Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][CH:21]=[C:22]([O:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:37][N:38]1[CH:42]=[C:41]([C:2]2[N:10]=[CH:9][C:8]3[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:6]4[N:19]=[CH:20][CH:21]=[C:22]([O:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25]5)[C:5]=4[C:4]=3[CH:3]=2)[CH:40]=[N:39]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccnc3c2c2cc(Br)ncc2n3COCC[Si](C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cc3c4c(O[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)ccnc4n(COCC[Si](C)(C)C)c3cn2)cn1
Temperature: 130 °C

Procedure:
A mixture of (R)-tert-butyl 3-(6-bromo-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yloxy)piperidine-1-carboxylate (50 mg, 0.09 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (90 mg, 0.43 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.3 mg, 0.009 mmol), and saturated aqueous sodium carbonate solution (0.1 mL) in acetonitrile (0.9 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The reaction mixture was concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as a light brown oil, which was used in the next step without any further purification (50 mg).
Reaction SMILES: [C:1]([C:9]1C=CC=C[CH:10]=1)(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>O1CCCC1>[CH3:10][CH2:9][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(=O)CC
Temperature: 25 °C

Procedure:
Anionic polymerization was also done. This was carried out in tetrahydrofuran at 0° C. by using benzophenone monothithium complex as an initiator. After a specified time, a sufficient amount of acetic anhydride was added to the solution and the resulting mixture was stirred at room temperature for several hours. The separation and purification of the polymer were similar to those described for the cationic polymerization. IR (film) 1738 (νC=O), 1125 (νC-O-C) cm-1 ; 1H NMR (CDCl3) δ6.12 (H-2eq), 5.95 (H-2ax), 3.8 4.2 (2H-6), 2.5-2.8 (H-5), 1.6 2.2 (2H-3, 2H-4); Anal. Calcd. for (C6H8O3)n ; C 56, H 6.29. Found; C 56.28 H 6.11.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:5]2)=[O:28])=[CH:30][CH:31]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cc1sccc1CN2
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccsc3Cc3ccccc32)cc1

Procedure:
As described for Example 26, 4,10dihydro-5H-thieno[3,2-c][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](O)=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:27](=[O:34])[C@@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:29][C@@H:28]([C:27]([N:26]([CH3:25])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:34])[CH2:30][CH2:31][S:32][CH3:33])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CSCC[C@@H](N)C(=O)N(C)CCCc1ccccc1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)N(C)CCCc1ccccc1
Yield: 27 %

Procedure:
By the method of part A of this sample N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (2.59 g.) was condensed with N-methyl-N-(3-phenylpropyl)-D-methioninamide (1.4 g.). The product was crystallized twice from ethyl acetate, affording [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-methyl-N-(3-phenylpropyl)-D-methioninamide (810 mg., m.r. 130°-131° C.).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].C1(C)C=CC(S(O[CH2:25][C@@H:26]([CH3:33])[CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=O)=O)=CC=1.OS(O)(=O)=O>O1CCCC1>[C:29]([O:28][CH2:27][C@H:26]([CH3:33])[CH2:25][CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)CCC[C@@H](C)CCBr
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)COC(C)(C)C)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.33 g. (0.097 mole) of powdered magnesium and a few iodine crystals in 23 ml. of dry tetrahydrofuran was stirred at reflux temperature while a solution of 17.9 g. (0.08 mole) of (R)-(-)-1-bromo-3,7-dimethyloctane in 51 ml. of dry tetrahydrofuran was added dropwise over 1 hour. The mixture was stirred at reflux for an additional 1 hour then cooled to room temperature. To a solution of 19.5 g. (0.065 mole) of (S)-(+)-3-tert. butoxy-2-methyl-1-propyl p-toluenesulfonate in 56 ml. of dry tetrahydrofuran, stirring at -78° C. was added the R-3,7-dimethyl-1-octyl magnesium bromide solution dropwise, followed by 3.3 ml. of a 0.1 M Li2CuCl4 solution in dry tetrahydrofuran. The resulting mixture was stirred at -78° C. for 10 minutes, for 2 hours at 0°-5° C. (ice bath) and finally for 18 hours at room temperature. At the end of this time, the reaction mixture was treated with 1 N aqueous H2SO4 and work up was carried out by extraction with ether in the manner of Example 1. The crude product was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume hexane-ether gave the desired product which was distilled under high vacuum yielding 12.5 g. of (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane as a colorless oil, b.p. 91°-95° C. (0.3 mm Hg); [α]25D+0.94° (c 2.01, hexane).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7](/[CH:10]=[CH:11]/[C:12](OC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C/C(=O)OC)n1Cc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C/CO)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoate (Example 11, Method A) (0.5 g, 1.5 mmol) in dry tetrahydrofuran (10 mL) held at -78° C. under argon was treated dropwise with a solution of diisobutyl aluminum hydride in toluene (3.30 mmol, 2.2 mL of 1.5 M). The mixture was allowed to warm to ambient temperature and stirred an additional 17 hours. Excess reducing agent was quenched with methanol and water, dilute acetic acid and methylene chloride were added, and the organic layer was washed with sodium bicarbonate solution, dried and concentrated to 0.507 g of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncncc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cncnc1-c1ccc(CBr)cc1
Yield: 105.5 %

