Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=S)[S:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Br:16])[CH:7]=1)C.[OH-].[K+].[CH2:20](Br)C.C([O-])([O-])=O.[K+].[K+]>O.CCO>[Br:16][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([S:5][CH2:4][CH3:20])[CH:7]=1
Reactant: CCOC(=S)Sc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1cc(Br)cc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
Dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl)ester O-ethyl ester (3.3 g, 10.3 mmoles) was dissolved into 30 mL of EtOH, 10 mL of H2O, and was sealed under nitrogen. To this stirring mixture was added KOH (2.8 g, 50 mmoles) and this mix was stirred at reflux (under nitrogen) for 12 hours. After this period the reaction mixture was evaporated in vacuo and combined with 50 mL of water. The pH was adjusted to <2 using 6N HCl and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine and dried over anhydrous MgSO4. Following evaporation in vacuo the crude thiol was dissolved into 50 mL of acetone. Ethyl bromide (1.5 mL, 20.1 mmoles) and K2CO3 (5 g, 36.2 mmoles) were added, and the mixture was stirring at ambient temperature (under nitrogen) for 6 hours. After this period the mixture was gravity filtered, and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 1-bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 45% yield) as a yellowish liquid. 1H-NMR (CDCl3): δ 7.56 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 3.0 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2].[H-].[Na+].Cl.[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19].O>CN(C=O)C>[CH2:1]([C:3]1[C:8]([O:9][CH2:21][CH2:20][N:18]([CH3:19])[CH3:17])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2]
Reactant: CN(C)CCCl
Reactant: CCc1c(O)nc(C)c2sccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
4-Ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.00 g, 10.3 mmol) was added to a suspension of NaH (60% in oil, prewashed with hexanes, 0.46 g, 11.4 mmol) in DMF (30 ml) and stirred at room temperature for two hours. To this was added a mixture of dimethylaminoethylchloride hydrochloride (3.0 g, 20.6 mmol) and NaH (60% in oil, prewashed with hexanes, 546 mg, 22.8 mmol) in DMF (30 ml). The reaction mixture was stirred for two days at room temperature, poured into H2O (300 ml) and extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with H2O (2×200 ml) and dried over MgSO4. The solvent was removed in vacuo to give an oil (3 g), which was purified by flash chromatography on silica gel 60 (100 g) eluted with 7% MeOH in CH2Cl2 to give an oil (1.5 g, 56% yield). The product was dissolved in CH2Cl2 (100 ml), washed with 1N aqueous NaOH (2×100 ml) and dried over MgSO4. The solvent was removed in vacuo to give the product (0.950 g, 35% yield) as a yellow oil; IR (neat) 1590 and 1440 cm-1 ; mass spectrum m/z 264 (M+); 1H NMR (CDCl3) δ 1.18 (t, J=7 Hz, 3H, CH2CH3), 2.35 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 2.63-3.10 (m, 4H, CH2CH2N, CH2CH3), 4.53 (t, J=6 Hz, 2H, CH2CH2N), 7.27 and 7.53 each (d, J=5 Hz, 1H, thiophene-H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:19]2[CH2:21][CH2:20]2)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1C1CC1
Temperature: 120 °C
Yield: 49.9 %

Procedure:
To a solution of 1.0 g (3.69 mmol) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester (synthesis is described in section b) of example 354) in toluene (20 ml) were added 634 mg (7.38 mmol) cyclopropyl boronic acid, 2.74 g (12.9 mmol) K3PO4, 104 mg (0.37 mmol) tri-cyclohexyl-phosphine and water (1 ml). After degassing for 30 min 82 mg (0.37 mmol) Pd(OAc)2 were added and the reaction solution was heated at 120° C. for 16 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 17:3) provided 500 mg (1.84 mmol, 80%) 2-cyclopropyl-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:30])=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:11][CH:12]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NCCc4ccccc4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCCc4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 182 in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 2.82 (t, J=7.17 Hz, 2 H) 3.16-3.28 (m, 1 H) 3.45 (dt, 2 H) 5.58 (s, 2 H) 6.62 (d, J=8.46 Hz, 2 H) 6.81 (d, J=8.46 Hz, 1 H) 7.12 (d, J=8.46 Hz, 2 H) 7.16-7.33 (m, 5 H) 7.58-7.68 (m, 2 H) 7.80 (d, J=1.47 Hz, 1 H) 8.51 (t, J=5.15 Hz, 1 H) 8.57 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 10.10 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[OH:1][CH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCCCCBr
Reactant: OCCc1c(O)ccc(Cl)c1Cl
Product: O=C(O)CCCCCOc1ccc(Cl)c(Cl)c1CCO

