Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@@H:9]2[C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.BrCC1C=CC([C:34]#[N:35])=CC=1>>[O:13]=[C:11]1[NH:10][C@H:9]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][C:7]([C:34]#[N:35])=[CH:2][CH:3]=2)[O:12]1
Reactant: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cccc(F)c2)O1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc([C@H]2OC(=O)N[C@@H]2c2cncc(C#Cc3ccccc3)c2)cc1

Procedure:
Prepared according to the same procedure as (4R,5R)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one, starting with 4-(bromomethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ: 8.80 (d, J=1.8 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.90 (t, J=2.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.53-7.63 (m, 2H), 7.35-7.48 (m, 5H), 5.39 (d, J=7.3 Hz, 1H), 4.77 (d, J=7.3 Hz, 1H). 13C-NMR (CDCl3, 126 MHz) δ: 158.1, 153.2, 146.8, 141.7, 136.4, 133.3, 133.2, 131.9, 129.4, 128.7, 126.4, 122.0, 121.6, 118.1, 113.6, 94.5, 85.0, 84.5, 62.4, 43.8, 15.0. Mass spec.: 365.9 (MH)+. The sample was further purified by SFC Prep HPLC (Chiralpak AS-H, 20% MeOH in CO2).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.C(=O)([O-])O.[Na+]>[Fe].C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[NH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Reaction time: 4 h
Yield: 28 %

Procedure:
To a suspension of 2-(4-benzylamino-3-nitrophenyl)benzoxazole (see Working Example 17-1) (340 mg, 0.985 mmol) was added 10% aqueous acetic acid solution (5 mL), ethanol (8 mL), and iron powder (165 mg, 2.95 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, this was filtered through Celite and then extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give an oil that was purified by silica gel column chromatography to yield the title compound (87 mg, 28% yield) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:46])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCO)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-hydroxybutyl]-benzenesulfonamide (336 mg, 0.827 mmol) in acetonitrile (4 mL) was added triphenylphosphine (433 mg, 1.65 mmol) and carbon tetrabromide (548 mg, 1.65 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 349 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a yellow oil in 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)CC3)c(Cl)cc2c1=O

Procedure:
When the product from Example A is reacted with 4-hydroxypiperidine in analogy to Example 17, then 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 226°-231° (with decomposition) is obtained.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:39])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[Cl:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCCCC3)c2)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCCCC3)c2)cc1Cl
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (275 mg; 0.46 mmol) was dissolved in ethanol (15 mL) and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 5% aqueous citric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 200 mg. HPLC-MS: m/z: 570.0 (M+); Rt: 2.07 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([N:13]1[CH2:12][CH2:11][N:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=2)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Benzoyl chloride (0.341 ml, 2.94 mmol) was added dropwise to a stirred mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol) and TEA (0.681 ml, 4.9 mmol) in DCM (25 ml). The resulting solution was stirred overnight at room temperature, then diluted with DCM and washed with water, with NaHCO3 (5% in H2O) and finally with citric acid (20% in H2O). The organic phase was dried over Na2SO4 and evaporated in vacuo. The resulting solid was triturated with di-isopropylether and filtered to give 687 mg of 1-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Zn]>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccc(Br)c1O
Agent: [Zn]
Product: Cc1cc(Cc2ccccc2)cc(Br)c1O
Temperature: 150 °C
Yield: 41.2 %

Procedure:
500 g of the so-obtained 6-bromo-2-methylphenol, together with 10 g zinc shavings, are heated to about 100° C. Within 20 minutes 453 g benzyl chloride are added dropwise with stirring and under moisture exclusion. For a further 12 minutes the reaction mixture is heated to 150° C. It is then held a total of 5 hours at the temperature of 150° C. After cooling, the zinc is separated. The reaction product is distilled in a vacuum at 0.03 up to 0.04 Torr. 305 g 6-bromo-2-methyl-4-benzylphenol are obtained as a weakly yellowish, oily liquid, which is nearly odorless.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH:26]1C2CC3C(=CC=CC=3)NC=2C=CC=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=4)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(CN3c4ccccc4Cc4ccccc43)coc2n1

Procedure:
N-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 9,10-dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(F)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccc(F)cc2)CC1)NC1CCCCC1
Yield: 85 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-fluorobenzyl)piperazine (2.0 g; 8 mmole) and cyclohexyl isocyanate (1.0 g; 8 mmole) in methylene chloride (20 ml) was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was mixed with ether (20 ml). The ether solution was filtered, and the filtrate was applied to a silica gel column (300 g) and developed in the same solvent. Fractions containing the product were eluted with methylene chloride/methanol/ammonium hydroxide (45:5:1), and on evaporation provided 1-{3-[4-(4-fluorobenzyl)piperazin-1-yl]propyl}-3-cyclohexylurea as a pale yellow oil (2.6 g; 85% yield). The product was dissolved in ether, precipitated with ethereal hydrogen chloride and recrystallized from ethanol to yield the title compound as colorless crystals (2.96 g; 80% yield), m.p. 203°-206° C.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][CH:5]1[CH:9]2[NH:10][C:11](=[O:13])[CH2:12][CH:8]2[CH2:7][CH2:6]1.[OH-].[Na+]>>[O:13]=[C:11]1[NH:10][CH:9]2[CH:5]([CH2:4][C:3]([OH:14])=[O:2])[CH2:6][CH2:7][CH:8]2[CH2:12]1
Reactant: COC(=O)CC1CCC2CC(=O)NC21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC1CCC2CC(=O)NC12
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Hexahydro-2-oxocyclopenta[b]pyrrole-6-acetic acid methyl ester (3aα, 6α, 6Aα), 2.2 g (0.011 m) is treated with 11 ml of 1N sodium hydroxide solution with stirring at 50° C. for 15 minutes. The reaction mixture is extracted with diethyl ether and the aqueous layer is passed through a Dowex-acid column. Concentration of the eluate followed by filtration to collect the crystalline product yields hexahydro-2-oxocyclopenta[b]pyrrole-6-acetic acid (3aα, 6α, 6aα) with a melting point of 230°-232° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](Cl)=[O:50]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:49]([C:48]1[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=1)=[O:50]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH2:37][CH:38]=O)[CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:40])=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH2:37][CH2:38][N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])[CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:40])=[O:13])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccnc(CCC=O)c5)ccn34)cc2F)no1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)CCCc1cc(-c2ccn3c(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)c(F)c4)cnc3c2)ccn1
Reaction time: 0.33 h

