Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]=[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH:30]=3)[C:25](=[O:37])[NH:24][C:23]2=[O:38])=[CH:16][CH:15]=1)=O)(C)(C)C.OP(O)(O)=O.CC#N.[OH-].[Na+]>C(Cl)Cl.O>[NH:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH:21]=[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH:30]=3)[C:25](=[O:37])[NH:24][C:23]2=[O:38])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(-c4ccsc4)cc32)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1NC(=O)c2ccc(-c3ccsc3)cc2C1=CNc1ccc(C2CC=CCN2)cc1
Yield: 78 %

Procedure:
2-{4-[(1,3-Dioxo-6-thiophen-3-yl-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (230 mg, ˜60-70% pure, ˜0.26-0.31 mmol) is mixed with H3PO4 (1 mL) in CH2Cl2 (1 mL) at room temperature. The resulting mixture is stirred until no starting material is detected by TLC. CH3CN and H2O and ice were then added to dilute the sample. The mixture is neutralized by NaOH and extracted with EtOAc. The EtOAc layer is washed with brine and dried. After removal of EtOAc, the residue is purified by flash chromatography to provide the title compound (80 mg, 78% for two steps). 1H NMR (400 MHz, DMSO) δ 12.53 (1H, d, J=12.8 Hz), 11.30 (1H, s), 9.02 (1H, d, J=12.4 Hz), 8.34 (1H, s), 8.21 (1H, s), 8.05 (1H, d, J=7.6 Hz), 7.44-7.85 (7H, m), 5.76-5.84 (2H, m), 3.77-3.81 (1H, m), 3.31-3.50 (2H, m), 2.09-2.21 (2H, m). MS (ESI): 428.1 (M+1)−1.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=O)/[CH:16]=[C:17](/[C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=2)\[C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH2:32][OH:33].O.[OH-].[Cs+]>C(Cl)(Cl)Cl.O.ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:16][C@:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:33][N:32]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(C(=O)/C=C(/c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: NO
Agent: [Cs+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
A 1500 mL reaction-vessel was charged at RT with 1-Anthracen-9-ylmethyl quininium chloride 13.77 mmol, 7.59 g) and tert-butyl 2-methyl-4-[(Z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl]benzoate (68.87 mmol, 34 g) and dissolved in chloroform (700 mL). The mixture cooled down to −30° C. Then, a solution of hydroxylamine (50 mass % in H2O, 9.1 g) in water (50.9 mL) and cesium hydroxide hydrate (185.9 mmol, 32.88 g) in water (60 mL) were added simultaneously dropwise to the reaction mixture over 30 min. After the addition the reaction was kept 16 h at −30° C. after which time the conversion was complete. The reaction was brought to room temperature diluted with dichloromethane and washed three times with water. The organic phase was dried over MgSO4 and evaporated to yield crude title product. The product was purified over a silica gel column (eluent: EtOAc/Heptane) to obtain 39.0 g of the title product. LCMS (Method GR): RT 1.44 min, no ionisation: 1H NMR (400 MHz, CDCl3) 16.0 (s, 9H), 2.60 (s, 3H), 3.70 (d, 1H), 4.10-4.20 (m, 2H), 7.25-7.90 (m, 5H), 19F-NMR (CDCl3, 376 MHz): −79.40.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1Cc1nc3cc(C#N)ccc3[nH]1)CCN2
Temperature: 25 °C