Procedure:
A mixture of 5-cyano-4-(p-tolyl)pyrimidine (2.5 g, 12.8 mmol), N-bromosuccinimide (2.4 g, 13.5 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (100 ml) was refluxed under light radiation for 1 hour. After cooling, insoluble materials were removed and the filtrate was concentrated to dryness to afford a yellow syrup (3.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=1)[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:71][CH:70]=1)[CH3:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzoic acid ethyl ester (43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 37 mg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.C(OCC)C>[Si:14]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(O)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-iodo-4-methylphenol 1-1 (500 mg, 2.14 mmol), tert-butyldimethylchlorosilane (387 mg, 2.57 mmol) and imidazole (175 mg, 2.57 mmol) in 11 mL of DMF was stirred at rt for 16 h, and then diluted with diethylether, washed with water, brine, dried (MgSO4) and evaporated. The residue was subjected to MPLC on a 40 g column of SiO2 eluting with hexanes to provide 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.17 (s, 6H), 0.93 (s, 9H), 2.29 (s, 3H), 6.81 (dd, 1H, J=8, 2 Hz), 7.20 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=2 Hz).
Reaction SMILES: [BrH:1].BrBr.[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([N:11]1[CH2:17][CH2:16][CH:15]([Br:1])[C:14](=[O:18])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Br
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1CCN(Cc2ccccc2)CCC1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33% hydrobromic acid in conc. acetic acid and 1.97 g bromine was added to 5 g 1-benzyl-azepane-4-one in 15 mL conc. acetic acid. The reaction was stirred 2 h at RT and completely concentrated under reduced pressure. The residue was diluted with ethyl acetate and refluxed for 1 h and crystallized with ethyl acetate to give 4 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:14]Br>O1CCOCC1>[Br:14][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][CH:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)C(C)CO2
Solvent: C1COCCO1
Product: CC1COc2ccc(C(=O)CBr)cc21
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
To a stirred solution of 1-[3-methyl-2,3-dihydro-benzofuran-5-yl]ethanone (1.4 g, 7.94 mmol) (Maybridge Chemical) in dioxane (10 mL) was added dropwise a solution of bromine (1.52 g, 9.5 mmol) in dioxane (30 mL). After stirring 15 minutes the mixture was concentrated in vacuo and the residue chromatographed on silica gel (2:1 hexane-dichloromethane) to provide 375 mg (19%) of 2-bromo-1-(3-methyl-2,3-dihydro-benzo-furan-5-yl)ethanone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:25][NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28]>>[CH3:25][N:26]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Reactant: CN[C@H](C)c1ccccc1
Product: C[C@H](c1ccccc1)N(C)CCCOc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1

