Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([F:19])[CH:3]=1.[Li]CCCC.[CH:25](N1CCCCC1)=[O:26].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=2)[CH:5]=[C:4]([F:19])[C:3]=1[CH:25]=[O:26]
Reactant: CCCCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Yield: 78.9 %

Procedure:
In a 500-ml three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 15.0 g (57.6 mmol) of 2,6-difluoro-4-(4-pentylphenyl)benzene was dissolved in 100 ml of THF under nitrogen atmosphere, and 43 ml (69.1 mmol) of n-BuLi (1.6M cyclohexane solution) was added dropwise at −65° C. or lower while stirring, followed by further stirring for one hour. Then, 7.2 g (63.4 mmol) of formylpiperidine was added dropwise thereto at −65° C. or lower, and the solution was further stirred for 2 hours. 200 ml of water was added to the reaction mixture, which was extracted with 400 ml of toluene, and the toluene layer was washed twice with 200 ml of water and then dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography with toluene as a developing solvent to obtain 13.1 g of 2,6-difluoro-4-(4-pentylphenyl)benzaldehyde.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[O:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)(=O)C.[Pt]=O>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[O:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OCC(=O)O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCC(=O)O)CC[C@@H]12

Procedure:
The unsaturated acid (3.2 g, from Step D) in glacial acetic acid (200 ml) and platinum oxide (1.0 g) was hydrogenated at 60° C. under 40 psi for 24 hours. The mixture was filtered through a pad of celite, and the filtrate concentrated to dryness. The residue was recrystallized from 5% MeOH in methylene chloride to yield the title acid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9](Br)[CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15].[C:19](=[O:21])=[O:20].Cl>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:19]([OH:21])=[O:20]
Reactant: FC(F)(F)Oc1ccc(Br)cc1Cl
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (4.4 ml of 2.5M solution in hexanes) in dry diisopropyl ether was treated at −78° C. under an inert atmosphere with 3-chloro4-trifluoromethoxy-bromobenzene (2.96 g) in diisopropyl ether. After 10 minutes, excess carbon dioxide (in the form of pellets) was added and the mixture left to slowly warm to ambient temperature. Ice-water was added and the organic layer run off. The aqueous layer was acidified with dilute hydrochloric acid, extracted (ether), dried (magnesium sulphate) and evaporated to dryness to give 3-chloro-4-trifluoromethoxybenzoic acid (1.51 g) as a white solid, m.p. 110.5-111.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Br[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:16]1[CH:22]=[CH:21][CH:20]=[C:18]([NH2:19])[CH:17]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Nc1cccc(Br)c1
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: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
2-trifluoromethoxyphenylboronic acid (0.143 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-5% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.086 g in 74% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+].Cl>C(#N)C.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.C(OCC)(=O)C>[C:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)CCc1ccc(Br)cc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Temperature: 90 °C

Procedure:
Tert-butyl 3-(4-bromophenyl)propionate (433 mg, 1.52 mmol) in acetonitrile-water (3:1, 13 ml) under argon atmosphere was treated with 4-(2-carboxyethyl)benzeneboronic acid (294 mg, 1.52 mmol), K2CO3 (251 mg, 1.82 mmol) and (Ph3P)4Pd (87 mg, 73 μmol), and the stirred mixture was heated at 90° C. for 4 hours. Excess ethyl acetate and 2 M HCl was added and the organic phase was washed with 2×2 M HCl and 2× water. Drying over MgSO4 and evaporation in vacuo gave the crude product, which was purified by chromatography on silica column eluted with ethyl acetate/hexane/acetic acid 50:50:1 to provide tert-butyl 3-[4′-(2-Carboxy-ethyl)-biphenyl-4-yl]-propionate, 330 mg (62%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24](C(OCC)=O)[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:24][S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCn3ccnc3C)cc2)c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nccn1CCOc1ccc(-n2c(=O)ccc3c(-c4ccccc4)csc32)cc1
Yield: 62.4 %

Procedure:
To a solution of the compound of Example 91 (60 mg, 0.12 mmol) in dioxane (1 mL) was added 4M HCl(aq) (1 mL) and the mixture heated at reflux for 48 h. Reaction was diluted with 2M NaOH(aq) (5 mL) and extracted with DCM (2×10 mL). The combined DCM extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was dried at 60° in a vacuum oven to afford the title compound (32 mg, 62%). δH (CDCl3) 7.76 (1H, d, J 9.6 Hz), 7.42–7.30 (6H, m), 7.00–6.92 (4H, m), 6.76 (1H, s), 6.58 (1H, d, J 9.6 Hz), 4.26–4.20 (4H, m), 2.46 (3H, s). LCMS (ES+) RT 2.48 minutes, 428 (M+H)+.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[C:18]#[C:19][Si](C)(C)C)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>CO.O>[C:18]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[C:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7])[C:12]([OH:14])=[O:13])#[CH:19]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1

