Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1Cc1cccc(C(F)(F)F)c1
Yield: 75.1 %

Procedure:
In the same manner as in Example 51, the title compound (52 mg) was prepared from the compound (50 mg) obtained in Example 50 and 3-trifluoromethylbenzyl chloride (35 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:3]=1.O1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:23]1([O:24][CH2:25][C:26]2[CH:16]=[CH:15][CH:8]=[CH:9][C:10]=2[C:5]2([N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:4][CH:3]=[CH:2][S:6]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:22]1
Reactant: Brc1cnc(N=C(c2ccccc2)c2ccccc2)s1
Reactant: C1COCCO1
Product: C1=CSC(N=C(c2ccccc2)c2ccccc2)(c2ccccc2COC2CCCCC2)N1
Reaction time: 18 h

Procedure:
24 g of tripotassium phosphate trihydrate, 16.7 g of 2-[(cyclohexyloxy)methyl]phenylboronic acid, obtained in step 1.2, and 2 g of tetrakis(triphenylphosphine)palladium(0) are successively introduced into 17 g of 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in step 1.3, in suspension in 250 ml of 1,4-dioxane, and the mixture is kept at 60° C. for 18 hours. The reaction medium is evaporated to dryness, the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a silica gel column, eluting with dichloromethane to give 37.2 g of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12].C[O-].[Na+].O>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1ccccn1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=O)CC(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
In an argon atmosphere at room temperature, 2-acetylpyridine (2.56 g) in methanol (26 mL) was added to dimethyl oxalate (5.00 g) and sodium methoxide (2.29 g) in methanol (26 mL), followed by stirring for 15 minutes. The mixture was stirred at 60° C. for 45 minutes, and then cooled in air. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether. The aqueous layer was partitioned by use of saturated aqueous ammonium chloride and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(2-pyridyl)-2,4-dioxobutanoic acid methyl ester as a solid (3.44 g, 79%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:20]1[C:28]([F:29])=[C:27]2[C:23]([CH2:24][CH2:25][CH:26]2[OH:30])=[C:22]([F:31])[CH:21]=1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:20]4[C:28]([F:29])=[C:27]5[C:23](=[C:22]([F:31])[CH:21]=4)[CH2:24][CH2:25][CH:26]5[OH:30])[C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: OC1CCc2c(F)cc(Br)c(F)c21
Reactant: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1
Product: O=C1[C@H](Oc2ccc(OCC3CC3)nc2)CCN1c1cc(F)c2c(c1F)C(O)CC2

Procedure:
Following Typical Procedure 1 (R)-3-((6-(cyclopropylmethoxy)pyridin-3-yl)oxy)pyrrolidin-2-one was reacted with 6-bromo-4,7-difluoro-2,3-dihydro-1H-inden-1-ol to provide the subtitle compound. MS ESI+: m/z=417 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cccc(C(F)(F)F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3c(C(F)(F)F)cccc23)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a room temperature mixture of 4-[(2-fluoro-3-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.40 g, 3.59 mmol) in THF (20 mL) under nitrogen was added potassium tert-butoxide (3.60 mL of a 1 M THF solution, 3.60 mmol) in one portion and the reaction heated at 60° C. for 1.5 h. After standing at room temperature overnight, the solvent was removed and the residue diluted with ethyl acetate (60 mL). The organics were washed with water (30 mL) and brine (30 mL) successively, dried over magnesium sulfate, filtered, and concentrated to give an amber solid. The crude product was chromatographed on silica using 40% ethyl acetateiheptane as eluent to afford 0.97 g (73%) of the desired product as a white solid, mp:111–113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]=NO)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)[OH:18]>>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[C:9]2[C:10]=1[C:13](=[O:18])[C:12](=[O:16])[NH:11]2
Reactant: O=C(C=NO)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2ccc(C(=O)O)c(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-chloro-4-[(-2-(hydroxyimino)ethanoyl)amino]benzoic acid (300 mg, 1.24 mmol) was dissolved in concentrated sulfuric acid (5 mL). It was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt, poured into ice water and it was extracted twice with ethylacetate. The title compound was obtained as an orange solid (256 mg, 92%) containing 12% of the regioisomer (6-chloro-2,3-dioxoindoline-5-carboxylic acid).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:20]=[O:21])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CCc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 9A) in THF (300 ml) was cooled to −78° C. At this temperature, 63.1 ml (107 mmol) of tert-butyllithium solution (1.7 M in n-pentane) were slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][C:14]1([CH3:21])[NH:17][C:16](=[S:18])[C:15]1([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:6]([S:18][C:16]1[C:15]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[N:17]=1)[CH3:7]
Reactant: CC[O+](CC)CC
Reactant: CC1(C)NC(=S)C1(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCSC1=NC(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.5 ml of triethyloxonium tetrafluoroborate as a 1M solution in CH2Cl2, a solution of 1 g (7 mmol) of tetramethylazetidinethione in 3 ml of dry CH2Cl2 was added under an inert atmosphere. The mixture was stirred at room temperature for 1 hour and then at reflux for 1 hour. After cooling, it was added dropwise to 10 ml of a 50% K2CO3 solution at -10° C. After filtration, the organic phase was separated out and immediately dried over MgSO4. Filtration was followed by removal of the solvent under vacuum and the oily residue was subjected to flash silica chromatography (pet. ether: ethyl acetate; 8:2) to obtain the product as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:7][CH:8]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (190 mg) in dichloromethane (6 ml) was added m-chloroperbenzoic acid (127 mg) under ice cooling. The mixture was stirred at ambient temperature for 30 minutes and diluted with dichloromethane. The solution was washed with an aqueous saturated sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of 2-propanol and ether to give 2-(4-methylsulfinylphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (168 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH3:11][Si:12]([CH2:15]Cl)([CH3:14])[CH3:13]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccccc1CN
Reactant: C[Si](C)(C)CCl
Solvent: CC#N
Product: COc1ccccc1CNC[Si](C)(C)C

