Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[O:13]=[C:14]1[N:18]([CH:19]2[CH2:20][CH2:21][N:22]([CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)[CH2:23][CH2:24]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (1.86 g), 4-(2-oxo-1-benzimidazolinyl)piperidine (1.98 g), 1,2-dichloroethane (40 mL), glacial acetic acid (0.52 mL) and sodium triacetoxyborohydride (3.47 g) was stirred at room temperature for 72 h. The reaction mixture was poured into dichloromethane (50 mL) and saturated Na2CO3 (50 mL) and the layers separated. The aqueous layer was extracted with 2×50 mL of dichloromethane and the combined organic layers dried over MgSO4 and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with a gradient of ethyl acetate; 0-8% methanol to yield the cis and trans isomers of ethyl 1-[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]cyclohexane4-carboxylate as a colorless solid (2.23 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:24])[O:16][C@H:15](/[CH:17]=[CH:18]\[C:19](OCC)=[O:20])[CH2:14][O:13]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl>[CH3:11][C:12]1([CH3:24])[O:16][C@H:15](/[CH:17]=[CH:18]\[CH2:19][OH:20])[CH2:14][O:13]1
Reactant: CCOC(=O)/C=C\[C@@H]1COC(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](/C=C\CO)O1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Diisobutyl aluminum hydride (1 M in CH2Cl2, 27.5 mL, 27.5 mmol,) was slowly added to a cold solution (−78° C.) of ethyl (2Z)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propenoate 4, (2.50 g, 12.5 mmol) in dichloromethane (30 mL). The solution was allowed to stir for 15 min at −78° C. (a color change from colorless to yellow and back to colorless indicates that the reaction is complete). A saturated solution of Rochelle's salt (20 mL) was added and the reaction mixture was warmed to room temperature. The reaction was stirred until both layers were clear. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The organic layers were combined, washed with brine and dried over MgSO4. The solid was filtered out and the organic layer was concentrated under vacuum. The crude mixture was purified on silica gel using 20% ethyl acetate/hexanes to obtain alcohol 5 (1.9 g, 95% yield) as a colorless oil. Rf=0.27 (40% ethyl acetate/hexanes). 1H NMR (400 MHz, CDCl3): δ 5.84-5.81 (m, 1H), 5.55 (t, J=8.5 Hz, 1H), 4.85 (q, J=9.6 Hz, 1H), 4.28 (dd, J=6.8, 7.3 Hz, 1H), 4.18 (d, J=4.8 Hz, 1H), 4.08 (t, J=6.5 Hz, 1H), 3.56 (t, J=9.0 Hz, 1H), 2.12 (bs, 1H), 1.41 (s, 3H), 1.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 133.1, 129.4, 109.4, 71.8, 69.4, 58.5, 26.6, 25.8
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2].[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:26]([C:25]1[CH:29]=[CH:30][C:22]([O:21][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:23][CH:24]=1)(=[O:27])[NH2:28]
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Temperature: 120 °C
Yield: 82.8 %

Procedure:
tert-butyl 6-cyano-7-fluorochroman-4-carboxylate (290 mg, 1.05 mmol), 4-hydroxybenzamide (172 mg, 1.25 mmol) and potassium carbonate (347 mg, 2.51 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 120° C. for 12 hours under a slight argon bubble. The reaction was cooled and loaded directly onto a biotage 40 M cartridge, eluting with 20% ethyl acetate/hexanes to 100% ethyl acetate to yield 1 g of the crude product which was found to contain NMP. The residue was taken up in ethyl acetate and washed twice with water and then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the desired product (343 mg, 83.2% yield) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1.[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]4[N:23]([CH2:28][CH3:29])[C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1
Reactant: CCI
Reactant: Cc1nc(N2CC(c3nc4ccccc4[nH]3)C2)cc(-n2nc(C)nc2C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(C2CN(c3cc(-n4nc(C)nc4C)nc(C)n3)C2)nc2ccccc21
Temperature: 60 °C

Procedure:
Example 107 (13 mg, 0.036 mmol), ethyl iodide (5.6 mg, 0.036 mmol), and cesium carbonate (58 mg, 0.18 mmol) were combined in degassed DMF (1 mL) and heated at 60° C. for 30 min. The mixture was cooled to room temperature, filtered and purified by reverse phase HPLC, providing Example 114 as a solid. 1H NMR: (400 MHz, d6-DMSO) δ 7.71-7.67 (m, 2H), 7.37-7.30 (m, 2H) 6.56 (s, 1H), 4.62-4.58 (m, 3H), 4.47-4.44 (m, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.77 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H), 1.34 (t, J=7.1 Hz, 3H) ppm; MS: m/z=389.4 (M+H).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[CH2:18]([CH:20](C(OCC)=O)[C:21](OCC)=O)[CH3:19]>>[C:1]([CH:4]([C:16]1[CH:21]=[CH:20][CH:18]=[CH:19][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCC(CCCCCC1=CCCC1=O)C(=O)O
