Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].C([Li])CCC.CCCCCC.[C:24](=[O:26])=[O:25]>O1CCCC1.O>[CH3:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Cc1c(Br)ccc2c1OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 300 ml of dry tetrahydrofuran, was dissolved 32.0 g of 6-bromo-5-methyl-1,4-benzodioxane and after cooling the solution to -78° C., 96.7 ml of n-butyl lithium (n-hexane solution)was added dropwise over 20 minutes or more. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured onto crushed dry ice and dry ice was sublimated while stirring. Water was added to the -mixture and the tetrahydrofuran was removed under reduced pressure. The resulting alkaline aqueous solution was washed with methylene chloride and adjusted to pH 3 with a 5% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 20.9 g of 5-methyl-1,4-benzodioxan-6-carboxylic acid (yield: 77%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[N:24]=2)[C:13]1=[O:35].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:25]1(=[O:33])[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[NH:28][C:23]([C:14]2[C:13](=[O:35])[N:12]([NH:11][CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[C:21]3[C:16]([C:15]=2[OH:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:24]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCc2ccccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 247A (0.070 g, 0.14 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.110 mL, 0.22 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.73 (s, 2 H) 3.27 (d, J=12.50 Hz, 4 H) 5.93 (d, J=3.68 Hz, 1 H) 7.07 (m, 6 H) 7.28 (t, J=7.54 Hz, 3 H) 7.55 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 8.07 (dd, J=7.72, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 485 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: ClCCCCCCl
Reactant: CCOC(=O)Cc1cccs1
Product: CCOC(=O)C1(c2cccs2)CCCCC1

Procedure:
The dialkylation of (1) was performed as described in Example 1, Step 1 using 1,5-dichloropentane to obtain the title compound (15).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1>C(#N)C.CCOC(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][OH:4])[CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1
Reactant: OCCBr
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 4 h
Yield: 7.3 %