Procedure:
2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (35 mg, 0.117 mmol) was suspended in DCM (1 mL), triethylsilane (0.37 mL, 2.33 mmol) and then TFA (0.5 mL) were added and the reaction was stirred at room temperature. After 1 hour the reaction was concentrated and then the resulting residue was dissolved in EtOAc and treated with 1 mL of aq. ammonium hydroxide. The residue was purified via FCC (0-100% EtOAc in heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (d, J=15.66 Hz, 1H) 8.02 (m) 7.88 (m) 7.56 (m) 7.50-7.54 (m) 6.60 (s, 1H) 5.08 (br. s., 1H) 4.08 (d, J=3.54 Hz, 2H) 3.40 (t, J=8.46 Hz, 2H) 2.91 (t, J=8.46 Hz, 2H) 2.09 (s, 3H) 1.94-2.03 (m, 3H). HRMS calcd. for C19H18N4 (M+H)+, 303.1604. found 303.1615.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][CH2:29][CH2:30][NH2:31])[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][NH:31][C:20]([C:14]1[C:15](=[O:19])[NH:16][C:17]2[C:12]([C:13]=1[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:21])[CH3:27]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.82 (1H, br s), 10.58 (1H, br s), 8.19 (1H, br s), 7.35-7.26 (3H, m), 7.15-7.10 (2H, m), 4.03 (2H, br s), 3.48-3.41 (6H, m), 1.11 (3H, t, J=8.4 Hz); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1501.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)=[C:5]([O:18][CH2:19][C:20]#[CH:21])[CH:4]=1.C([O-])(=O)/C=C/[C:25]([O-])=[O:26]>>[CH3:25][O:26][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[C:5]([O:18][CH2:19][C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C#CCOc1cc(OC)ccc1-c1nc2ncccc2[nH]1
Product: C#CCOc1ccc(OC)cc1-c1nc2ncccc2[nH]1

Procedure:
2-(4-Methoxy-2-propargyloxyphenyl)imidazo(4,5-b)-pyridine, fumarate, m.p. 220°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CC(=O)OCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)nc(-c2ccccc2)n1

Procedure:
2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (930 mg), phenylboronic acid (610 mg), tetrakis(triphenylphosphine)palladium (265 mg) and potassium phosphate (2.12 g) were dissolved in anhydrous dioxane (25 ml) under argon. The mixture was refluxed overnight and worked up with water/EA. The org. phases were dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/5) offered 875 mg of the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[CH:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:42])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 164-166° C.; MS m/e 524 (M+);
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[S:11][CH:12]=1.C1COCC1.[OH-].[Na+]>CCO>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])[N:9]=1
Reactant: COC(=O)CCCCc1csc(-c2ccccc2O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCCc1csc(-c2ccccc2O)n1

Procedure:
Combine 5-[2-(2-hydroxy-phenyl)-thiazol-4-yl]-pentanoic acid methyl ester (2.2 g, 7.6 mmol) with THF (2.5 mL), EtOH (2.5 mL) and 2N NaOH (14 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.0-3.0 using aqueous HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[2-(2-hydroxy-phenyl)-thiazol-4-yl]-pentanoic acid (1.5 g, 72%). MS (ES): (M+1)+ 278.1 m/z.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])([O-:18])=[O:17]
Reactant: CCCCC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2.5 g (0.01 mol) of 2-pentanoylamino-5-methoxy-nitrobenzene are dissolved in 30 ml of dimethylformamide, treated with 550 mg (0.11 mol) of sodium hydride (50% in oil) and stirred for 30 minutes at 80° C. 3.5 g (0.01 mol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are then added and stirred for a further 2 hours at 80° C. The solvent is distilled off in vacuum, the oily residue obtained is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography (silica gel: 0.06-0.2 mm, eluting agent: methylene chloride).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:8]=2[CH:32]=1)#[N:3].[C:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=O)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)(=[O:35])[CH3:34].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[C:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[CH:12][C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:32][C:8]=3[CH:9]=2)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: CCOC(=O)C(=O)c1ccc(OC(C)=O)cc1
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cc2cc(C#N)ccc2o1)c1ccc(OC(C)=O)cc1
Reaction time: 18 h
Yield: 85.6 %

