9 fluorenylmethylchloroformate (285 mg, 1.1 mmole), and potassium bicarbonate (370 mg; 3.7 mmole) in 5 ml of water was stirred for 20 hours at room temperature. The gelatinous mixture is acidified to pH 2 with hydrochloric acid, evaporated to dryness under reduced pressure, and extracted with acetone. The acetone extracts are adsorbed onto silica gel and chromatographed on 40 g of silica gel with methylene chloride:isopropanol:acetic acid (100:3:1). Fractions of 20 ml are collected and monitored by TLC (U.S. visualization). The first 8 fractions contain component derived from the chloroformate reagent only including 9 fluorenylmethyl alcohol. Fractions 11-17 contain 206 mg of chromatographically homogeneous 3-chloro-α-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid, and fractions 21-50 contain 132 mg of chromatographically homogeneous 3-chloro-α-[[(3-chloro-4,5-dihydro-5-isoxazolyl)[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino]-4,5-dihydro-5-isoxazolacetic acid. Crystallization of fractions 11-17 from aqueous methanol and recrystallization from acetone-cyclohexane yields 3-chloro-α-[[ (9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid m.p. 175°-176°.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Cl)[N:31]=1>CN(C)C=O>[Cl:29][C:30]1[N:31]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(Cl)n4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15.9 mg, 37%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:8][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of p-aminophenol (0.200 g, 1.83 mmol), 4-trifluoromethylbenzyl alcohol (025 ml, 1.83 mmol) and triphenylphosphine (0.529 g, 2.02 mmol) in 5 ml anhydrous tetrahydrofuran was added diethyl azodicarboxylate (0.318 ml, 2.02 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. It was then diluted with 70 ml ethyl acetate and the resulting solution was washed sequentially with 50 ml saturated aqueous sodium bicarbonate solution, 50 ml water and 50 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 8:2 hexane/ethyl acetate to yield the title compound as an off-white solid (0.272 g, 55% yield). MS: 284.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(CC3C=CC=CC=3)(=O)=O)[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1
Reactant: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
Prepared by the method of example 30, using the product from example 56 part (a) and benzeneacetyl chloride to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C@H:30]1[O:34][C:33](=[O:35])[NH:32][C@@H:31]1[CH3:36].[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>C1COCC1>[F:48][C:47]([F:49])([F:50])[C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([C:51]([F:54])([F:52])[F:53])[CH:44]=1)[CH2:40][N:32]1[C@H:31]([CH3:36])[C@@H:30]([C:21]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=2[C:4]2[CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=3[CH3:19])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:34][C:33]1=[O:35]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N[C@@H]3C)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.17 h

Procedure:
The starting methyl 4′-methoxy-2-methyl-2″-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl]-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (40 mg, 0.080 mmol) was dissolved in anhydrous THF (1 mL) and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 3.5 mg, 0.088 mmol) was added into the mixture. The reaction mixture was stirred cold (ice bath) for 10 min followed by addition of 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (22 μL, 36.8 mg, 0.120 mmol). The resulting mixture was stirred cold for 20 min then the cold bath was removed. Aliquot at reaction time 2.5 hours indicated about 50% conversion. Reaction crude was cooled (ice bath) and quenched by NH4Cl (aq., sat.). The resulting bi-phasic mixture was worked up with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford an oil. This oil was purified by a preparative reverse-phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluted with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled and evaporated to afford methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Un-reacted starting material was also recovered. LCMS calc.=725.18; found 726.19 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([S:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CO>[C:5]1([S:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][N:26]2[CH2:27][CH2:28][CH:23]([C:22]([F:30])([F:29])[F:21])[CH2:24][CH2:25]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)(CC=O)CS(=O)(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(CCN1CCC(C(F)(F)F)CC1)CS(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (78 mg, 1.2 mmol) was added to a stirred solution of the crude 4-benzenesulfonyl-3,3-dimethyl-butyraldehyde (240 mg, 1 mmol) and 4-trifluoromethylpiperidine (321 mg, 2.1 mmol) in methanol (4 ml). The mixture was stirred for 1 hour, quenched with sat. aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica (dichloromethane:methanol) to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[NH:17][C:18]2=[O:27])=[N:13]1.Br[CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[N:17]([CH2:34][CH2:35][OH:36])[C:18]2=[O:27])=[N:13]1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cn1c(=O)n(CCO)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 2-bromoethanol using potassium carbonate as a base. Mass: 496.17 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CCC(Br)=C2Oc1ccc(OCCN2CCCCC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(Br)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
