Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:23]([C:17]1[CH:18]=[CH:19][C:20]([O:22][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:21][C:16]=1[OH:15])(=[O:24])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)c2ccccc2)c(O)c1
Yield: 58 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (46.10 g), (2,4-dihydroxyphenyl)(phenyl)methanone (50.14 g), potassium carbonate (48.51 g) and acetone (700 mL) was heated under reflux for 20 hrs. The reaction mixture was concentrated, water was poured into the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(4-benzoyl-3-hydroxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole as colorless crystals (49.6 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[C:17](=[O:22])N(OC)C)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:44][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:39]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[C:17](=[O:22])[CH3:44])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Mg]Br
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(C)=O
Reaction time: 6 h

Procedure:
To a solution of 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (0.1 g, 0.162 mmol) in anhydrous THF (2 mL) was added methyl magnesium bromide [0.35 ml, 1.4M solution in Toluene/THF (75:25)] at 0° C. and allowed to come to room temperature and stirred for 6 h. Reaction was quenched with aq NH4Cl and extracted with EtOAc. Organic layer was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by silicagel column chromatography to get pure 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide (0.055 g)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:19]([O:21][CH2:22][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:24][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][O:21][C:19](=[O:20])[C@H:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:13])=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Chloromethyl chloroformate (2.70 mL, 30 mmol) was added to a solution of 1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (7.27 g, 14.8 mmol) and pyridine (7.2 mL, 89 mmol) in 60 mL dry CH2Cl2, in an ice bath, under N2. After stirring for 1 h 45 min, the reaction mixture was diluted with 100 mL CH2Cl2 and washed with 40 mL water. The aqueous phase was reextracted with 20 mL H2O. The organic phases were combined, washed with 40 mL saturated NaHCO3, followed by 2×50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography on silica gel with 2/1 hexane-EtOAc gave 8.03 g (93%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl chloromethyl carbonate).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].[Al+3].[H-].[H-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 118.4 %

Procedure:
A 750-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet, cooled with a CO2/acetone bath, was charged with a solution of 49.15 g of crude methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (ca. 0.16 mol) and 90 ml of toluene and stirred. 400 ml of dusobutyl aluminiumhydride 1.2 M in toluene were added under argon at ca. −20 to −25° C. during 60 min. After additional 15 mi a solution of 191 g of citric acid monohydrate in 400 ml of deionized water was added with cooling during 30 min, so that the temperature did not exceed 5-10° C. The aqueous phase of the clear biphasic mixture was extracted with 200 ml of toluene. The combined organic phases were washed twice with 40 ml, a total of 80 ml of deionized water, twice with 40 ml, a total of 80 ml of brine and dried (Na2SO4). Rotary evaporation (50° C., 8 mbar, 1 h) afforded 38.5 g of crude 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (theor. amount 32.4 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:3]1.Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:8][CH:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH2:5]1
Reactant: CC1CC(C)CN(Cc2cccc(OCCCN)c2)C1
Reactant: Nc1nnc(Br)s1
Product: CC1CC(C)CN(Cc2cccc(OCCCNc3nnc(N)s3)c2)C1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(3,5-dimethyl-1-piperidinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)[CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:30][C:23]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:29][CH:21]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:11]=3)[CH2:22]1)[CH2:24]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCCC2CCOCC2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCCC2CCOCC2)c1