Reactant: CCOC(=O)C(CC)C(=O)OCC
Product: O=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1

Procedure:
This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyoctyl)cyclopent-2-en-1-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1.C(P(CCCC)CCCC)CCC.[CH3:30][O:31][C:32](=[O:46])[CH:33]([CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35].CCCCCCC>C1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:16][CH2:15][CH2:14][N:12]2[C:13]3[CH:1]=[N:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:43][CH:44]=1)[C:32]([O:31][CH3:30])=[O:46]
Reactant: OCCn1c2ccccc2c2ccncc21
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCn2c3ccccc3c3ccncc32)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Under a nitrogen atmosphere, 2-β-carbolin-9-yl-ethanol (212 mg, 1.0 mmol), tributylphosphine (303 mg, 1.5 mmol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (238 mg, 1.0 mmol) were successively dissolved in dry benzene (40 mL). Solid azodicarboxylic dipiperidide (ADDP) (378 mg, 1.5 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was chromatographed eluting with dichloromethane graduated with ethyl acetate to give 355 mg (82%) of the title compound; 1H NMR (300 MHz, CDCl3): δ 3.10 (d, 2H), 3.55 (t, 1H), 3.65 (s, 6H), 4.35 (t, 2H), 4.75 (t, 2H), 6.70 (d, 2H), 7.05 (d, 2H), 7.30 (t, 1H), 7.3-7.63 (m, 2H), 7.97 (d, 1H), 8.13 (d, 1H), 8.48 (d, 1H), 9.02 (s,1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[I-:11].[Na+]>I>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([I:11])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: [I-]
Agent: I
Agent: [Na+]
Product: COc1nc(I)ncc1Br
Temperature: 40 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Prepared using General Procedure 16: To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (100 mg, 0.447 mmol) in 57% aq. HI (1.0 mL) was added sodium iodide (125 mg, 0.838 mmol). The reaction mixture was stirred at 40° C. for 16 h, cooled, then quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated to afford 22.0 mg (16%) of 5-bromo-2-iodo-4-methoxypyrimidine as an off-white solid. LCMS-ESI (m/z) calculated for C5H4BrIN2O: 314.9. found 315.9 [M+H]+, tR=8.22 min. (Method 2). 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.07 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26]COS(C)(=O)=O)[CH:17]=2)=[CH:3]1.C[S-].[Na+].[CH3:38][S:39]([CH3:41])=O>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:38][S:39][CH3:41])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CS(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
100 mg of the product of Example 58 in 5 ml of DMSO were treated with 30 mg of sodium methanethiolate. The solution was stirred for 30 minutes and then diluted with water. The precipitate was filtered off, washed with water and dried to give 52 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(methylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: COc1ccc(B(O)O)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: [I-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 13.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 4-methoxyphenylboronic acid (0.034 g; 0.220 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.045 g; 0.431 mmol), sodium iodide (0.064 g; 0.431 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.012 g (12%) of the title compound as a white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:48]([NH2:52])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([NH:52][C:42](=[O:43])[CH2:41][N:38]1[CH2:39][CH2:40][N:35]([C:33]([N:13]2[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=[C:12]2[C:9]2[CH:10]=[N:11][C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:7][C:8]=2[O:45][CH2:46][CH3:47])=[O:34])[CH2:36][CH2:37]1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CC(C)(C)N
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with tert-butylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O3 [(M+H)+] 721.3394, observed 721.3399.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23]C(S)=[CH:21][CH:20]=1)=[O:17].C(#N)C.C(N(CC)CC)C>O>[Cl:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:12]([S:9][C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[N:5]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccc(S)cc1)c1ccccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A 250 mL round bottom flask was charged with 4,6-dichloro-2-methanesulfonylpyrimidine (7.00 g, 26.6 mmol), 2-chloro-N-(4-mercapto-phenyl)-benzamide (6.33 g, 27.9 mmol) and acetonitrile (100 mL) under nitrogen. Once the solid had dissolved, the reaction mixture was cooled to 0° C. and triethylamine (3.7 mL, 26.6 mmol) was added dropwise. The solution was stirred at 0° C. for 10 min and then allowed to warm to room temperature and stirred for 1 h. After this time, water (50 mL) was added and a white solid precipitated and the reaction mixture stirred for an additional 4 h. After this time, the reaction mixture was filtered and the solid washed with acetonitrile (2×10 mL) to give the title compound as a white solid (8.03 g, 74%). 1H NMR (DMSO) 7.4-7.6 (5H, m), 7.7 (1H, s), 7.80-7.85 (2H, d), 10.9 (1H, s). MS (ES+): 412
