Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.I[C:11]1[CH:19]=[C:18]2[C:14]([C:15](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:16][N:17]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1>O1CCOCC1.C(OCC)(=O)C.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>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](/[CH:28]=[CH:29]/[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[CH:13][CH:12]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40.1 %

Procedure:
A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexanethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s,1H), 7.69–7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), −0.03 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[C:14]([S:17]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:1]([NH2:2])=[O:3])(=[O:11])[NH2:12]
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Reactant: COc1ccc(N)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Solid 2-[2-(carbamoylmethoxy)-5-(chlorosulfonyl)phenoxy acetamide (Intermediate A85, 161.25 g, 0.5 mol) was added to a solution of p-anisidine (49.2 g, 0.4 mol) in pyridine (3.5 L) and stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduce pressure. The residue was treated with 0.75 M hydrochloric acid (3 L) and the resulting solid was collected. The solid was washed with water (3×1 L), methanol (750 mL) and dried to give 99 g (60%) of the title compound, sulfonamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]([NH2:12])=O>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]#[N:12]
Reactant: NC(=O)c1cc(Br)c(F)c(Br)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
(I14B): Phosphoryl trichloride (8.0 ml, 86 mmol) was added to a suspension of 3,5-dibromo-4-fluorobenzamide (11.27 g, crude, ˜22.7 mmol) in acetonitrile (400 ml) at room temperature. The reaction mixture was heated to reflux for 30 minutes. Additional phosphoryl trichloride (8.0 ml, 86 mmol) was added and the mixture heated to reflux for an additional hour, then stirred at room temperature overnight, A precipitate had formed and was removed by filtration. (The product is well soluble in acetonitrile) The reaction mixture was evaporated to dryness, and then partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed one more time with aq. NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness. Purification by column chromatography on silica (gradient 100% hexanes to 25% DCM in hexanes). 3,5-dibromo-4-fluorobenzonitrile (7.5 g) was obtained. The material is (by 1H NMR and 19F NMR) a 76:17:7 mixture of 3,5-dibromo-4-fluorobenzonitrile (desired product), 2,3,5-tribromo-4-fluorobenzonitrile (over-bromination) and 2,5-dibromo-4-fluorobenzonitrile (wrong regio-isomer). The material was used without further purification in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:27])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:11]([CH3:25])([CH3:24])[CH:10]2O)=[O:4].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:27])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:11]([CH3:24])([CH3:25])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc([N+](=O)[O-])c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc([N+](=O)[O-])c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 6-chloro-4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (7.8 g, 20 mmol) and triethylsilane (30 mL) at 25° C. was added trifluoroacetic acid (15 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1 g, 13%) as a white solid: LC/MS m/e calcd for C19H19ClN2O4 (M+H)+: 375.83, observed: 375.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCC(C)C)c1
Yield: 76 %

Procedure:
A mixture of 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (50 mg, 0.14 mmol), potassium carbonate (48 mg, 0.35 mmol), and 1-bromo-3-methylbutane (23.5 mg, 0.15 mmol) was heated in N,N′-dimethylformamide (3 ml) at 90° C. for 4 hours. The reaction mixture was then poured into water and extracted with ethyl acetate; the organic layers were dried over MgSO4 and evaporated. The residue was chromatographed through a SPE column using 10% ethyl acetate in iso-hexane as eluent to yield the title compound as a white solid (45 mg, 75%).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[NH:20]1[CH2:25][CH2:24]N[CH2:22][C@@H:21]1[CH2:26][CH2:27][OH:28]>>[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([N:19]3[CH2:24][CH2:25][NH:20][C@@H:21]([CH2:26][CH2:27][OH:28])[CH2:22]3)[C:7]=2[N:6]=1)([CH3:4])[CH3:3]
Reactant: OCC[C@H]1CNCCN1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCO)C1