Procedure:
The product from Example 11A and N-methyl-N-[(1R)-1-phenylethyl]amine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[CH3:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([CH3:34])[CH:33]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Product: Cc1cc(C)cc(-c2ccc(C(=O)NCCCCCC(=O)Nc3ccccc3N)cc2C)c1
Yield: 77 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 3,5-dimethyl phenyl boronic acid instead of phenyl boronic acid to obtain the title compound (35 mg, 77%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].Cl.[O:27]1CCC[CH2:28]1>O>[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:28]=[O:27])[C:18]=1[F:24]
Reactant: COC(=O)Nc1ccc(F)cc1F
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Into a reaction flask under nitrogen, diisopropylamine (24.87 g, 250 mmol) is combined with 160 mL of anhydrous tetrahydrofuran and the solution is cooled to −78° C. n-Butyllithium (154 mL, 1.6 M in hexanes, 250 mmol) is added dropwise, maintaining the temperature below −70° C. After stirring at −78° C. for 1 hour, (2,4-difluoro-phenyl)-carbamic acid methyl ester (2, 20.00 g, 110 mmol) in 40 mL of tetrahydrofuran is added dropwise, maintaining the temperature below −70° C. The reaction is stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for 1 minute. The reaction is poured into 250 mL of water, the pH is adjusted to 1 with addition of 2M hydrochloric acid, and the mixture is extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried in hexane and the resulting solid is collected by filtration and dried to provide the desired compound (3, 19.38 g, 84%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: OB(O)c1ccccc1Cl
Reactant: O=Cc1c(Br)ccc2c1OCO2
Product: O=Cc1c(-c2ccccc2Cl)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (0.458 g, 2.00 mmol) and 2-chlorophenylboronic acid (0.469 g, 3.00 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:15]=[C:14]2[C:12](=[C:11]([F:16])[CH:10]=1)[N:13]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]2[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(SCc2ccccc2)cc1F
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Product: CCOC(=O)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A neat mixture of 3.58 g of compound of 4-(benzylsulfanyl)-2-fluoroaniline and 3.48 g of diethyl ethoxymethylenemalonate is heated at 135° C. under a slow argon sweep for 1 h, then diluted with 25 mL of diphenyl ether and heated to 260° C., with maintenance of the argon sweep, and kept at that temperature for 90 min. The mixture is then cooled to ca 100° C. and added to 300 mL of stirred heptane. The precipitate is filtered, washed with heptane, and dried in vacuo to provide 4.01 g of ethyl 6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:21]([F:24])([F:23])[F:22])=[N:11][N:12]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[NH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:21]([F:22])([F:24])[F:23])=[N:11][N:12]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[N:14]=[CH:27][N:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1c(-c2cc(Cl)cc(Br)c2)c(C(F)(F)F)nn1-c1ncccn1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(-c2cc(Cl)cc(Br)c2)c(C(F)(F)F)nn1-c1ncccn1

Procedure:
1.19 g (2.84 mmol) of 4-(3-bromo-5-chlorophenyl)-1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (known from WO 2008/077843 A) and 0.51 g (4.26 mmol) of dimethylformamide dimethyl acetal are dissolved in 20 ml of toluene and stirred under reflux for 18 hours. After cooling, the toluene solution is washed with water, the organic phase is separated off, dried with magnesium sulphate and filtered and the filtrate is concentrated under reduced pressure using a rotary evaporator. The residue is stirred with a solvent mixture of cyclohexane and ethyl acetate (vol. 1:1) and the precipiated solid is filtered off and air-dried. This gives 0.99 g (67% of theory) of the compound N′-[4-(3-bromo-5-chlorophenyl)-1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(C)c(N=C=O)c1
Product: Cc1ccc(C)c(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
75.9 mg of solid white 3-{4-[3-(2,5-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2,5-dimethylphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:12][C@@H:13]1[CH2:20][N:19]([CH2:21][CH2:22][CH2:23][C@@H:24]2[N:28]3[C:29](=[O:34])[C@H:30]([CH3:33])[NH:31][CH2:32][C:27]3([CH3:35])[O:26][CH2:25]2)[CH2:18][CH2:17][C:14]21[CH2:16][CH2:15]2>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:31]2[C@@H:30]([CH3:33])[C:29](=[O:34])[N:28]3[C@@H:24]([CH2:23][CH2:22][CH2:21][N:19]4[CH2:18][CH2:17][C:14]5([CH2:15][CH2:16]5)[C@H:13]([OH:12])[CH2:20]4)[CH2:25][O:26][C:27]3([CH3:35])[CH2:32]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H]1NCC2(C)OC[C@H](CCCN3CCC4(CC4)[C@H](O)C3)N2C1=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: C[C@H]1C(=O)N2[C@@H](CCCN3CCC4(CC4)[C@H](O)C3)COC2(C)CN1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenyl isocyanate (28 mg, 0.15 mmol) was added at 0° C. to a solution of (3S,6S)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-6,8a-dimethyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (50 mg, 0.15 mmol), then the ice bath was removed. After 30 min the reaction mixture was evaporated and the residue chromatographed (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) to pruduce the title compound (57 mg, 73%). Colourless gum, MS: 525.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:25])([F:24])C(OC)=O.O>CN(C=O)C>[F:24][CH:19]([F:25])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (6 g), Cs2CO3 (25.7 g) and methyl 2-chloro-2,2-difluoroacetate (5 ml) in DMF (50 ml) was stirred at 90° C. for 1 h. At room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1:1 (v/v)] as eluent.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10](OC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C/C=C/c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC/C=C/c1ccccc1

Procedure:
In an analogous manner to that described in Example 5 (b), by reducing methyl (E)-4-phenyl-but-3-enoate by means of lithium aluminium hydride in tetrahydrofuran there was obtained (E)-4-phenyl-but-3-en-1-ol, which was converted into (E)-4-phenyl-but-3-enyl methanesulphonate in analogy to the procedure described in J.Chem.Soc. Perk.Trans. 1 (1988), (6), 1517-1519 for the preparation of the (Z) isomer.