Procedure:
7.70 g (23.4 mmol) of methyl 4-(pyrrolidin-1-ylcarbonyl)-3-(2-trimethylsilylethynyl)benzoate is dissolved in 30 mL of methanol, combined with 46.7 mL (93.4 mmol) 2 molar potassium hydroxide solution, and refluxed for 2 hours. After the elimination of volatile constituents in vacuo, the residue is diluted with demineralized water and acidified with 2 molar hydrochloric acid solution. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate, and then the solvent is eliminated in vacuo. Yield: 3.14 g (55%); Rf value: 0.59 (silica gel; dichloromethane/ethanol=4:1); C14H13NO3 (243.27); mass spectrum: (M+H)+=244.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])OC(C)(C)C)=[N:6][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>C(#N)C>[Br:1][C:2]1[C:3]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[N:20]=2)=[CH:4][C:5]([NH:8][C:9]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl 5-bromo-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-ylcarbamate (Intermediate 87, 25 g, 59 mmol), isopropyl amine (250 mL) and acetonitrile (100 mL) was heated at 130° C. in a Parr Bomb apparatus for 50 h (˜150 PSI). The reaction mixture was cooled to room temperature and the reaction filtered through Celite, and the filtrate was washed with tetrahydrofuran (˜300 mL). The solvents were evaporated and the residue was triturated with methanol (200 mL), filtered and the solid was dried to give 14.6 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][N:7]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:6]=2[CH:38]=1)=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=4.[OH-].[Na+].[OH-].[Li+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][N:7]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:6]=2[CH:38]=1)=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=4
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CCN2CCCCC2)CC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CCN2CCCCC2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of ethyl 3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (309 mg, 0.579 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 1N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool to room temperature, 4N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool to room temperature, water (100 ml) was added, and the mixture was extracted with ethyl acetate (20 ml) and ether (10 ml). The aqueous layer was adjusted to pH 7 with 1N hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried in vacuo to give 3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydro-benzo[2,3]azepino[4,5-b]indole-9-carboxylic acid (212 mg, yield 72%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:30])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28](=[S:40])[NH2:30])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 100 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.35 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.4 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.4 g, yield 100%) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([C:6](=[O:14])C(=O)[NH:8]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[OH-].[Na+].OO.C(O)(=[O:25])C>O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([NH2:8])[C:5](=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1)[C:6]([OH:14])=[O:25]
Reactant: COc1c(Cl)cc(C(F)(F)F)c2c1NC(=O)C2=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(Cl)cc(C(F)(F)F)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
6-Chloro-7-methoxy-4-trifluoromethylisatin (13 mg, 0.046 mmol) was dissolved in NaOH (0.68M, 0.20 mL, 0.13 mmol) and H2O (0.20 mL) and then cooled to +7° C. Hydrogen peroxide (30%, 14 L, 0.14 mmol) dissolved in NaOH (0.68M, 0.49 mL, 0.33 mmol) was added dropwise during 1 min. The reaction mixture was stirred for 1 h 15 min at room temperature. Additional H2O2 (10 L) was added at 7° C. and then stirring was continued at room temperature for 2 h. Acetic acid (54 L, 0.94 mmol) was added, but no precipitation occured. Ethyl acetate (2 mL) was added and pH was raised to 6 with NaHCO3 (aq, sat.). The water phase was washed with EtOAc (3) and the combined organic layers were evaporated and co-evaporated with toluene (2). Purification by flash chromatography (SiO2, gradient EtOAc EtOAc-HOAc 100:1) yielded the title compound (5 mg). 1H NMR (CD3OD): 6.98 (s, 1 H), 3.87 (s, 3 H). MS (EI, 70 eV): m/z (rel. int.) 271/269 (M+, 17/48).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:13][C:3]1[C:2]([CH3:1])=[CH:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cn(-c2ccccc2)nc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cn(-c2ccccc2)nc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 202 %

