Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:40]=[C:28]3[N:29]=[C:30]([CH3:39])[C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:32]([Cl:33])[N:27]3[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C2[O:49]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:40]=[C:28]3[N:29]=[C:30]([CH3:39])[C:31]([CH:34]([OH:49])[C:35]([O:37][CH3:38])=[O:36])=[C:32]([Cl:33])[N:27]3[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 1.50 mL, 0.78 mmol) in THF (12 mL) at −78° C. was added a solution of methyl 2-(2-(3-(benzyloxy)phenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.35 g, 0.83 mmol) in THF (12 mL) dropwise over 40 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.33 g, 1.25 mmol) in THF (24 mL) was added over 20 min and the reaction mixture was stirred for additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (80 mg, 22%). Used as is in the next step.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar and a reflux condenser, to a solution of trans-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate (45 mg, 0.195 mmol) in THF (2.5 mL) was added PPh3 on polystyrene (1.6 mmol/g, 120 mg, 0.193 mmol) and water (0.15 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was then filtered and the filtrate dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford trans-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate as a pale yellow oil. LC-MS-conditions 10: tR=0.48 min; [M-CH3+H]+=190.38.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][Cl:36])[CH2:29][CH2:28]1.Cl>CCOCC.C(C(C)=O)C>[ClH:36].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][O:11][C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH2:31][CH2:32]1
Reactant: Oc1cccc2c1CCCC2
Reactant: Cc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1
Yield: 72 %

Procedure:
A mixture of 8.15 g. (55 mMole) 5,6,7,8-tetrahydro-1-naphthol, 7.60 g. (55 mMole) powdered dry potassium carbonate and 100 ml. anhydrous methyl ethyl ketone was heated under reflux for 2 hours and then cooled somewhat. 0.2 g. potassium iodide were added thereto and a solution of 12.64 g. (50 mMole) 4-(2-methylphenyl)-1-(3-chloropropyl)-piperazine in 50 ml. anhydrous methyl ethyl ketone then added dropwise, whereafter the reaction mixture was heated under reflux for a further 16 hours. After filtering with suction, the filter cake obtained was washed with acetone. The combined organic filtrates were evaporated in a vacuum, the oily evaporation residue was taken up in chloroform and the chloroform solution was extracted several times with a dilute aqueous solution of sodium hydroxide and then with distilled water. After drying and evaporating in a vacuum, there was obtained an oily product which was dissolved in ether and treated with dry hydrogen chloride. The precipitated 4-(2-methylphenyl)-1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-prop1 -yl]-piperazine hydrochloride thus obtained was filtered off with suction, washed with some ether and finally with alcohol to which some concentrated hydrochloric acid had been added. The yield was 72% of theory and the product has a melting point of 243°-244°C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])C.[CH3:21][NH2:22]>C(O)CO>[CH3:21][NH:22][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Solvent: OCCO
Product: CNC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.81 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is suspended in 15 ml of ethylene glycol and, while cooling with ice, methylamine is introduced until saturation point is reached. The mixture is then stirred at room temperature for 16 hours, stirred into 100 ml of ice water and the product is filtered off, dried and recrystallized from ethanol-chloroform. 1.42 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid N-methylamide of melting point 281°-285° C. is obtained.
Reaction SMILES: [N+:1]([O-:15])([O:3][CH2:4][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[O:2].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18].N1C=CC=CC=1>C(Cl)Cl.O>[C:17](=[O:18])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:4][O:3][N+:1]([O-:15])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To the solution of 6-hydroxyhexane-1,2-diyl dinitrate (150 mg, 0.67 mmol) in CH2Cl2 (15 mL) at rt was added 4-nitrophenyl chloroformate (202 mg, 1.00 mmol) and followed by pyridine (159 mg, 2.01 mmol). The mixture was stirred at rt over night and diluted with H2O. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column 25M; TLC method: n-hexane/ethyl acetate 7/3; Rf=0.35), affording product (210 mg, yield 81%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N(Cc4ccccc4)Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N)CC3)c(F)c2)C(=O)O1
Yield: 100 %