Procedure:
In a manner such as that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.558 g, 1.89 mmol) and (S)-2-piperazin-2-yl-ethanol (0.493 g, 3.79 mmol) to obtain the title compound: mass spectrum (APCI): m/z=372.4 (M+1).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:34]=[C:33]([OH:35])[C:26]3[CH2:27][CH:28]([CH:30]([F:32])[F:31])[O:29][C:25]=3[CH:24]=2)=[O:22])=[N:16]1>>[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:34]=[C:33]([O:35][C:10]3[CH:11]=[CH:12][C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[CH:8][CH:9]=3)[C:26]3[CH2:27][CH:28]([CH:30]([F:32])[F:31])[O:29][C:25]=3[CH:24]=2)=[O:22])=[N:16]1
Reactant: O=C(c1ccc(F)cc1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl(4-fluorophenyl)methanone (57.4 mg, 0.32 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (99 mg, 0.32 mmol) to give a white solid (12 mg, 8% yield). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1 H) 7.55-7.71 (m, 2 H) 7.22-7.31 (m, 1 H) 7.13-7.19 (m, 1 H) 7.06-7.12 (m, 1 H) 6.96-7.03 (m, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 5.75-6.08 (m, 1 H) 4.93-5.19 (m, 1 H) 4.35 (br. s., 2 H) 4.24 (br. s., 2 H) 3.79 (s, 3 H) 3.57-3.63 (m, 1 H) 3.14-3.31 (m, 2 H) 2.30-2.42 (m, 1 H.); LCMS for C24H22F2N4O4 m/z 469.00 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4].C(Cl)Cl.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[CH2:2]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH:3]=[CH2:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C=CCNCCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CCCC)C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ten and five-tenths grams of allyl-n-butyl amine hydrochloride was added to 100 ml. of methylene chloride followed by 14.5 g. of triethylamine. The mixture was stirred in a water bath at room temperature while 10.4 g. of dichloroacetyl chloride was added dropwise, and stirring was continued for 30 minutes after addition was complete. The mixture was washed and the solvent stripped under vacuum. Yield was 13 g., nD30 1.4603. The intermediate was used without further purification to prepare Compound No. 12 (Example VII).
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.O[CH2:17][CH:18]1[CH2:27][CH2:26][N:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19]1>>[S:1]1[C:5]2=[C:6]([C:13]([O:15][CH2:17][CH:18]3[CH2:27][CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19]3)=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1
Reactant: OCC1CCN2CCCCC2C1
Reactant: O=C(O)c1c2n(c3ccccc13)CCS2
Product: O=C(OCC1CCN2CCCCC2C1)c1c2n(c3ccccc13)CCS2

