Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1.Cl>CO>[N:14]1([CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[CH2:13][CH2:12][CH:11]([N:3]2[C@@H:4]3[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Agent: Cl
Solvent: CO
Product: O=C1C[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]-1,4′-bipiperidine-1′-carboxylate (180 mg, 0.44 mmol) in MeOH (3 mL) was added 4M HCl (1 mL) and the mixture was stirred at room temperature. The solvents were then removed under reduced pressure to provide the title compound as yellow oil (120 mg). Ms (M+1): 306.3
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[S:20][CH:21]=3)[CH:13]=2)[CH:5]=[CH:4][NH:3]1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[S:20][CH:21]=3)[CH:13]=2)[CH:5]=[CH:4][N:3]1[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(NCC(F)(F)F)c1cc(-c2cnn3cc(-c4cc[nH]c(=O)c4)cnc23)cs1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(NCC(F)(F)F)c1cc(-c2cnn3cc(-c4ccn(CCN5CCCCC5)c(=O)c4)cnc23)cs1
Temperature: 67.5 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[6-(2-oxo-1,2-dihydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide (0.140 g, 0.334 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.092 g, 0.5 mmol), Cs2CO3 (0.435 g, 1.34 mmol), and NaI (0.010 g, 0.067 mmol) was evacuated and flushed with argon. DMF (15 mL) was added. The mixture was stirred for 16 h at 65-70° C. and evaporated. The residue was washed on a filter with water, ether, and purified on HPLC. Yield of 4-{6-[2-oxo-1-(2-piperidin-1-ylethyl)-1,2-dihydropyridin-4-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-N-(2,2,2-trifluoro ethyl)thiophene-2-carboxamide (bis-TFA salt): 0.022 g. 1H NMR (400 MHz, DMSO-d6): 1.57-1.77 (4H, m), 1.82-1.92 (2H, m), 2.90-3.02 (2H, m), 3.40-3.50 m), 4.05-4.15 (2H, m), 4.33 (2H, dd, J=6.85 Hz, J=6.85 Hz), 6.98 (1H, dd, J=7.1 Hz, J=2.2 Hz), 7.13 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=7.1 Hz), 8.25 (1H, d, J=1.2 Hz), 8.50 (1H, d, J=1.2 Hz), 8.73 (1H, s), 9.11 (1H, d, J=2.2 Hz), 9.17 (1H, br s), 9.23 (1H, dd, J=6.35 Hz, J=6.35 Hz), 9.70 (1H, J=2.2 Hz). LC-MS APCI: m/z 531.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].B1([CH:24]2[CH2:26][CH2:25]2)OC(=O)CN(C)CC(=O)O1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:24]1([C:2]2[C:3]([F:12])=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=2)[NH2:5])[CH2:26][CH2:25]1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1F
Reactant: CN1CC(=O)OB(C2CC2)OC(=O)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc([N+](=O)[O-])cc(C2CC2)c1F
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-nitroaniline (2.20 g, 9.36 mmol, 1 equiv), cyclopropylboronic acid MIDA ester (Aldrich; 11.07 g, 56.17 mmol, 6 equiv), Cy3P (1.05 g, 3.74 mmol, 0.4 equiv), Cs2CO3 (54.90 g, 168.50 mmol, 18 equiv) in toluene/H2O (5:1; 450 mL:90 mL) followed by Pd(OAc)2 (0.420 g, 1.87 mmol. 0.20 equiv) was de-gassed by sonicating under vacuum for 10 minutes and back-filled with N2. The mixture was then heated at 100° C. overnight. After allowing to cool to room temperature, the mixture was concentrated to dryness. The residue was taken in DCM, and silica gel was added at this stage so that the residue was absorbed directly on to silica gel. After removing the solvent under vacuum, the crude product was purified by column chromatography on silica gel using DCM to give the product 3-cyclopropyl-2-fluoro-5-nitroaniline (1.27 g, 69%) as a yellow solid.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][C:51]1[S:52][C:53]([CH2:56][NH2:57])=[CH:54][N:55]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[S:52][C:51]([CH3:50])=[N:55][CH:54]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1ncc(CN)s1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1ncc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)s1
Yield: 45 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (2-methylthiazol-5-yl)methanamine, the title compound was obtained as a colorless solid in 45% yield: mp 213-215° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.07-7.01 (m, 3H), 6.29 (br s, 1 H), 4.62 (d, J=5.3 Hz, 2H), 4.46 (s, 2H), 4.10-4.05 (m, 2H), 3.483.43 (m, 2H), 2.71 (s, 3H), 2.61 (s, 3H); MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (532 mg, 1.33 mmol, 72%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1>C(#N)C>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([NH:34][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)=[O:11])[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-L-proline (2.81 g) in anhydrous acetonitrile (40 ml), N,N-carbonyldiimidazole (1.42 g) was added at room temperature, followed by stirring for one hour. The reaction mixture was allowed to react under ice cooling with a solution of 3-amino-1-(tert-butoxycarbonyl)azetidine (1.31 g) in anhydrous acetonitrile (10 ml) in a similar manner to that described in Referential Example 1-(1), whereby 2.74 g of 1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-L-prolylamino]azetidine were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C@@:10]12[CH2:17][CH2:16][C:15](=[O:18])[C@@H:14]1[C:13](=[O:19])[N:12]([C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[CH2:11]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C)C=O>[C:3]([O:7][C:8]([C@@:10]12[CH2:17][CH2:16][C:15](=[O:18])[C@:14]1([CH3:28])[C:13](=[O:19])[N:12]([C@@H:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])[CH2:11]2)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@@H]2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@]2(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