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:30]=[C:29]([F:28])[CH:37]=[C:36]([F:38])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[Cl:19])[C:14](Cl)=[O:15]>O1CCOCC1.O>[CH3:12][N:13]([S:17][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[Cl:19])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CCOC(=O)C(Cl)(SN(C)C(=O)Cl)C(=O)OCC
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(Cl)(SN(C)C(=O)ON=C1SC(C)(C)C(=O)N1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.91g (0.011m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 5.0g (0.011m) of a 70 percent solution of N-methyl-N-(bis-ethoxycarbonylchloromethanesulfenyl) carbamoyl chloride and 1.11g (0.011m) of triethylamine in 100 ml of dioxane was stirred overnight at room temperature. The reaction mixture was diluted with water, the product was extracted into ethylacetate and the organic phase was washed with water, and dried over magnesium sulfate. Removal of the solvent gave a residual oil which was purified by chromatography through silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH:22]=O)[CH:15]=[CH:14]1.C(O)(=O)C>C1(C)C=CC=CC=1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH2:22][NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])[CH:15]=[CH:14]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cccc3cc[nH]c23)c(OC)c1

Procedure:
Add 2,4dimethoxybenzylamine (27.64 g, 165.3 mmol) to a solution of indole-7-carboxaldehyde (20.0 g, 137.7 mmol) and acetic acid (8.26 ml, 137.7 mmol) in toluene (250 ml). Reflux and collect water using a Dean-Stark trap while replacing with fresh anhydrous toluene. Concentrate under reduced pressure, dissolve the residue in methanol and add sodium borohydride in portions. Dilute with ethyl acetate and wash sequentially with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide the desired compound as a brown oil.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+:26]>[Ag].O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
The organic silver salt dispersion was produced as follows: 25 kg (73.5M) behenic acid was dispersed with stirring at 80° C. in 100 L of a 10% solution of Surfactant Nr. 1 per g behenic acid made up to 250 L with deionized water at a temperature of 80° C.; then 36.75 L of a 2M aqueous solution of sodium hydroxide was added over a period of 10 to 20 minutes to give a clear solution substantially containing sodium behenate; then 25 L of a 2.94M aqueous solution of silver nitrate was added with stirring at a rate of 0.163 moles/moles silver behenate-min to convert the sodium behenate completely into silver behenate; and finally ultrafiltration was carried out with a 500000 MW polysulfone cartridge filter at room temperature to concentrate the resulting silver behenate dispersion while adding ammonium nitrate to convert Surfactant Nr 1 into its ammonium salt, the final AgBeh-concentration was 20.4% with 0.062 g of ammonium alkyl-phenylsulfonate/g AgBeh, the residual conductivity was 11.0 mS/cm.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=3)[CH2:23]2)=[O:21])[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:29][N:28]=3)[CH2:25]2)=[O:21])[N:14]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(Br)cn2)C1
Reactant: COc1cccc(B(O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1F
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A solution of 2-fluoro-3-methoxyphenyl boronic acid (0.065 g, 0.38 mmol) in THF/H2O (10:1; 2 mL) was added to a microwave vial containing 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (prepared in Step 1) (0.100 g, 0.25 mmol) and potassium carbonate (0.105 g, 0.76 mmol). Nitrogen gas was bubbled through the mixture for 5 mins then 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.020 g, 10 mole %) was added and the vial sealed and heated at 100° C. in microwave synthesiser for 30 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with sat. aqueous sodium carbonate solution (20 mL) then sat. sodium chloride solution (20 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a brown gum, which was purified by flash chromatography, eluting with a gradient of 80 to 100% ethyl acetate in hexane to a afford an off-white solid (0.079 g, 78%).