Procedure:
Following the procedure of Example 1C, two millimoles each of 2-(2-hydroxyethyl)-3,4-dichlorophenol and 6-bromohexanoic acid were reacted to provide 55 mg. of the desired title product which crystallized from methylene chloride.
Reaction SMILES: [O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]1([CH3:18])[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[O:1]=[C:2]([CH2:9][CH:10]([S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C#CC(=O)CCCC(=O)O
Reactant: Cc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(SC(CC(=O)CCCC(=O)O)Sc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-oxohept-6-ynoic acid 3 (1.0 g), 4-dimethylaminopyridine (DMAP, 0.87 g) and p-toluenethiol (1.77 g) dissolved in dry dichloromethane (15 mL) was stirred at room temperature for 72 h. The reaction mixture was then diluted with ethyl acetate (40 mL) and the resulting organic phase washed with acidified water (2×15 mL, made from adding 2 ml of 1N HCl to 250 ml of deionised water) and finally saturated brine (1×10 mL). Volatiles were removed under reduced pressure (rotary evaporation) to yield a reddish brown ‘sticky’ residue which was further purified using silica based flash chromatography (Silica gel 100 C18-reversed phase, Fluka cat. No. 60754). A mobile phase consisting of hexane:ethyl acetate (60:40 v:v) was used to elute the product 7, (0.32 g, TLC Rf=0.50 using a mobile phase of hexane:ethyl acetate (25:10 v/v) acidified with acetic acid). 1H NMR (400 MHz, acetone-d6): δ 1.71 (p, 2H), 2.21 (t, 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.83 (d, 2H), 4.78 (t, 1H), 7.09 (d, 4H), 7.30 (d, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:20][CH2:19]4)[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:2]2[N:7]3[N:8]=[C:9]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH:18]5[CH2:20][CH2:19]5)[CH2:13][CH2:12]4)[N:10]=[C:6]3[CH:5]=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:3]=2)[N:32]=1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(CC5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC5CC5)CC4)nn23)ccc1C(=O)C(F)(F)F
Temperature: 130 °C

Procedure:
50 mg (0.10 mmol) of 5-chloro-2-[1-(cyclopropylmethyl)piperidin-4-yl]-7-(2,4-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 47A), 35 mg (0.12 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.110 ml (0.6 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (48% of theory) of the product as a solid.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(B(O)O)C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>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>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Cc1ccccc1
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: OB(O)c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccccc1
Temperature: 90 °C
Yield: 84.2 %

Procedure:
A 500 mL round bottom flask was charged with toluene (250 mL), phenyl boronic acid (10 g, 82 mmol), 2,5-dibromonitrobenzene (23.1 g, 82.3 mmol), Pd(PPh3)4 (2.8 g, 2.5 mmol), and 2M Na2CO3 aqueous solution (124 mL). Then, at 90° C., the mixture was heated under reflux for 6 hours. After the reaction was completed, the resultant product was diluted with addition of distilled water at room temperature. Then, the resultant product was extracted with methylene chloride and water. The organic layer was dried with MgSO4, and concentrated. Then, the produced compound was purified by silica gel column (methylene chloride:hexane=1:1) to give 19.2 g of a product (84.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][C:28]([NH:30][NH2:31])=[O:29].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH3:27])=[O:14])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)O)cc12
Reactant: CC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2oc(C(=O)NNC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution (700 ml) of 4-methoxybenzo(b)furan-2-carboxylic acid (43.4 g) in THF was added 1,1′-carbonylbis-1H-imidazole (CDI) (38.4 g) and the mixture was stirred at room temperature for 1 hr. Acetohydrazine (17.6 g) was added to this reaction mixture, and the mixture was stirred for 1 more hr. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried to give the title compound (38.4 g) as pale-brown crystals.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1>CO>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@H:15]3[C@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C@:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(-c3nnn[nH]3)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (522 mg) was resolved on a Berger SFC machine under 100 bar, 30° C. with 35% of methanol on an O.D. column gave two separated peaks. Peak 1, 186 mg (desired), peak 2, 185 mg (undesired).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.Br[C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C1CCCCC1=O)(=O)C.CN(C=O)C>[O:21]1[C:17]2[CH:16]=[C:15]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)[CH:23]=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: NCCc1ccc(C(F)(F)F)nc1
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)OCC3)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (955 mg, 5.0 mmol) were added 6-bromo-2,3-dihydro-benzofuran (1.00 g, 5.0 mmol), cuprous iodide (48 mg, 0.25 mmol) and cesium carbonate (3.27 g, 10.0 mmol) under an Ar-atmosphere. Then DMF (2.0 ml) and 2-acetylcyclohexanone (133 μl, 0.10 mmol) were added and the reaction mixture was stirred for 2 h at 120° C. It was cooled to ambient temperature and separated between TBME (40 ml) and water (15 ml). The organic layer was washed with brine (15 ml) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (803 mg, 52%) as a yellow oil. MS m/e: 309.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[CH:4]([CH2:5][CH2:6][C:7](=[O:12])[CH:8]=2)[CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:11][CH2:10][C@H:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:12])[CH2:8]2)[CH2:3]1
Reactant: CN1CCC2=CC(=O)CCC2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC[C@@H]2CC(=O)CC[C@@H]2C1