Procedure:
15.93 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride and 8.29 g of ethyl 2-(4-acetoxyphenyl)-2-oxoacetate were dissolved in a mixture solution of 80 ml of tetrahydrofuran and 80 ml of ethanol. At room temperature, 5.34 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the above solution, and the mixture was stirred for 18 hours at the same temperature. The resulting reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant to obtain 11.28 g of ethyl 2-(4-acetoxyphenyl)-3-(5-cyano-2-benzofuranyl)acrylate in the form of light yellow crystals as a mixture of E and Z forms.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH:12]=1
Reactant: OC1(c2cnccn2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C1=C(c2cnccn2)C2CCN1CC2
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Thionyl chloride (0.24 g. 1.55 mmol) was added dropwise to a rapidly stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol (0.21 g, 1.02 mmol) in dichloromethane (10 ml) at -5° C. The reaction mixture was warmed to room temperature and then refluxed for 3 h. Water (5 ml) was added to the solution, basified to pH >10 with potassium carbonate and extracted with dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4), the solvent removed under vacuum and the residue chromatographed through alumina (Grade II-III) using dichloromethane/methanol (98:2) as eluant to give 3-(2-pyrazinyl)-1-azabicyclo[2.2.2]oct-2-ene as a pale yellow solid (0.14 g), δ (360 MHz, CDCl3) 1.54-1.61 (2H, m, CH2); 1.77-1.95 (2H, m, CH2); 2.63-2.71 (2H, m, CH2 --N); 3.02-3.09 (2H, m, CH2 --N); 3.53-3.56 (1H, m, CH-bridgehead); 7.30 (1H, d, J=1.5 Hz vinyl-H); 8.41 (1H, d, J=2 Hz, pyrazine-H); 8.52 (1H, dd, J=1 and 2 Hz, pyrazine-H) 8.78 (1H, d, J=1 Hz, pyrazine-H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.Br[C:45]1[CH:46]=[C:47]2[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]2=[N:49][CH:50]=1>O.C(#N)C>[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:45]2[CH:46]=[C:47]3[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]3=[N:49][CH:50]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: CN1Cc2cc(Br)cnc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cnc2C1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
Potassium carbonate (176 mg) in water (2 mL) was added to (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 329 mg), 3-bromo-6-methyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (Example 32, step (ii), 144 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (12 mL) at 20° C. under nitrogen. The resulting solution was stirred at 80° C. for 90 min. The reaction mixture was cooled and filtered and the filtrate diluted with ethyl acetate, and washed with water. The aqueous was then extracted with dichloromethane and the combined organics dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with methanol/ethyl:acetate (15:85 to 25:75). Pure fractions were evaporated to dryness to afford the sub-titled compound (278 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>N1C=CC=CC=1.C1CCCCC1.C(OCC)C>[CH3:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of N-tert-butoxycarbonylpyrrolidin-3-ol (19.8 g, 0.106 mol) in pyridine (200 ml) at 0° C. under nitrogen was added tosyl chloride (22.3 g, 0.117 mol) portionwise. Stir at 0° C. for 2 hr, warm to room temperature and stir at room temperature overnight. The pyridine was evaporated in vacuo and the residue was partioned between EtOAc and saturated aqueous citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2×200 ml) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave an oil which was purified by flash silica gel column chromatography using 10% EtOAc/cyclohexane as eluent to give in F40-85 an oil. The oil was dissolved in a small volume of cyclohexane/diethylether (5:1, 50 ml), cooled and scratched with a spatula to induce crystallisation. The resulting solid was filtered to give tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate (10.5 g, 29%) as a white solid. Rf in EtOAc/cyclohexane=0.13. 1H NMR (CDCl3, 250 MHz): 7.79 (2H, d), 7.35 (2H, d), 5.04 (1H, m), 3.43 (4H, m), 2.46 (3H, s), 2.03-2.20 (2H, bm), 1.43 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)=[O:2].S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>C1COCC1.CC(O)(C)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)([OH:19])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1cc2cc(C=O)ccc2o1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-formylbenzofuran-2-carboxylate (3.8 g, 17.4 mmol) was dissolved in a mixture of THF (80 mL) and t-BuOH (20 mL). A solution of sulfamic acid (4.0 g, 41.2 mmol) and sodium chlorite (3.4 g, 37.6 mmol) in water (70 mL) was added dropwise at RT. After 3 h an additional portion of sulfamic acid (1.2 g) and sodium chlorite (1.4 g) in water was added in one portion. The reaction mixture was stirred overnight at RT, then extracted twice with EtOAc, dried over sodium sulfate and concentrated under vacuum to give the crude product, 4.87 g which was suitable for use without purification. 1H NMR (DMSO-d6) 8.42 (m, 1H), 8.07 (m, 1H), 7.49-7.81 (m, 2H), 4.37 (q, 2H, OCH2), 1.34 (t, 3H, OCH2CH3); m/z 234.94 [M+H]+.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH2:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH:19][C:22](=[O:23])[CH2:21][Cl:20])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1