Procedure:
To a solution of (4-methyl-1-phenyl-1H-pyrazol-3-yl)methanol (158 mg, 0.84 mmol) and triphenylphosphine polymer bound (422 mg, 1.26 mmol) in dichloromethane (4.5 mL) was added carbon tetrabromide (416 mg, 1.26 mmol) at 0-5° C. The ice bath was removed after 15 min and the mixture was stirred at RT for 2 h. The mixture was filtered, washed with dichloromethane and the solvent was evaporated to give 426 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow oil (115 mg, 458 μmol, 38.3%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11]/[C:12](/[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:13]\[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[C:8]([C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[O:7][C@H:6]1[C@H:45]([OH:50])[C@H:46]([OH:49])[CH2:47][OH:48])(=[O:3])[CH3:2].[C:51](N1C=CN=C1)(N1C=CN=C1)=[O:52]>C(#N)C>[C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[C:8]([C:29]([O:31][CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:30])[O:7][C@H:6]1[C@H:45]([OH:50])[C@H:46]1[CH2:47][O:48][C:51](=[O:52])[O:49]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@@H]1N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H]2COC(=O)O2)OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@@H]1NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Benzhydryl (2R,3R,4S)-3-(acetylamino)-4-({(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate (see J. Med. Chem. 1998, 41, 787–797) (12.38 g; 17.7 mmoles) was dissolved in dry acetonitrile (130 ml) under nitrogen at room temperature. The solution was stirred and 1,1′-carbonyldiimidazole (2.87 g; 17.7 mmoles) was added. After 16 hours LC/MS showed the presence of starting triol so further 1,1′-carbonyldiimidazole (total of 0.493 g; 3 mmoles) was added. After a few hours LC/MS showed no triol present. The solvent was evaporated and the residue flash columned on silica, eluting with 1:1 ethyl acetate/40–60 petroleum ether. Fractions containing wanted product were evaporated then taken up in dichloromethane, dried with sodium sulphate, filtered and evaporated to give Intermediate 1 as an off white solid (11.05 g; 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:28]1[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=1)[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(C(=O)/C=C/c2cc(Cl)ccc2Cl)ccc1=O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2Cl)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(2,5-dichlorophenyl)acryloyl)-1-methylpyridin-2(1H)-one was reacted with 4-(methylsulfonyl)phenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI+): m/z=464.1 [M+H]+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=[C:14]1[C:21](O)=[O:22].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:21]([C:14]3[S:13][C:17]4[S:18][CH:19]=[CH:20][C:16]=4[CH:15]=3)=[O:22])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccsc2s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-b]thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.53-7.58 (m, 1H), 8.06 (s, 1 H). MS (DCI/NH3) m/z 319. Anal. Calculated for C16H18N2OS2.HCl: C, 54.15; H, 5.40; N, 7.89. Found: C, 54.19; H, 5.25; N, 7.72.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 87.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.024 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 59 (0.034 g, 0.07 mmol, 91%) as a white solid. LCMS m/z (%)=463 (M+H79Br35Cl, 82), 465 (M+H81Br35Cl, 100), 467 (M+H81Br37Cl, 29). 1H NMR (400 MHz, acetone-d6) δ: 8.24 (s, 1H), 8.17 (s, 1H), 7.65 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.6 Hz, 2H), 4.42-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=2)[CH:12]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>ClCCl.S(Cl)(Cl)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[N:15]=2)[CH:12]=1
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)c1cn2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 ml of dimethylformamide is added to a solution of 0.196 g of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid in 3 ml of dichloromethane and 0.146 ml of thionyl chloride. The reaction mixture is stirred at ambient temperature for 3 hours. 0.273 ml of aniline is added and the mixture is stirred at ambient temperature for 22 hours. 20 ml of dichloromethane and 10 ml of water are added. After separation by settling, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure, and then the residue is purified on a silica column, elution being carried out with dichloromethane. The fractions comprising the product are combined and concentrated to dryness under reduced pressure to give 0.204 g of 6-chloro-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][C@H:2]([CH3:3])[CH2:4][OH:5]
Reactant: Clc1ccccn1
Reactant: C[C@@H](N)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ccccn1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
(R)-Alaninol (107.3 g, 1.43M) was added dropwise with stirring to a solution of potassium tertiary butoxide (160 g, 1.43M) in tetrahydrofuran (1L). After the exothermic reaction had cooled to room temperature, 2-chloropyridine (162.4 g, 1.43M) was added dropwise. The reaction mixture was heated under reflux overnight, cooled, filtered and evaporated to an oil. The oil was dissolved in xylene (1,5L) and toluene-p-sulphonic acid (0.5 g) was added. The mixture was heated under reflux overnight. On cooling to room temperature the product crystallised to give (R)-N-(2-pyridyl)-2-aminopropanol (190 g), [α]D26 =30° (c=1 in CHCl3).