Procedure:
Prepared from 3-(tetrahydro-pyran-4-ylethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 400 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[BH-](O[C:31]([CH3:33])=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:8][C@@H:7]([C:31]2[CH:33]=[CH:12][CH:11]=[CH:4][CH:3]=2)[CH3:6])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: COc1ncc(C=O)cc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ncc(CN[C@H](C)c2ccccc2)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
R-α-Methyl benzylamine (0.12 mL, 0.928 mmol) and 6-methoxy-5-(4-(trifluoromethyl)phenyl)-3-pyridinecarbaldehyde (0.261 g, 0.928 mmol) were dissolved in 3.0 mL of 1,2-dichloroethane in a 10 mL round bottom flask. The solution was allowed to stir at 25° C. for 1 h, at which point NaBH(OAc)3 (0.295 g, 1.39 mmol) was added in one portion. The reaction was then stirred for 16 h at 25° C. The reaction was quenched by adding 5N NaOH (1.5 mL) and stirring vigorously for 30 min. The layers were separated and the aqueous layer was washed with DCM (3×2.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give crude product, which was then purified by silica gel chromatography (1:1 hexane-EtOAc) to afford (1R)—N-((6-methoxy-5-(4-(trifluoromethyl)phenyl)-3-pyridinyl)methyl)-1-phenylethanamine 1. MS m/z: 387 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in THF (10 mL) was added excess methylamine (2M solution in THF). The reaction solution was stirred at room temperature for 1 hr. Water was then added and the product was extracted into chloroform. The combined extracts were washed, dried over sodium sulfate, filtered and evaporation to yield 2.3 g of the crude 4-chloro-N-methyl-3-nitrobenzenesulfonamide as an oil. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:21]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[C:15]([OH:21])=[O:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: CCC[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentan-1-ol (37.1 g, 109 mmol in dry acetonitrile (500 mL) at −78° C. was added a solution of periodic acid (71.7 g) and chromium trioxide (144 mg) in dry acetonitrile (630 mL) over 1 hour. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was concentrated under reduced pressure to a total volume of approximately 500 mL. A solution of citric acid (22 g in 250 mL H2O) was added and the mixture was extracted with ethyl acetate (800 mL). The solution was washed with freshly prepared NaHSO3 (2×200 mL, 25 g solid dissolved to 200 mL with water) brine (300 mL), dried over MgSO4, filtered, and evaporated to give a pale orange solid, which was triturated with 5% ethyl acetate/hexanes to give (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid. Additional acid was obtained by concentrating the mother liquors, partitioning the residue between ether and aqueous NaHCO3, acidifying the aqueous layer with citric acid, extracting with ethyl acetate, drying over MgSO4, filtering, and evaporating the solvent.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:13]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Temperature: 77.5 °C
Yield: 25.1 %

Procedure:
To a mixture of the amidine of step 1 (4.75 g, 16 mmol) and sodium bicarbonate (2.86 g, 34.4 mmol) in isopropanol (400 ml), 3-bromo-1,1,1-trifluoroacetone (2.7 ml, 26 mmol) was added. After heating at 75-80° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude product (16.2 g) was purified by chromatography (silica gel, ethyl acetate/isopropanol (95/5)) to give 4-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.55 g, 23%) as a white solid: mp 219° C., Anal. Calc'd. for C16H14N3SO3F3 C, 49.87, H, 3.66, N, 10.90, S, 8.32. Found: C. 49.93, H, 3.51, N, 10.79, S, 8.66.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a suspension of Intermediate 71a (2.28 g, 9.49 mmol) in EtOAc (25 mL) and aqueous NaOH (1M, 23.7 mL, 23.7 mmol) was added 2,2,2-trichloroethyl chloroformate (1.57 mL, 11.4 mmol) dropwise over 2 min. A precipitate formed which redissolved after 15 min, then the orange solution was stirred at RT for 90 min. 2,2,2-Trichloroethyl chloroformate (0.391 mL, 2.85 mmol) was added and the orange mixture stirred at RT for 16h. The layers were separated and the aqueous extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange-red oil. Recrystallisation from cyclohexane gave an off-white solid (3.12 g, 79%). LCMS (Method 3): Rt 4.46 min, m/z 415, 417 [MH+].
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@:13]12[CH2:14][C@H:15]([CH3:18])[C@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CNC[C@H]12