Procedure:
2-Methyl-1,2,3,4,6,7,8,8a-octahydroisoquinol-6-one (3.30 g) in ethanol (75 ml) was hydrogenated at 60 p.s.i. in the presence of 5% Pd/C (0.5) for 2.5 hours. The catalyst was filtered off and the filtrate evaporated to give a light brown oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:34]([CH3:38])[C:35](=O)[CH3:36]>C(O)C>[CH3:38][C:34]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:35]=1[CH3:36]
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C(N)=S)cn1
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(-c2nc(C)c(C)s2)cn1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A mixture of ethyl ((1S-5-{3-[[5-(aminocarbonothioyl)-2-pyridinyl]-(propyl)-amino]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 266) (90 mg, 0.20 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h. The solution was then concentrated and the residue purified by column chromatography (2:1 hexanes/EtOAc) to provide the title compound (0.1 g, 100%). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (d, 1H), 7.89 (d, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.56 (d, 1H), 4.16 (q, 2H), 4.01 (t, 2H), 3.74 (t, 2H), 3.55-3.45 (m, 3H), 2.95-2.78 (m, 2H), 2.76-2.68 (m, 1H), 2.46-2.30 (m, 8H), 2.11 (qt, 2H), 1.72-1.62 (m, 3H), 1.28 (t, 3H), 0.97 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[CH:22]2)=[CH:11][C:10]=1[NH:35][S:36]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[NH:47][CH2:46][CH2:45][CH2:44]2)(=[O:38])=[O:37])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:33][C:18]([NH:17][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[C:43]3[C:48]=2[NH:47][CH2:46][CH2:45][CH2:44]3)(=[O:37])=[O:38])[CH:11]=1)[OH:34])([CH3:32])[CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[CH:22]1
Reactant: [H][H]
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2cccc3c2NCCC3)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2cccc3c2NCCC3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
0.10 g palladium (5% on activated charcoal) were added to a solution of 0.20 g (0.41 mmol) (R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid (2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)-amide in 20 mL ethanol. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at ambient temperature for 6 h. The hydrogen pressure was released, the palladium filtered off and the filtrate was freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%) (R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-amide were obtained as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.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>[Br:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Br)cncc2Br)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: NC(=O)C1CCN(c2c(Br)cncc2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 170 °C

Procedure:
To a solution of 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27 (50 mg, 0.14 mmol), 4-trifluoromethylbenzene boronic acid (0.11 g, 0.56 mmol) and potassium phosphate (0.20 g, 0.96 mmol) in toluene (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (18 mg, 10 mol %). The mixture was heated at 170° C. in a microwave reactor for 60 min, then poured into a saturated solution of sodium hydrogencarbonate (25 mL). The mixture was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) and further purified preparative hplc (H2O, MeCN, gradient 90:10 to 10:90 over 30 min) (11 mg, 9%), m/z (ESI) C18H18BrF3N3O requires 428.0580 found [M+H]+ 428.0574.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27](SC)[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[NH:28]([C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:26][CH3:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN=C(Nc1ccccc1)SC
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC)Nc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and methyl N′-methyl-N-phenylcarbamimidothioate (11.5 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath and mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 5 mg, yield 18% of the desired product.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cccc(CBr)c1F
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,3-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.43 (m, 1 H), 7.20-7.04 (m, 5 H), 6.94 (dd, J=4.9, 8.4 Hz, 1 H), 6.32 (dd, J=3.5, 11.1 Hz, 1 H), 5.75-5.53 (m, 3 H), 4.33-4.26 (m, 2 H), 3.00-2.81 (m, 2 H), 2.79 (s, 3 H), 2.17-2.07 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=521.33 (M+1).