Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[N:12]=1)[CH2:5][OH:6].C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([N:7]3[C@H:4]([C:3]([O:2][CH3:1])=[O:20])[CH2:5][O:6][C:29]3=[O:31])[S:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
2-[4-(4-Bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 3.08 mmol), prepared in the previous step, was dissolved in 40 mL of methylene chloride and triethylamine (4.3 mL, 30.8 mmol) was added. The mixture was cooled to 0° C. and triphosgene (2.3 g, 7.7 mmol) was added. The mixture was stirred for 1 h and then diluted with methylene chloride, washed with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 15% acetone/hexane) afforded the title compound (510 mg, 44%) as a white solid. mp 165-167° C. HRMS: calcd for C14H, BrN2O4S+H+, 382.96956; found (ESI, [M+H]+), 382.9718. Analytical HPLC: retention time 9.9 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([F:40])[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>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>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:6][CH:7]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cc(F)cc(F)c4)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d of Example 1D above (0.2 g), 3,5-difluorophenyl boronic acid (0.135 g), tetrakistriphenylphosphinepalladium (0) (0.023 g), and potassium carbonate (0.2 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (3 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.205 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (100 mg, 0.30 mmol) from Step C in THF (4 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.22 mL, 0.36 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.060 mL, 60 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 409 (M+1), 411 (M+3); Rt=4.19 min.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:18][C:19]1[C:24](O)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].C1CCC(N=C=NC2CCCCC2)CC1.O>CN(C=O)C>[F:18][C:19]1[C:24]([O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A mixture of N-Cbz-L-serine (Novabiochem) (100 g, 0.42 mol) and pentafluorophenol (Aldrich) (84.7 g, 0.46 mol) in anhydrous DMF (250 ml) are cooled with stirring under N2 to -10° C. To this solution, a solution of DCC (95.0 g, 0.46 mol) in anhydrous DMF (125 ml) is added over 30 min while keeping the reaction temperature at -10° C. The reaction mixture is stirred at -10° to -5° C. for an additional 30 min and then at room temperature for 3 hours. The reaction mixture is poured into water (3.76 1). After stirring for 15 min, the solid that precipitated out is filtered, washed over the filter with water (3×500 ml) and air dried at room temperature. The solid is then taken up in EtOAc (1 l) and the residual solid (mainly dicyclohexylurea) is filtered off and washed with more EtOAc (3×150 ml). The combined EtOAc solutions are evaporated to dryness under reduced pressure. The residual solid is dissolved in hot CH2Cl2 (3.2 l). The hot solution is gravity filtered and the solvent is boiled off until solid began to crystallize. The solid which crystallized is filtered and air dried to ambient temperature to give N-Cbz-L-serine pentafluorophenyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([N:39]=[N+:40]=[N-:41])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)N=[N+]=[N-])c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.38 g, 0.99 mmol) and TEA (0.414 mL, 2.97 mmol) in anhydrous THF (15 mL) was added diphenylphosphoryl azide (0.341 mL, 1.58 mmol) in one portion, under nitrogen. The reaction mixture was allowed to stir at rt overnight, and was concentrated. The residue was purified by column chromatography to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carbonyl azide (0.318 g, 79%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1>>[C:20]1(/[C:17](/[CH2:18][CH3:19])=[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)\[C:13]2[CH:14]=[N:15][C:10]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCCN1CCCC1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCCC2)nc1)c1ccccc1
Yield: 113.4 %

Procedure:
Following the same procedure as described in example 3, 2-(pyrrolidin-1-yl)ethanol (343 mg, 10 eq) and (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) were used as starting material to get the desired product (140 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.15-7.20 (m, 2H), 7.01-7.13 (m, 6H), 6.92 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.68 (brs, 1H), 4.26 (bs, 2H), 2.91 (brs, 2H), 2.72 (brs, 4H), 2.50 (q, J=7.2 Hz, 2H), 1.89 (brs, 4H), 0.91 (t, J=7.6 Hz, 3H); m/z=415 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18]1[CH2:22][O:21][CH2:20]C1>>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:22]3[CH2:20][O:21]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: C1CCOC1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
At rt a solution of 3,6-dibromo-9H-carbazole (5.23 g, 16.10 mmol) in anhydrous THF (200 mL) is treated with NaH (0.703 g, 16.10 mmol, 55% in mineral oil) and a solution of (±)-3-nitro-benzene sulfonic acid oxiranyl methyl ester (4.17 g, 16.10 mmol) in anhydrous THF (30 mL). After 16 hours of stirring at rt the reaction mixture is quenched with a saturated aqueous solution of sodium hydrogenocarbonate (200 mL). Extraction with Et2O (500 mL+2×250 mL), drying over MgSO4 and evaporation under reduced pressure gives a yellow solid. Flash chromatography on a 7×27 cm2 column of SiO2 using DCM/Petroleum Ether (1/1) gives the title compound (3.65 g, 9.58 mmol) as a white solid in a 59% yield.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8]1.CI>CN(C)C=O>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([O:20][CH3:1])=[O:19])=[CH:8]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
36.2 g of powdered potassium carbonate was added, with ice-cooling, to a solution of 24.8 g of 3-(indol-3-yl)propionic acid in 500 ml of N,N-dimethylformamide, followed by the addition of a solution of 10.2 ml methyl iodide in 50 ml of N,N-dimethylformamide. The reaction mixture was then warmed to room temperature and stirred for 3 hours. After this time, ice water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic extract was then washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 500 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 25.8 g of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@:14]([OH:20])([C@H:17]([OH:19])[CH3:18])[CH2:15][OH:16].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@:14]([OH:20])([C@H:17]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:18])[CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C[C@@H](O)[C@](O)(CO)c1cccc(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(COS(C)(=O)=O)c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
5.71 g (50 mmol) of methanesulfonyl chloride were added to a solution of 3.51 g (16.1 mmol) of (2R,3 R)-2-(2,3-difluorophenyl)-1,2,3-butanetriol [obtained as described in Step 7(ii) above] in 18 ml of pyridine at 0° C. After stirring the resulting mixture for 0.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and then washed with aqueous sodium chloride solution and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel (100 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to afford 5.04g (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5](OC)=[O:6])=[O:3].[NH3:11]>CO>[CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5]([NH2:11])=[O:6])=[O:3]
Reactant: N
Reactant: COC(=O)C(O)P(C)(C)=O
Solvent: CO
Product: CP(C)(=O)C(O)C(N)=O
Reaction time: 144 h
Yield: 82.2 %