Procedure:
2-Bromoethanol (18 mg, 0.14 mmol) was added to stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (50 mg, 0.12 mmol) (Example-32) in acetonitrile (0.5 mL) and stirring was continued at 70° C. for 4 h. The reaction mixture was diluted with EtOAc, washed the organic layer with water and dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford the crude product, which was purified by Preparative HPLC [Column:21.2×150×5 um, waters× bridge C-18, Mobile phase-A: 0.1% TFA in water, B:ACN, Gradient (Time/% B): 0/20, 2/30, 1870 and Flow rate:20 mL/min] to afford 4.1 mg of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35]CC#N)[CH:30]1[CH2:39][OH:40].Cl>O1CCCC1>[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH:30]1[CH2:39][OH:40]
Reactant: CC1CC(C)N(CCC#N)C1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cccc2c(=O)[nH]c(CCN3C(C)CC(C)C3CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Diisopropylamine (3.3 g) was dissolved in tetrahydrofuran (20 mL) and n-butyllithium (1.58M, hexane solution, 19 mL) was is added dropwise under a nitrogen stream at −78° C. After the completion of the dropwise addition, a solution (20 mL) of N,N-diethyl-2,3-dimethylbenzamide (5.2 g) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 hr. A solution (20 mL) of 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g) in tetrahydrofuran was added dropwise to the reaction mixture and the temperature of the reaction mixture was raised to room temperature. After the completion of the reaction, the reaction mixture was acidified by adding conc. hydrochloric acid. The reaction mixture was concentrated and washed with hexane. The aqueous layer was basified by adding potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography The fraction eluted with chloroform:methanol=30:1 was concentrated and the obtained residue was again purified by silica gel column chromatography (NH silica gel, Fuji Silysia Chemical). The fraction eluted with chloroform was concentrated and ether was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-[2-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.5 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)C(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound from EXAMPLE 2 in CH2Cl2 was added isobutyric chloride, triethylamine and a catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hr. The solvent was removed and the residue was heated with 10 mL 2 N NaOH in 40 mL methanol at 50° C. for 1 hr. Methanol was removed under vacuum. The residue was diluted with water and the aqueous was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent was removed. The residue was purified by preparative TLC (80:20 EtOAc:hexane), 0.07 mg. M++1: 558.16.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:37])[N:36]=1.[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:34]2[S:33][C:32]([CH3:31])=[N:36][C:35]=2[CH3:37])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3sc(C)nc3C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
A solution of tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191; 100 mg; 0.20 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (73 mg; 0.30 mmol) was placed in a microwave vial and treated with caesium fluoride (93 mg; 0.61 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg; 0.02 mmol). The tube was sealed and degased with N2 before adding dioxane (2 ml) and water (1 ml). The resulting reaction mixture was irradiated in a microwave reactor at 120° C. for 10 minutes. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as a brown sticky solid (78 mg, 73%).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O:22][C:23](=[O:36])[C@@H:24]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[CH2:25][C:26](O)=[O:27])(C)(C)C.C(O)(=O)CCC=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([S:17][C:26](=[O:27])[CH2:25][C@H:24]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]([OH:36])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: C=CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
DIC (N,N′-diisopropylcarbodiimide) (2.41 ml, 15.5 mmol), DMAP (N,N-dimethylaminopyridine) (315 mg, 2.58 mmol) and phenylmethanethiol (1.82 ml, 15.5 mmol) were added to a solution of the mixed crude product A (2.51 g, 12.9 mmol) of (S)-4-(tert-butoxy)-4-oxo-3-(pent-4-enamido)butanoic acid (Compound 1b-I) and pent-4-enoic acid (1:0.8) in CH2Cl2 (35 ml), and the mixture was stirred at room temperature for 4 hours. TFA (21 ml) was then added to the reaction mixture, which was stirred at room temperature for 9.5 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=80/20→40/60) to afford (S)-4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-ID) (1.65 g, 74%).
Reaction SMILES: ClS(O)(=O)=O.[CH3:6][O:7][C:8](=[O:26])[N:9]([CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH2:15][CH:16]=[CH2:17])[CH2:10]OCC.[OH-].[Na+].C(=O)([O-])[OH:30].[Na+].[C:34](#[N:36])[CH3:35]>>[CH3:6][O:7][C:8]([N:9]1[CH2:10][CH2:17][C@H:16]([NH:36][C:34](=[O:30])[CH3:35])[CH2:15][C@H:14]1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[O:26]
Reactant: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)OC
Reactant: CC#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N1CC[C@H](NC(C)=O)C[C@H]1Cc1ccc(Cl)cc1

Procedure:
At -40° C., 20.6 ml (308 mmol) of chlorosulfonic acid are introduced into 500 ml of acetonitrile. A solution of 48.0 g (154 mmol) of N-[1-(4-chloro-benzyl)-but-3-enyl]-N-ethoxymethyl-carbamic acid methyl ester in 50 ml of acetonitrile is added dropwise in such a manner that the reaction temperature does not exceed -10° C. The mixture is then stirred for 20 minutes at -15° C. before 370 ml of 2 N sodium hydroxide solution and 100 ml of 10% aqueous sodium hydrogen carbonate solution are added to the reaction. The phases are separated and the aqueous phase is then extracted twice with toluene. The combined organic phases are dried over sodium sulfate. The crude product is crystallised from toluene and yields the title compound in the form of white crystals. M.p.: 169-170° C. TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.42, FD-MS: M+ =325.
Reaction SMILES: C/[C:2](=[CH:6]\[C:7]1[S:8][CH:9]=[C:10](Br)[CH:11]=1)/[C:3]([OH:5])=[O:4].B([O-])([O-])O[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[C:24](=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[C:7](/[CH:6]=[CH:2]/[C:3]([O:5][CH3:24])=[O:4])[S:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: C/C(=C\c1cc(Br)cs1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1cc(-c2ccc(C)cc2)cs1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Under argon atmosphere, a solution of methyl (E)-3-(4-bromothiophen-2-yl)acrylic acid (3.0 g), 4-methylphenyl borate (1.82 g) and potassium carbonate (3.36 g) in toluene-ethanol-water (120-12-12 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.42 g), and the mixture was refluxed for 24 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5→1:2) to give methyl (E)-3-[4-(4-methylphenyl)thiophen-2-yl)acrylate (2.40 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[C:23](=O)[CH2:24][CH2:25][CH2:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C([O:32]CC)C>>[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH2:23][CH2:24][C:25]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)([OH:32])[CH2:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Reactant: CCOCC
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(OC)cc3)CC2)CC1