Procedure:
Dissolve 1-(5-tert-butyl-isoxazol-3-yl)-3-(2-fluoro-4-{7-[2-(3-oxo-propyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-urea hydrochloride (0.5 g, 0.89 mmol) in acetic acid (20 mL) under nitrogen. Add diethylamine (0.46 mL, 5 equiv.) and stir overnight at room temperature. In the morning, add sodium triacetoxyborohydride (0.38 g, 2 equiv.) and stir 20 minutes. At this point add excess diethylamine and stir overnight at room temperature. Concentrate to dryness and purify by silica gel (10% Methanol:DCM) to give impure product. Purify by reverse phase (25% MeCN:0.03% HCl in water→100% MeCN). Dilute product containing fractions with ethyl acetate then wash with 1 N NaOH followed by aqueous saturated sodium chloride. Dry the organics over MgSO4, filter and concentrate to give the freebase (0.083 g, 16%) as a yellow solid. LCMS (ES), m/z 584.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16]C)=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([OH:16])=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: COc1cnc(-c2ccc(Cl)c(C(F)(F)F)c2)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2ccc(Cl)c(C(F)(F)F)c2)ncc(O)c1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 625 mg (1.96 mmol) 2-[4-chloro-3-(trifluoromethyl)phenyl]-5-methoxy-3-methylpyrimidin-4(3H)-one in 25 ml CH2Cl2 was added 5.88 ml (5.88 mmol) of a 1 M solution of BBr3 in CH2Cl2. The reaction mixture was stirred for 1 h, then quenched with 25 ml MeOH, and concentrated in vacuo. Purification by HPLC gave 418 mg (70% yield) of 2-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-one. 1H NMR δ (ppm) (CDCl3): 7.86 (1H, d, J=1.95 Hz), 7.73 (1H, s), 7.67-7.61 (2H, m), 3.54 (3H, s). HRMS (ESI positive) calc (M+H)+=305.0299 found 305.0300.
Reaction SMILES: C([Li])CCC.[Br-].[CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=O.[O:19]1[CH2:23]CC[CH2:20]1>CCCCCC>[CH3:20][O:19][CH:23]=[CH:7][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an atmosphere of argon, a solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphoni bromide dissolved in tetrahydrofuran (THF), and the mixture was stirred for one hour at room temperature. A solution containing 50 g of methyl 4-formylbenzoate dissolved in THF was added thereto, and stirring was continued for two hours. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 47 g of methyl 4-(2-methoxyethenyl)benzoate (45).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:37][C:38]([O:40]CC)=[O:39])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[C:38]([CH2:37][C:7]1[N:8]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[CH:30][CH:31]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[CH:11][CH:10]=2)([OH:40])=[O:39]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-(4-trifluoromethylphenoxy)indole-3-carboxylic acid ethyl ester (150 mg, 0.26 mmol, see step (c) above), NaOH (aq, 2 M, 2 mL) and dioxane (2 μL) was stirred at 120° C. for 6 h, cooled and acidified with HCl (aq, 1 M) to pH 4 and extracted with EtOAc. The combined extracts were washed with water and brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound as a gray powder. Yield 90 mg (66%), mp 234-236° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[ClH:7].Cl.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:24])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:9].[ClH:7].[CH:1]([NH:4][C:5](=[SH:24][CH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:26][CH:25]=2)[CH2:16][CH2:17]1)[OH:6])([CH3:3])[CH3:2]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 56.3 %

Procedure:
The procedure described in Example 2 was followed, using 0.5 g of isopropyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.7 g (28% of theory) of N-isopropyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 247°-250° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[CH3:29]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>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>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(Cl)nc3)nc3ccccc3c2=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: [K+]
Solvent: C1COCCO1
Product: CCC(C)c1ccc(-n2c(-c3ccc(C)nc3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
3-(4-sec-butylphenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one (0.345 g, 0.89 mmol), trimethyboroxine (0.124 mL, 0.89 mmol), Pd(PPh3)4 (0.102 g, 0.09 mmol), and K2CO3 (0.368 g, 2.67 mmol) were combined in dioxane (10 mL) and heated at reflux under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, with THF washings, concentrated, and purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/heptane to 100% ethyl acetate, to afford the title compound as a white solid (0.195 g, 59%). 1H-NMR (300 MHz, DMSO-6): δ 8.43 (d, J=2.0 Hz, 1H), 8.20 (d, J=6.9 Hz, 1H), 7.89-7.94 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.55-7.65 (m, 2H), 7.13-7.27 (m, 4H), 7.07 (d, J=8.1 Hz, 1H), 2.55-2.60 (m, 1H), 2.36 (s, 3H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.66 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 370 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])C.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH:23]1([CH2:22][O:21][C:19]2[CH:20]=[C:15]([CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=2)[CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:28])=[C:8]([CH3:27])[CH:9]=2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)ccc1OCC(=O)O

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.