N,N-Dimethylformamide (2.0 mL) was added to sodium hydride (152 mg, 3.48 mmol) in an argon atmosphere. A solution of (1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (1.00 g, 2.91 mmol) in N,N-dimethylformamide (8.0 mL) was added dropwise to this suspension under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. Subsequently, methyl iodide (0.217 mL, 3.49 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled and then the reaction was quenched with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give 0.79 g of the title compound as a pale yellow solid.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[Cl:14].N(OC(C)(C)C)=O.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[C:8]([C:7]1[CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=[C:3]([Cl:14])[C:2]=1[Cl:22])#[N:9]
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1Cl
Reaction time: 2 h

Procedure:
4-Amino-3-chloro-5-cyanotrifluoromethylbenzene (5.1 g) (Preparation 9) in dry acetonitrile (25 ml) was added dropwise to a stirred suspension of copper (II) chloride (3.72 g) and tertiary butyl nitrite (12.24 g) in dry acetonitrile (75 ml) whilst the temperature was maintained between 0° and +5° C. After the addition was complete, stirring was continued for a further 2 hours, whereupon the reaction mixture was diluted with dilute aqueous hydrochloric acid, and extracted with ethylacetate. The organic layer was washed with water, and after drying over anhydrous magnesium sulphate, evaporation of the solvent under reduced pressure gave an orange oil which crystallised on standing. Kugelrohr distillation gave 3-cyano-4,5-dichloro-trifluoromethylbenzene as a pale yellow solid which crystallised on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([OH:14])[C:10]([O:12]C)=[O:11].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([OH:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@H](O)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a solution of 19 g of methyl(2R)-2-(methoxyphenyl)-2-hydroxyethanoate (cf. Journal of Chemical Society, Parkintrans 1, 2253-2255 (1992)) in 50 ml of methanol, 50 ml of 3N aqueous sodium hydroxide solution was added, followed by 12 hours' stirring at room temperature. Distilling the methanol off under reduced pressure, the reaction liquid was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, to provide 11 g of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>CS(C)=O>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]#[C:26][Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1O[C@@H](Cn2cc(C#CBr)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.5 g, 0.87 mmol) was dissolved in DMSO (87 ml) and cooled to 15° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.262 ml, 1.75 mmol), dissolved in DMSO (1.7 ml), was added drop wise under stirring over 30 minutes. The temperature was maintained at 15–18° C. and after 6 hours more DBU (0.125 ml, 0.83 mmol) was added drop wise via a syringe and the resulting solution stirred for another 30 minutes. The reaction was quenched with cold aqueous HCl (0.5 M), extracted with dichloromethane, washed with water and dried over sodium sulfate. Chromatography on silica gel with hexanes/acetone (1.5:1 to 1:1) gave 108 mg (25%) of the title product as a colourless solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]([F:16])([F:15])[CH:7]([OH:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([CH3:5])[CH3:4].[NH:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20]>>[C:25]([NH:17][C@H:18]([C:22]([NH:1][CH:2]([C:6]([F:15])([F:16])[CH:7]([OH:14])[CH:8]([NH:13][C:22](=[O:23])[C@H:18]([CH:19]([CH3:21])[CH3:20])[NH:17][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([CH3:4])[CH3:5])=[O:23])[CH:19]([CH3:21])[CH3:20])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: CC(C)CC(N)C(O)C(F)(F)C(N)C(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)CC(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(O)C(F)(F)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Yield: 56 %

Procedure:
Using the procedure described in Example 182, the product from Example 263 was coupled to Cbz-Val to give the desired compound (56%). Mass spectrum: (M+H)+ =705. 1H NMR (CDCl3) δ0.82 (m, 12H), 3.90 (m, 1H), 4.02 (m, 1H), 4.30 (m, 1H), 4.55 (m, 1H), 5.02 (s, 4H), 5.80 (br d, 1H), 7.20 (br d, 1H), 7.35 (m, 10H), 7.70 (br d, 1H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:27])[C@@H:9]([O:25][CH3:26])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:4]([CH3:7])[CH2:5][OH:6].C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:27])[C@@H:9]([O:25][CH3:26])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:4]([CH3:7])[CH:5]=[O:6]