Reactant: O=C(Cl)CCl
Reactant: CC1OCCC(CN)(c2ccccc2Cl)O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1OCCC(CNC(=O)CCl)(c2ccccc2Cl)O1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Fifteen milliliters (ml) of water, 25 ml of dichloromethane, 4 ml (0.075 mole) of 50% sodium hydroxide and 7.2 grams (g) (0.03 mole) of 2-methyl-4-(aminomethyl)-4-(2-chlorophenyl)-1,3-dioxane were added to a reaction flask and cooled to 5° C. with an ice bath. Four and a half g of chloroacetyl chloride in 10 ml of dichloromethane were added at a rate slow enough to keep the temperature under 10° C. The reaction mixture was stirred for 1/2 hour and allowed to come to room temperature.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CCCCCC.Cl[P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25].Cl[Sn:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35]>CCOCC>[CH2:40]([Sn:31]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:2]=1[CH3:1])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42][CH3:43]
Reactant: CC1=Cc2ccccc2C1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)C1=C(C)C(P(C(C)C)C(C)C)c2ccccc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
150 ml of ether were placed in a round-bottomed flask containing 5.08 g (0.039 moles) of 2-methylindene 13; the solution was cooled to −20° C. 17.0 ml of a 2.3 molar solution of butyllithium in hexane (0.039 moles) were added over 5 min to form a yellow solution. After removal of the cooling bath, the solution was heated to room temperature and subsequently stirred for 1 h. The reaction mixture was then cooled to −20° C. and 5.8 g (0.039 moles) of chlorodiisopropylphosphine were added over 5 min to form a precipitate. The cooling bath was then removed and the reaction mixture was stirred for 1 h at room temperature. After cooling to −20° C., 17.0 ml of a 2.3 molar solution of butyllithium in hexane (0.039 moles) were added dropwise. When the addition was complete, the cooling bath was removed and the solution was heated slowly to room temperature and stirred for 1.5 h. After cooling of the suspension to 0° C., 12.4 g (0.038 moles) of chlorotributyltin were added dropwise. The suspension formed was heated to room temperature and stirred for 1.5 h. The ether was removed under vacuum, the crude product was dissolved in hexane again, the solution was filtered and the filtrate was concentrated to dryness under vacuum to leave 20.4 g (yield: 98%) of compound 14 in the form of a heavy yellow oil. Two isomers were identified by 31P NMR. 31P NMR (161.9 MHz, CD2Cl2): δ=−5.9 and −6.6 in a ratio of 2:1.
Reaction SMILES: [K+].[S:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=O)=[CH:8][CH:7]=1)([OH:5])(=[O:4])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:19][NH2:20].S(Cl)([Cl:30])=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH2:19][NH:20][C:10]([C:9]1[CH:8]=[CH:7][C:6]([S:2]([Cl:30])(=[O:4])=[O:5])=[CH:14][CH:13]=1)=[O:12]
Reactant: O=C([O-])c1ccc(S(=O)(=O)O)cc1
Reactant: NCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=S(Cl)Cl
Agent: [K+]
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1
Yield: 45 %

Procedure:
The title compound was prepared from 4-sulphobenzoic acid monopotassium salt and 3-chloro-4-(trifluoromethyl)benzylamine in 45% yield following the procedure described in Preparation 1. The thionyl chloride solution was heated at reflux for 3 hours.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][C:13]2([CH3:20])[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([N:1]=[O:2])[CH2:14][C:13]2([CH3:20])[CH3:19]
Reactant: CC1(C)CNc2ccc(F)cc21
Reactant: CC(C)CCON=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)CN(N=O)c2ccc(F)cc21
Yield: 96 %

Procedure:
Isoamyl nitrite (3.4 mL, 25.42 mmol) is added to a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (3.75 g, 22.69 mmol) in DCM. The mixture is refluxed overnight. The mixture is cooled and portioned between DCM and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.23 g, 96%) as a solid. MS: 195 (M+H). 1H NMR (300 MHz, CD3Cl)): δ 7.77 (dd, 1H), 7.08-6.98 (m, 2H), 3.94 (s, 2H), 1.39 (s, 6H).