Procedure:
16.6 g (0.1 mol) of methyl 2-(dimethylphosphinoyl)-2-hydroxyacetate are dissolved in 70 ml of methanol, which has first been gassed with NH3 gas for 10 minutes. After the mixture has been left to stand in a bomb tube at 25° for six days, it is filtered and concentrated and the oily residue is digested with ethyl acetate. 12.4 g (82.2%) of the amide of melting point 155° are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]2[C:16](=[CH:15][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:13])([F:12])[F:1])[C:17]3[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=3[CH2:19][CH2:20][C:21]=2[CH:26]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2cc(Cl)ccc21
Yield: 90 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 2-(trifluoromethyl)phenylboronic acid (59 mg, 0.31 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (91 mg, 0.28 mmol) provides 97 mg (90%) title compound. GC/MS data: retention times in minutes (MS data for M+.ion): 18.19 (384), 18.38(384)Mass Spec (EI+) 384
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17](O)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>O1CCCC1>[N:41]1[CH:42]=[CH:43][C:38]([NH:37][C:17](=[O:18])[CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[CH:8]=2)=[CH:39][CH:40]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(Cc1cn(Cc2ccc(F)cc2)c2ccccc12)Nc1ccncc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
3.5 g (12.3 mMol) [1-(4-fluorobenzyl)indole-3-yl]acetic acid are dissolved in 100 ml anhydrous tetrahydrofuran. To this solution are added 2.54 g (12.3 mMol) dicyclohexylcarbodiimide and 1.16 g (12.3 mMol) 4-aminopyridine. After stirring for 24 hours at 0° C., the formed dicyclohexyl urea is separated off. After mixing in the solvent, the residue is purified by column chromatography on silica gel. Eluting agent:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]#[N:13])[CH2:3][CH2:2]1>C(O)C.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: N#CC=C1CCOc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: N#CCC1CCOc2ccccc21
Reaction time: 12 h

Procedure:
The unsaturated compound obtained in Step A (Z+E mixture), solubilised in ethanol (20 ml), is introduced into the reactor of a Parr apparatus. 10% (by weight) palladium-on-carbon is then added. The double bond is hydrogenated at a pressure of 45 psi for 12 hours. The catalyst is removed by filtration; the solvent is then evaporated. The residual oil is purified on a silica column eluted by a mixture of AcOEt/PE 3/7. Colourless oil.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[N:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 65 °C
Reaction time: 16 h
Yield: 16.9 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (0.530 g, 2.35 mmol,) in acetonitrile (25 mL) was added 5-chloro-2-nitro-pyridine (0.561 g, 3.53 mmol,) and powdered potassium carbonate (1.30 g, 9.40 mmol). The reaction mixture was then heated to 65° C. for 4.0 hr, then at 45° C. for 16 hr. The reaction mixture was then allowed to cool to room temperature and filtered through a 10.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 50 mL of (1:1) methanol in dichloromethane, 25 mL of methanol, followed by 7N ammonia in methanol (50 mL). The filtrate was concentrated under vacuum to obtain a compound which was purified again by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) to afford 0.110 g (17%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (62 mg, 55%). LCMS: 542.20 (M+H), HPLC purity: 100%, MP: 202-204. 1H-NMR (CDCl3, 400 MHz) δ 10.34 (s, 1H), 8.42 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.55-7.49 (m, 2H), 7.43-7.34 (m, 2H), 7.28-7.27 (m, 2H), 3.66-3.63 (m, 2H), 3.26-3.22 (m, 1H), 2.35-2.32 (m, 2H), 2.12-2.06 (m, 2H), 1.38-1.34 (m, 12H), 1.10 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([OH:13])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:13]
Reactant: CN(C)c1cc(F)ccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc(F)ccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.64 g) is added to a solution of (2-dimethylamino-4-fluorophenyl)acetic acid (2 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.3 g) and triethylamine (2.8 g) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.1 g) is obtained in the form of white crystals melting at 164° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH3:6])[CH:8]([CH3:9])[CH3:4])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 4.8 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg). The reaction mixture was heated to 150° C. for 20 minutes in microwave. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and N-methyl-2-propanamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (12 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-n2ccnc2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4ccnc4)n3)cnc2n1
Yield: 15.9 %

Procedure:
2-Bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g, 0.8 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.9 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-10%) and trituration with ethyl acetate gave 3-[6-(1H-imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (42 mg) as an off-white solid: δH (400 MHz, CDCl3) 7.30 (1H, s), 7.35 (1H, d, J 8), 7.43 (1H, d, J 7), 7.65 (1H, s), 7.79 (1H, d, J 8), 8.00 (1H, dd, J 8 and 8), 8.38 (1H, s), 8.59 (1H, s), 10.24 (1H, d, J 7); m/z (ES+) 331 (M++H).