Procedure:
Using the amino compound, (S)-N-{3-[4-(4-dibenzylamino-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 5) was synthesized by the same method as in Example 1. To a methanol solution (200 ml) of this compound (5.28 g), palladium hydroxide on carbon (20%, 3.3 g) was added and the mixture was stirred at room temperature under 3 atm hydrogen atmosphere. Palladium hydroxide on carbon was filtered off and the filtrate was concentrated under vacuum to afford the title compound (3.48 g) in a yield of 100%.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]([O:14][OH:15])([CH2:7][CH2:8][C:9]([CH3:13])([O:11]O)[CH3:10])[CH3:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:16]([O:15][O:14][C:5]([CH3:6])([CH3:4])[CH2:7][CH2:8][C:9]([OH:11])([CH3:13])[CH3:10])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CCC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 18.7 g (0.150 mole) of 45% KOH, 15.0 g of water, 27.6 g (0.120 mole) of 77.6% (wetted solid) 2,5-dimethyl-2,5-dihydroperoxyhexane and 100 ml of methylene chloride. To the resulting two liquid phase mixture at 28° to 30° C. was added 12.8 g (0.100 mole) of 94.3% pivaloyl chloride over a period of about 30 minutes. The resulting mixture was then stirred for 2.0 hours at 28° to 30° C. after which the mixture was cooled to 15° to 20° C. and was allowed to separate into phases. The upper aqueous layer was removed and was discarded. The resulting product solution was then washed with 50 ml of 20% KOH solution at 0° C. and then with 50 ml of 7.7% sodium hydrogen carbonate solution at 15° to 20° C. The methylene chloride solution was then cooled to 0° to 10° C. and was reacted with 187 g of buffered sodium sulfite solution (consisting of 7.6 g of acetic acid, 8.4 g of sodium acetate, 19 g of sodium sulfite and 152 g of water) in order to covert the 4-hydroperoxy-1,1,4,4-tetramethylbutyl peroxypivalate that was formed in the peroxidation reaction to 4-hydroxy-1,1,4,4-tetramethylbutyl peroxypivalate, the desired product. A thick emulsion resulted which required three days of storage in the refrigerator to separate into two liquid phases. The upper aqueous layer was removed and an equal volume of diethyl ether was added in order to facilitate further processing. The solution was dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the solvents were remove in vacuo at 0° to 10° C. Some solids were removed by filtration and the resulting liquid weighed 20.4 g. The assay of the product was 90.3% according to peroxyester active oxygen content. The corrected yield was 74.9%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3400 cm-1.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O)([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=O)[CH3:2].Cl.C(Cl)Cl>COCCOC.[Zn]>[CH2:6]([C:3]1([CH2:1][CH3:2])[CH:4]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC=CC(C=O)(CC)CSc1ccccc1C=O
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCC1(CC)C=Cc2ccccc2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.6 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccc2Br)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Bromo-5-methyl-benzoic acid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N:14]1([C:19]2[N:24]=[C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH2:31][NH2:32])[CH:22]=[C:21]([CH3:33])[N:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:32][CH2:31][CH2:30][N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[C:23]3[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:14]4[CH:18]=[CH:17][N:16]=[CH:15]4)[N:24]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCc1ccc2c(c1)OCCO2
Reactant: Cc1cc(C2CCCN2CCN)nc(-n2ccnc2)n1
Product: Cc1cc(C2CCCN2CCNCCc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1