To a round bottom flask, add 1-(2-(4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yloxy)phenoxy)ethyl)piperidine (6.7 g, 6.6 mmol) and acetonitrile (50 mL). Stir the mixture at 25° C. for 5 min. Add 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (3.2 g, 14.1 mmol) slowly to the reaction mixture. Heat the mixture to 80° C. and stir at the temperature for 14 hours. Cool the reaction mixture to room temperature and quench with ice-water. Extract the mixture with ethyl acetate three times and discard the aqueous phase. Dry the combined organic layers (MgSO4), filter, and concentrate to dryness. Purify by flash chromatography to give 1-(2-(4-(2-bromo-6-methoxynaphthalen-1-yloxy)phenoxy)ethyl)piperidine as a brown solid (817 mg). 1HNMR (d-DMSO, 300 MHZ): 7.68 (3H, m), 7.43 (1H, s), 7.15 (1H, m), 6.97 (2H, d), 6.72 (2H, d), 4.26 (2H, s), 3.85 (3H, s), 3.48 (4H, m), 2.96 (2H, m), 1.70 (6H, m).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=[O:46])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N+:19]([O-:46])=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: COc1ccc(N(C)c2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N(C)c2ccc(C(Cc3cc[n+]([O-])cc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
To a solution of 4-[2-[3,4-bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-methoxyphenylamino)3-pyridyl]ethyl}pyridine from Example 112 (60 mg, 0.11 mmol) in a mixture of 3.0 mL of CH2Cl2 and 0.3 mL MeOH, was added 84 mg (0.136 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was then washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 40% to 50% EtOH/ethyl acetate) to afford 27 mg (45%) of the title compound
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=N[N:18]([CH2:29]OCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.C[N:44](C=O)C>ClCCl>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:29][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([NH2:44])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(O)C(N)=O)c3)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (92 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and oxalyl chloride (145 mg, 1.14 mmol) and DMF (10 μL) were added. The resulting solution was heated to 60° C. with stirring overnight. The mixture was concentrated and ammonium hydroxide (30% w/v in water, 1 mL) was added and the stirring was continued for 15 minutes. The mixture was neutralized to pH 7 and extracted with ethyl acetate (5 mL×5). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. To the residue was added trifluoroacetic acid (2 mL) and the resulting mixture was sonicated until the residue was completely dissolved. The volatiles were evaporated and the residue was treated with ethylene diamine (0.2 mL). The resulting mixture was directly purified by mass-triggered reverse-phase HPLC to afford 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide as a white solid (32 mg, 45%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 3.86 (s, 3H), 4.95 (s, 1H), 6.09 (s, 1H), 7.11 (t, 1H), 7.21 (s, br, 1H), 7.23 (d, 1H), 7.47 (m, 4H), 7.67 (d, 2H), 7.81 (s, 1H), 8.31 (d, 1H), 8.83 (d, 1H), 8.73 (s, 1H), 13.82 (s, 1H).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26].C(ON=O)(C)(C)C>O1CCCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[CH:2]=[C:3]([C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:4]([C:19]([F:22])([F:21])[F:20])=[N:5]1
Reactant: C[Si](C)(C)C#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethyl4-trimethylsilylethynylpyrazole (6.39 g) in tetrahydrofuran (50 ml) at 65° C. was added dropwise over one hour t-butylnitrite (7.15 g) in tetrahydrofuran (10 ml). Heating was continued for 2 hours then the mitue was left at room temperature overnight. After evaporation the residue was taken up in hexane and decanted free from insoluble materials. The solution was evaporated and the residue purified by column chromatography on silica gel eluted with dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions, followed by recrystallisation from hexane, provided the title compound as a pale yellow solid, m.p. 105-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(-c2cc(CCl)ccn2)cc1OC
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccc(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,4-dimethoxyphenyl)pyridine (264 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OS(C1C=CC(C)=CC=1)(=O)=O)[C@H:12]1[O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]2[CH2:13][O:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC[C@@H]1CO1
Yield: 107.6 %

Procedure:
Preparation according to Preparation 1 using 5-bromo-2-hydroxybenzaldehyde (6 g, 30 mmol), (S)-glycidyltosylate (8.2 g, 36 mmol), K2CO3 (4.9 g, 36 mmol) and DMF (12 ml). Water (100 ml) was added and the solution was extracted with EtOAc (3×100 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1 N, 100 ml), brine, were dried and concentrated to give the crude title compound (8.3 g). MS m/z (rel. intensity, 70 eV) 257 (M+, 38), 256 (M+, 39), 200 (bp), 199 (87), 57 (88).