Procedure:
(1R,5S,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.89 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([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)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(O)(=O)C>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([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)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
In a 1 liter round-bottom flask, triphenylmethanol (26.0 grams, 0.100 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) and aniline (14.6 milliliters, 0.160 mol) were added to a solution of concentrated aqueous hydrochloric acid (47 milliliters) in acetic acid (312 milliliters). The resulting solution was stirred and heated at reflux for 48 hours. The yellow solution was then cooled to room temperature and solvents were removed by evaporation under reduced pressure. Ethanol (700 milliliters) was added to dissolve all the off-white solid residue, and the stirred solution was cooled to −10° C. Sulfuric acid (52 milliliters) was then added, and the cold mixture was stirred for 20 minutes. Isopentylnitrite (31.2 milliliters; obtained from Aldrich Chemical Co.) was then added and the solution was stirred for an additional 20 minutes. Thereafter, hypophosphorous acid (89 milliliters, 50 percent by weight aqueous solution; obtained from Aldrich Chemical Co.) was added, still at −10° C., and the solution was gradually heated to reflux and stirred for 2 hours. The mixture was then cooled to room temperature, giving an off-white precipitate, which was recovered by filtration, successively washed with water, hexanes, methanol, ethanol, methanol, and finally with pentane, and dried under reduced pressure to give the targeted tetraphenylmethane as a colorless solid (28.0 grams, 90 percent yield).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[C:13]([CH3:34])[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[C:13]([CH3:34])[CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(C#N)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1C#N)C(C(=O)O)CCO2
Reaction time: 48 h
Yield: 32.6 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate (0.0063 g, 0.0125 mmol) was taken up in 0.5 ml THF and treated with aqueous 1.0 molar LiOH (0.0250 ml, 0.0250 mmol) at ambient temperature. After 48 hours, the reaction was neutralized with acetic acid and concentrated in vacuo. Purification of the crude material by preparative thin layer chromatography using 5% MeOH/DCM with 1% HOAc as the mobile phase provided the title compound (2 mg, 38%). MS (apci) m/z=491.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)C=CC=CC=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][N:15]([C:27]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CCNC2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc2c(s1)CCN(C(=O)Nc1cccnc1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (1.0 eq) obtained in step VIII in DMF was treated with Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq) in presence of base like Et3N and stirred at 50° C. for 8 h Reaction was then quenched with water and extracted with ethyl acetate and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([NH2:15])=[CH:7][CH:6]=1.[N:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=2)[CH:20]=1>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:13])([F:14])[F:12])=[CH:9][C:8]([NH:15][C:35](=[O:36])[CH2:34][C:31]2[CH:30]=[CH:29][C:28]([N:21]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:27]4[N:19]=[CH:20]3)=[CH:33][CH:32]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 but using 3′-bromo-2-trifluoromethyl-biphen-4-ylamine and (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid. Title compound: ES-MS: 552.8 [M+H]+; tR=5.24 min (System 1); Rf=0.20 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C:10]3=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([C:7]2[N:8]=[C:9]3[CH2:16][CH2:15][NH:14][CH2:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)N1CCc2nc(N3CCOCC3)cnc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1nc2c(nc1N1CCOCC1)CCNC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 2-morpholin-4-yl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate (105 mg, 0.359 mmol) is dissolved in MeOH (5 mL) and H2O (5 mL). KOH (1.00 g, 17.9 mmol) is added, and the reaction mixture is stirred overnight at 50° C. The mixture is cooled and partitioned between brine (50 mL) and DCM (50 mL). The mixture is extracted with DCM (2×50 mL). The combined organic extracts are dried and evaporated to yield the title compound. MS (+VE) m/z 221.21 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:20])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](C#Cc1ccc(Cc2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.6 g (5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsily)-ethynyl]-phenyl}-methanol and 4.1 ml triethylsilane in 50 ml dichloromethane is cooled in an ice bath. Then 4.7 ml trifluoroacetic acid are slowly added dropwise, and the solution is stirred for 4 h at ambient temperature. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulphate the solvent is removed and the residue is purified using silica gel (cyclohexane).