Procedure:
2,3-Dihydrothiazolo[3,2-a]indole-9-carboxylic acid (D15) was converted to its acid chloride and reacted with eq-2-hydroxymethylquinolizidine using a procedure analogous to that described in Example 10.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)Cc2ccccc2)ccc1F
Temperature: 50 °C
Yield: 60.2 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (25 g, 162 mmol) in THF (150 mL) was added a solution of benzyl magnesium chloride (2 M solution in THF, 122 mL, 243 mmol) in THF (50 mL). The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and quenched by addition of sat. NH4Cl. The reaction mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 0-40% EtOAc/hexane) to yield 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol as a yellow oil (24 g, 60% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.32 (m, 2H), 7.21-7.27 (m, 1H), 7.16 (d, J=7 Hz, 2H), 7.01 (dd, J=11, 8 Hz, 1H), 6.92 (dd, J=8, 2 Hz, 1H), 6.82 (ddd, J=8, 4, 1 Hz, 1 H), 4.80-4.88 (m, 1H), 4.66 (d, J=6 Hz, 1H), 3.84 (s, 3H), 2.91-3.04 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:1](=[S:31])[NH2:2])[CH2:4][C:5]2=[O:17])=[CH:11][CH:12]=1
Reactant: S
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a cooled (0° C.) solution of 4-cyano-1-(4-fluorobenzyl)-4-phenylpiperidin-2-one (3.39 g, 10.9 mmol) in pyridine (77 mL) was added triethylamine (45.0 g, 0.77 mol). The reaction mixture was saturated with hydrogen sulfide gas, the reaction vessel was sealed and then brought to ambient temperature. After stirring for 24 hours, the reaction mixture was cooled (0° C.), the reaction vessel was opened, then the solvents were concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-70% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.68 (s, 1H), 7.35 (m, 4H), 7.26 (t, J=7 Hz, 1H), 7.13 (t, J=8.3 Hz, 2H), 7.04 (t, J=8.9 Hz, 2H), 4.48 (d, J=15 Hz, 1H), 4.35 (d, J=15 Hz, 1H), 3.16 (m, 2H), 3.93 (d, J=17 Hz, 1H), 2.82 (m, 1H), 2.51 (m, 2H) ppm. ES MS M+1=343.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][OH:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][O:57][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: OCC1CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using cyclohexanemethanol (31 μL, 0.25 mmol) to give 5-{3-[2-[4-(6-cyclohexylmethoxy-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][C:8]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([NH2:21])[CH3:20]>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][C:8]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: CC1(c2ccccc2)CCc2c(Cl)nc(Cl)nc21
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nc(Cl)nc2c1CCC2(C)c1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of 2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation V) (43.1 mg, 0.154 mmol) in THF (772 μL) at rt was added a solution of 2M Ethylamine (386 μL, 0.772 mmol) diluted with 390 uL MeOH (overall reaction is 0.1M in 1:1 THF/MeOH). Let stir at rt. Removed the solvent and subjected the residue to a Silica gel column with an EtOAc/Hex gradient to afford 2-chloro-N-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (38.0 mg, 0.132 mmol, 86% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=O)=O)=[CH:28][C:27]=1[F:36]>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[F:36]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cc(S)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A stirred ice-cooled solution of triphenylphosphine (23.0 g, 87.7 mmol), in CH2Cl2 (50 mL) and DMF (1.6 mL) was treated with a solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (8.00 g, 29.2 mmol) in CH2Cl2 (50 mL) and stirred room temperature for 16 hours. The mixture was washed with 1N aqueous HCl (80 mL) and concentrated in vacuo. The resulting solid was diluted with 1N aqueous NaOH (160 mL), the solid filtered and the filtrate washed with 2-methoxy-2-methylpropane (3×150 mL) and acidified to pH 1 with 1M aqueous HCl. Extraction of the aqueous layer with 2-methoxy-2-methylpropane (3×100 mL), followed by drying over sodium sulphate and concentrating in vacuo gave the title compound as a yellow oil 66% yield, 3.97 g.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19]Br)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)c(CN2CCCCC2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
4',5,7-Trihydroxy-2-bromomethylisoflavone (160 mg) was dissolved in 2 ml N,N-dimethylformamide, 100 mg piperidine was added to the solution, and the mixture was stirred at room temperature for three hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=96:4), and the solid thus obtained was recrystallized from ethanol, giving 150 mg of 4',5,7-trihydroxy-2-piperidinomethylisoflavone.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
To a suspension of 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature for 24 h. The mixture was poured onto 30 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to provide the crude product which was purified by silica gel flash chromatography to afford the title product (68 mg, 25%); LCMS; 95%; APCI+, Calcd 493.05. Found m/z 493.2 (M). 1H NMR (400 MHz, CDCL3); δ 1.47 (d, J=5.6 Hz, 3H), 1.52-2.01 (m, 6H), 2.21-2.59 (m, 4H), 2.79-2.98 (m, 2H), 3.12-3.23 (m, 1H), 3.68-3.89 (m, 2H), 5.10-5.17 (m, 1H), 6.81 (d, J=9.2 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 7.22-7.26 (m, 5H), 7.29 (d, J=4.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2O)cc1C(F)(F)F
Yield: 80.2 %

Procedure:
Using 5-chlorosalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH:14]([CH3:15])[C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:16]
Reactant: BrBr
Reactant: CCC(=O)c1cc(C(=O)OC)c(C)cc1C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 122.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5, 600 mg, 2.72 mmol) in chloroform (20 mL). Bromine (154 μL, 3.00 mmol) was added and the resulting solution was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure to yield the title compound as a yellow oil (1.0 g, crude), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[CH:5][N:4]=1.[CH2:8]([O:10][CH2:11]Cl)[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([O:10][CH2:11][N:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:7]1)[CH3:9]
Reactant: CSc1ncn[nH]1
Reactant: CCOCCl
Solvent: Cc1ccccc1
Product: CCOCn1cnc(SC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
A suspension of 5-methylthio-1,2,4-triazole (6.19, 53 mmol) and chloromethyl ethyl ether (2.5 ml, 26 mmol) in toluene (40 ml) was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica by elution with ethyl acetate/diethylamine (95:5) to yield the title compound (1.1 g, 27%), as a colourless oil, which was characterised by