Procedure:
A mixture of 2-methoxybenzylamine (25 g, 182.2 mmol) and trimethylsilylmethyl chloride (11.2 g, 91.1 mmol) in acetonitrile (140 ml) was refluxed overnight. Then the mixture was concentrated under vacuum at 70° C. with a rotary evaporator to remove all volatiles. The white residue was mixed with n-heptane (250 ml) and filtered over a glass filter. The salt residue was washed with n-heptane (2×25 ml). The combined heptane filtrates were concentrated under vacuum to give the crude product 2-methoxy-N-[(trimethylsilyl)methyl]benzenemethanamine as a clear oil (21.5 g; >100%) in quantitative yield. The product (92% pure according to GC-MS) was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][CH:8]=2)([O-])=O.C(N(CC)CC)C>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccc(OCCN3CCCC3)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc2ccc(OCCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Nitro-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline (134 mg, 0.46 mmol) was dissolved in EtOAc (10 mL) and the solution was sparged with N2 for several minutes. Triethylamine (0.065 mL, 0.46 mmol) was then added followed by a catalytic amount of 10% Pd/C. Sparging with N2 was repeated after each addition. A balloon of H2 was connected to the reaction flask and the reaction mixture was stirred at room temperature under H2 atmosphere for 48 hours. The mixture was then filtered through a Celite pad and concentrated to obtain crude 3-amino-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline, which was used as is in the next reaction. LC/MS (m/z): 258.1 (MH+), Rt 0.33 minutes.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([C:32]#[N:33])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][C:18]=1[C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: N#Cc1cccnc1-c1cc(B(O)O)ccc1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1cccnc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 71 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (35 mg, 0.15 mmol) was coupled to 4-fluoro-3-(3-cyanopyridin-2-yl)phenylboronic acid (54 mg, 0.22 mmol) as described in Example 7 part g), affording 2-[2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl]nicotinonitrile (42 mg, 71%). δH (360 MHz, CDCl3) 7.44-7.57 (2H, m), 7.62-7.70 (2H, m), 7.75 (1H, dd, J 2.5 and 6.7), 7.87 (1H, d, J 8.8), 8.17 (1H, dd, J 1.8 and 7.7), 8.62 (1H, d, J 8.4), 8.95 (1H, dd, J 1.6 and 4.7), 9.29 (1H, d, J 4.6). m/z (ES+) 395 [MH]+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH:23]S(O)(=O)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)=[O:23]
Reactant: N#CC1=CCSc2ccccc21
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=CC1=CCSc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 g of 4-cyano-2H-1-benzothiopyrane in 2 ml of benzene are reacted with 2 ml of a 20% solution of diisobutylaluminium hydride in toluene and the mixture stirred for 4 hours at room temperature. The resulting mixture is poured onto 20% H2SO4 and the organic phase separated, washed with saturated aqueous NaCl and dried over MgSO4. After concentration by evaporation the product is purified by chromatography over kieselgel (eluant hexane/ethyl acetate).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][C:13]=3[O:12][CH:11]([CH3:34])[C:10]=12)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:15]1[CH:16]=[CH:17][C:18]2[C:9]3[C:10](=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=[CH:7][CH:8]=3)[CH:11]([CH3:34])[O:12][C:13]=2[CH:14]=1
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Reaction time: 12 h
Yield: 88.1 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.15 g, 0.319 mmol) in dichloromethane (25 mL) at room temperature was added TFA (0.246 mL, 3.19 mmol) and the mixture stirred for 12 h. After completion of reaction, the solvent was removed under reduced pressure to afford N-(8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (0.18 g, 0.281 mmol, 58% yield) as a brown oil. The product was carried forward into the next step without further purification. LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H28N3O3 370.2]; LC/MS retention time (Method C): tR=1.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a pale yellow solid (128 mg, 53.6%)
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH:14]([CH2:16][CH3:17])[CH3:15].[Li+].[OH-]>C1COCC1.CO>[CH:14]([O:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:18])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Oc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)Oc1cc(F)ccc1C=CC(=O)O
Yield: 82.7 %