Procedure:
[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine was prepared following the procedures described in the preparation of Example 127 using (2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetaldehyde and 2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethylamine. [M+H]+ 435.54; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.75 (d, 1H), 6.70-6.60 (m, 2H), 4.18 (s, 4H), 3.54 (t, 1H), 3.15 (m, 1H), 2.94-2.74 (m, 5H), 2.52 (s, 3H), 2.40-2.20 (m, 4H), 1.95-1.66 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccnc(Cl)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 133 mg of (2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25 (m, 1H), 7.32 (m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd, 1H, J=9.2 Hz, 2.4 Hz), 7.67 (m, 2H), 7.77 (d, 1H, J-8.8 Hz), 8.55 (d, 1H, J=5.2 Hz), 10.09 (s, 1H). MS: m/z 463.0 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)CC>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[CH:6][N:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Product: NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing (6-chloropyridin-3-yl)methanamine 33-2 (375 mg, 2.63 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid 33-1 (500 mg, 2.63 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (124 mg, 0.30 mmol) and potassium phosphate (1.90 g, 9.00 mmol) under argon was added 2-butanol (4 mL). The mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give (2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 33-3 as a yellow solid. MS m/z 254.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:25].C(N(CC)CC)C.[C:34]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:42](=[O:43])[CH2:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][C@H:7]([NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:25]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CNc2ccccc21
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of (3S)-2-oxo-3-benzoylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester (200 mg, 0.57 mmol) in CH2Cl2 (10 ml) was treated with triethylamine (119 mg, 1.13 mmol) and 3-phenylpropionyl chloride (114 mg, 0.68 mmol). The reaction was stirred at RT for 30 min and diluted with CH2Cl2. The solution was washed with aq. 10% HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo to give 240 mg (87%) of 602a as a white foam.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33][CH3:34])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH3:43]>C(#N)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH2:42][CH3:43])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33][CH3:34])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCI
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnnn2CC)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.9 g) was dissolved in acetonitrile (190 ml). To the solution were added potassium carbonate (1.65 g) and ethyl iodide (0.76 ml), and the mixture was stirred at 50° C. for 16 hours. The solvent was concentrated to 1/3 under reduced pressure, which was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1→1/2) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1-ethyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.05 g) and methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethyltetetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.42 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2)(=O)C.[NH4+].[OH-]>CO>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[N:36]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A mixture of tert-butyl 5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.6 g) and 28% NH4OH (2.8 mL) in MeOH (160 mL) was stirred at RT for 24 h. A solid separated out which was collected via filtration. The solid was triturated with hexane and dried under vacuum to give the desired compound tert-butyl 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.6 g). MS 578.4 (M+1). HPLC retention time 7.66 mins.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]2[C:6]([NH:7][C:8]3[C:9]([C:18]([OH:20])=[O:19])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=O)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[Al]>CCO.Cl[Hg]Cl>[CH2:1]([C:3]1[CH:16]=[C:15]2[C:6]([N:7]=[C:8]3[C:13](=[CH:14]2)[CH:12]=[CH:11][CH:10]=[C:9]3[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(C(=O)O)cccc3c(=O)c2c1
Agent: Cl[Hg]Cl
Agent: [Al]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ccc2nc3c(C(=O)O)cccc3cc2c1
Yield: 81.7 %

Procedure:
A suspension of the above acridone acid (1.00 g, 3.75 mmol) in 50% aqueous EtOH was stirred and heated, then sufficient triethylamine added to obtain a clear yellow solution. Portions of aluminium foil (0.83 g) were amalgamated in a solution of HgCl2 (3 g) in EtOH, then added to the above vigorously boiling solution over 30 min. After the reaction was observed to be complete by tlc, the reaction mixture was filtered and the solids collected were washed with a solution of KOH in aqueous EtOH. The filtrate was then strongly acidified with concentrated HCl and treated with FeCl3 under reflux for 45 min. The reaction mixture was concentrated under reduced pressure and sufficient potassium acetate added until the pH was neutral. Crystallization of the product occurred upon cooling and filtration and recrystallisation of the resulting brown solid gave 7-ethylacridine-4-carboxylic acid (0.77 g, 82%), mp (acetone) 210-211.5° C. 1H NMR [(CD3)2SO] δ 1.35 (t, J=7.5 Hz, 3 H, CH3), 2.91 (q, J=7.5 Hz, 2 H, CH2), 7.83 (dd, J=8.3, 7.2 Hz, 1 H, H-2), 7.97 (dd, J=9.0. 1.9 Hz, 1 H, H-6), 8.09 (br s, 1 H, H-8), 8.26 (d, J=9.0 Hz, 1 H, H-5), 8.54 (dd, J=8.4, 1.2 Hz, 1 H, H-1), 8.71 (br d, J=7.0 Hz, 1 H, H-3), 9.43 (s, 1 H, H-9), 17.09 (br s, 1 H, COOH). Anal. (C16H13NO2) C, H, N.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:24][C:25]1[C:26]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]>>[Cl:24][C:25]1[C:26]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([O:32][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:31]
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)O)cc2Cl)C1
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)C1

Procedure:
Following the procedure as described in Example 158 step 2 and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acid with 5-chloro-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid, the title compound was obtained as pale yellow oil (3.20 g, 99%): MS (ES−) m/z 316.9 (M−54).