Procedure:
A solution of 5.8 g of 4-bromoanisole in 30 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for one hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-(4-methoxyphenyl)-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: OC1CCOCC1
Reactant: Cc1cc(Br)cnc1O
Product: Cc1cc(Br)cnc1OC1CCOCC1

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-3-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([Br:28])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[CH3:29][O:30][C:31]([NH:33][CH:34]([CH:38]([CH3:40])[CH3:39])C(O)=O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:32])[NH:33][CH:34]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([Br:28])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:5])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 142.2 %

Procedure:
2-[5-(4-Bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.80 g), 2-methoxycarbonylamino-3-methyl-butyric acid (2.57 g), and HATU (5.88 g) were dissolved in anhydrous DMF (85 mL), and N-methylmorpholine (2.86 mL) was added. The reaction mixture was stirred at ambient temperature for 22 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-50% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(4-bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (6.10 g, crude) as a tan solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:24])=[C:21]([F:28])[CH:20]=1
Reactant: COC(=O)C(C)N
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)NC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
N,N-Diisopropylethylamine (2.0 mL, 0.011 mol) was added to a mixture of methyl 2-aminopropanoate hydrochloride (0.64 g, 0.0046 mol), 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.12 g, 0.00479 mol) in N,N-dimethylformamide (10.0 mL, 0.129 mol). The reaction mixture was stirred overnight at RT, quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 60% EtOAc in hexanes to afford the desired product (1.33 g, 96%). LCMS: (M+H)=303.9/305.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:44][CH:45]=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1C=CC=CC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:47]=[CH:44][CH:45]=[O:46])=[CH:19][CH:20]=1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A solution of 3,3-bis (4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal (1.0 g, 3.07 mmoles) and triphenylphosphoranylidene acetaldehyde (0.93 g, 3.07 mmoles) in benzene was heated at reflux for 1 hour. The benzene was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 15% (v/v) ethyl acetate in hexane to give 0.7 g of the title compound; m.p.156°-157.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=1[O:39][CH3:40]>>[CH3:40][O:39][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][C:24]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1)[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared according to the procedure described for Example 48 using (2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide and diethyl (4-amino-3-methoxybenzyl)phosphonate. 1H NMR (CD3OD, 400 MHz): δ=1.27 (t, J=7.07 Hz, 6H), 2.90 (s, 3 H), 3.20-3.28 (m, 2 H), 3.91 (s, 3 H), 4.01-4.11 (m, 4 H), 6.80 (dt, J=8.21, 2.21 Hz, 1 H), 6.99 (t, J=2.15 Hz, 1 H), 7.19 (td, J=7.58, 1.26 Hz, 1 H), 7.48 (ddd, J=8.46, 7.20, 1.52 Hz, 1 H), 7.64 (dd, J=7.83, 1.52 Hz, 1 H), 7.96 (d, J=8.08 Hz, 1 H), 8.30-8.36 (m, 2H). MS (ES+): m/z 568.1542 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].C1C2C=CC3C(=CC=C4C=3C=CC=C4)C=2C=C(C=O)C=1.NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]2[CH:27]=[CH:26][C:25]3[C:24]([C:15]=2[CH:14]=1)=[CH:23][CH:22]=[C:21]1[C:16]=3[CH:17]=[CH:18][CH:19]=[CH:20]1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CC(N)(CO)CO
Agent: O=Cc1ccc2ccc3c4ccccc4ccc3c2c1
Product: CC(CO)(COS(C)(=O)=O)NCc1ccc2ccc3c4ccccc4ccc3c2c1

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-3-carbaldehyde (19G) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((3-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 180°-182° (dec), (EtOH/Et2O), (C,H,N,S).