Procedure:
3-(2-sec-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (105 mg) was reacted with 1N LiOH (5 ml) in THF and CH3OH for 2 hrs as described above to yield title compound (82 mg)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([Cl:14])=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:12]([Cl:14])[C:11]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[Cl:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClC(=Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromoaniline (40 mg, 0.12 mmol) and 2,4-dichloro benzoyl chloride (69 μL, 0.12 mmol) in dichloromethane is added triethylamine (20 μL, 0.144 mmol). After stirred at room temperature for 30 min, the solvent is removed. The residue is added 0.5 mL of thionyl chloride. The reaction mixture is heated at 80° C. for 1h, concentrated. The product is used in the next step reaction.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Si]([I:28])(C)(C)C.II>C(Cl)Cl>[I:28][N:6]1[C:7](=[O:16])[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: C[Si](C)(C)I
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) were stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([C:24]2[CH:25]=[C:26]([C:30]([F:34])([F:33])[C:31]#[N:32])[CH:27]=[CH:28][CH:29]=2)[CH:17]=1>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:34])([F:33])[C:31]3[NH:32][N:3]=[N:2][N:1]=3)[CH:25]=2)[N:19]=[C:20]([O:22][CH3:23])[N:21]=1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C#N)c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)c3nnn[nH]3)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Sodium azide (10 mg, 0.15 mmol) is added to a stirred solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetonitrile (50 mg, 0.11 mmol) in N,N′-dimethylformamide (4 mL) and the reaction is stirred for 4 hours at 80° C. The reaction is quenched with water, acidified to pH 2 (0.05 N HCl), extracted twice with ethyl acetate. The combined extracts is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is diluted in toluene and concentrated in vacuo to afford [2-(2,4-dichloro-phenyl)-ethyl]-(6-{3-[difluoro-(1H-tetrazol-5-yl)-methyl]-phenyl}-2-methoxy-pyrimidin-4-yl)-amine [45 mg, Example 82(c)]. LCMS: RT=2.29 minutes, LCMS: 492, 494 (M+H). IC50=0.1 nM
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH3:11])[C:7]=2[CH:12]=1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:23]1([C:21]([C:9]2[N:8]([CH3:11])[C:7]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:10]=2)=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncn(C)c2c1
Reactant: CON(C)C(=O)C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2nc(C(=O)C3CCCCC3)n(C)c2c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution (100 mL) of 6-methoxy-1-methyl-1H-benzoimidazole (4.07 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added a 1.6M solution (30.1 mL) of n-butyllithium in hexane at −78° C., and the mixture was stirred under nitrogen atmosphere for 30 min. A solution (50 mL) of N-methoxy-N-methylcyclohexanecarboxamide (5.15 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added, and the mixture was stirred at −78° C. for 1 hr and at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5, volume ratio) to give the title object compound (5.80 g, 85%) as white crystals.
Reaction SMILES: [C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=O.[C:20](Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:20]
Reactant: O=C(O)c1cccc2c1CCc1ccccc1C2=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)c1cccc2c1CCc1ccccc1C2=O

Procedure:
25 g. of 1-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 250 ml. of benzene are heated with 20 g. of oxalyl chloride for 2 hours at reflux and subsequently concentrated under reduced pressure. The resulting crystalline 1-chlorocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is dissolved in 200 ml. of benzene and then it is added dropwise to a solution of the magnesium salt of diethyl malonate (about 50 g. in 500 ml. of ether) over a period of about 5 minutes and heated at reflux for 12 hours. Subsequently, the reaction mixture is divided between ether and dilute sulfuric acid, washed with water, sodium bicarbonate solution and water, dried and evaporated. The residue is heated in 30 ml. of ethyl acetate, 20 ml. of water and 3.7 ml. of concentrated sulfuric acid at reflux for 15 hours. Then, it is poured over ice water and extracted with ether. The ethereal extract is washed with water, sodium bicarbonate solution and water, dried and evaporated, whereby 1-acetyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one having a melting point of 65°-68°C. is obtained.