Reactant: CCCC[Sn](/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO)(CCCC)CCCC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCC[Sn](/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C=O)(CCCC)CCCC
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To (E)-(2S,3S,4R,5R)-3,5-Dimethoxy-2,4-dimethyl-7-tributylstannanyl-hept-6-en-1-ol (100 mg, 0.2 mmol) in anhydrous dichloromethane (2 ml) at room temperature and under an atmosphere of nitrogen was added activated 4A molecular sieves (50 mg), N-methylmorpholine-N-oxide (71 mg, 0.61 mmol) and TPAP (3.6 mg, 0.01 mmol). The reaction was stirred for 30 minutes and filtered through a SiO2 pad, and the pad washed well with diethyl ether. The filtrate was concentrated in vacuo to afford the product as a clear oil (98 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.74 (d, J=2.6 Hz, 1H), 6.08 (d, J=19.0 Hz, 1H), 5.58 (dd, J=19.0 Hz, 8.2 Hz, 1H), 3.77 (dd, J=9.1 Hz, 2.3 Hz, 1H), 3.34 (s, 3H), 3.25 (t, J=9.3 Hz, 1H), 3.18 (s, 3H), 2.54 (m, 1H), 1.59 (m, 1H), 1.44 (m, 6H), 1.24 (m, 6H), 0.93 (d, J=7.0 Hz, 3H), 0.82 (m, 15H), 0.75 (d, J=7.0 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[C:11](=[O:12])[CH:10]([CH3:13])[S:9][C:8]=2[C:14]=1[Cl:15]>C(O)C>[Cl:3][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH:11]([OH:12])[CH:10]([CH3:13])[S:9][C:8]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(c(Cl)c1Cl)SC(C)C2O
Reaction time: 1 h

Procedure:
Sodium borohydride (2.5 g) is added, in small portions, to a stirred solution of 5.0 g of 6,7-dichloro-5-methoxy-2-methylbenzo[b]thiophen-3(2H)-one one (5.0 g), in 120 ml of ethanol. Stirring is continued at room temperature for 1 hour and excess solvent is removed under reduced pressure. The residue is triturated with dilute sodium hydroxide solution and extracted 3 times with ether. The combined ether solution is washed thoroughly with water, dried and concentrated. Removal of ether leaves an oily residue which crystallized upon cooling. For analysis, a small sample was washed with pentane and dried at 60° to give 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-methylbenzo[b]thiophene.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To 2,6-dichloropurine (25.0 g) (available from, for example, Aldrich, UK) was added ethyl acetate (260 ml), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 50° C. and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50° C. for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl>CN(C=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
A solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (2 g, 10 8 mmol) in DMF (10 mL) was added dropwise to a suspension of sodium hydride (1.05 g, 26.3 mmol, 60% in oil dispersion) in DMF (10 mL) and cooled to 0° C. in an ice water bath. After addition, the mixture was warmed to room temperature and stirred for 30 min. The suspension was cooled to 0° C. and a solution of 1-chloro-2-(2-chloroethoxy) ethane (2 g, 13.98 mmol) in DMF (20 mL) was added dropwise over a period of 30 min. The dark suspension was warmed to room temperature and stirred for an additional 1.5 h. The mixture was quenched by addition of aq. 10% LiCl solution (50 mL) and diluted with EtOAc (100 mL). The organic extract was separated and the aqueous layer was extracted with EtOAc (30 mL, 2×). EtOAc extracts were combined, washed with 10% aq. LiCl solution (30 mL, 3×), and brine (25 mL, 2×), dried (MgSO4), filtered, and concentrated to obtain a dark brown oil (HPLC and LC/MS). The crude oil was chromatographed on a silica gel column. Elution with 10% EtOAc in heptane, followed by 20% EtOAc in heptane afforded 4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carbonitrile as a light yellow solid (2.31 g, 84% yield). HPLC: tR=2.75 min, YMC Combi S5 ODS 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.2% H3PO4; Final solvent: 90% aq. MeOH-0.2% H3PO4. LC/MS: m/e 256.06 (M+H)+, 229.02 (M+H-HCN)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[C:34]([F:35])([F:36])[F:37])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
75 mg (0.14 mmol) of tert-butyl 4-[(2-{5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 15.1E) were hydrolysed with TFA according to General Method 2. Yield: 56 mg (83% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH:11]([CH3:13])[CH3:12])[N:7]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH:11]([CH3:13])[CH3:12])[N:7]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)C(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)-2-methylpropylamine (135 mg, 0.48 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (110 mg, 0.48 mmol) and DIPEA (0.4 mL, 2.4 mmol) in n-butanol (2 mL) was heated for 18 h at 100° C. in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 206 (75 mg, 39%). LCMS (Method K): RT 3.19 min [M+H]+ 403.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.85 (1H, s), 8.86-8.59 (2H, m), 8.18-7.88 (3H, m), 7.79-7.47 (3H, m), 7.11 (1H, td, J=9.31, 2.48 Hz), 6.93 (1H, br d, J=8.83 Hz), 5.21 (1H, br s), 0.99-0.90 (4H, m), 0.85 (3H, br s)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.