Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][CH2:7][C@@H:8]2[CH2:13][N:12]([CH3:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)=[CH:4][C:3]=1[CH3:22].C([Li])CCC.[C:28](=[O:30])=[O:29]>O1CCCC1>[CH3:22][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:13][N:12]([CH3:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:19]=[C:20]([CH3:21])[C:2]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, the compound (219 g) prepared in Example 8 was dissolved in anhydrous tetrahydrofuran (1.7 L) and stirred at −78° C. n-butyl lithium (1.58 M n-hexane solution, 421 mL) was added to the solution and was stirred for 1 hour. After carbon dioxide was blown into the solution, the solution was stirred for 2 hours while heating up to 0° C. After the residue obtained by removing the solvent was diluted with a 1N sodium hydroxide aqueous solution, the solution was washed by tert-butylmethylether. A 5N hydrochloric acid was added to the aqueous phase while stirring to obtain a crystal. The title compound (183 g) having the following physical data was obtained by filtrating and drying the crystal.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:8][C:7]2=O)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:25])=O.O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[Cl:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1N=C(C(=O)OC)CC2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12

Procedure:
The product of step (b) (3 g, 0.0099 mole) was dissolved in dry benzene (50 mls), treated with phosphoryl chloride (2.5 mls) and refluxed for 1 hour. The reaction mixture was cooled, poured into water and extracted with ether, which was then washed with water and dried over magnesium sulphate. The solvent was evaporated to leave 2.8 g of yellow-brown solid. Recrystallisation from cyclohexane gave yellow needles mp 163°-164°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Product: COc1ccc(C(=O)c2sc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1F
Yield: 23 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro4-methoxy-phenyl)methanone (0.11 g, 0.31 mmol) (Example 7) was treated with methanesulfonyl chloride in a manner similar to Example 9 to give 30 mg (23% yield) of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.46 (m, 2H, CH2), 2.01 (m, 2H, CH2), 2.90 (m, 5H, CH2 & SCH3), 3.55(m, 2HCH2), 3.6-4.0 (broad, 1H, CH), 3.91 (s, 3H, OCH3), 7.24 (t,1H, Aromatic), 7.47 (t,1H, Aromatic), 7.59 (t,1H, Aromatic), 7.9-8.5 (brd, 2H, 2NH), 8.71 (brd, 1H, NH). HRMSEI: (M+H)+: observed: 428.0982; calcd for 428.0988.
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)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: Cc1ccccc1
Solvent: CCO
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C(C)C)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (0.3 g, 0.67 mmol) and 4-isopropyl-phenylboronic acid (0.24 g, 1.0 mmol) in toluene (16 mL) and EtOH (4 mL) is added 2 M K2CO3 (0.6 mL, 1.34 mmol). The mixture is purged with argon for 30 minutes. Pd(PPh3)4 (0.077 g, 0.067 mmol) is added and the mixture is heated at 100° C. overnight. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth. The filtrate is diluted with water (30 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash using 24 g redisep column) eluting with 45% EtOAc/hexane to give the title compound as a brown liquid (0.22 g, 68.75%). LCMS m/z 481 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][N:6]=[C:7]=[S:8].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[CH2:5][NH:6][C:7]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[S:8]
Reactant: Fc1cc(CN=C=S)ccc1OCC(F)(F)F
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Product: Fc1cc(CNC(=S)NCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 24 h

Procedure:
3.15 g of 3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl isothiocyanate and 1.5 ml of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetate, and the solution was left to stand for 24 hours. Ethyl acetate was evaporated under reduced pressure. The resulting white crystals were recrystallized from hexane to give 3.92 g of the desired 1-[3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-3-(2,2,2-trifluoroethyl)thiourea.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.Cl[C:17](=[C:22]([Cl:27])[C:23]([F:26])([F:25])[F:24])[C:18]([F:21])([F:20])[F:19]>C(#N)C>[Cl:27][CH:22]([C:17]1([C:18]([F:19])([F:20])[F:21])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reaction time: 2 h

Procedure:
110 g of pyrocatechol were dissolved in 1500 ml of acetonitrile, and the solution was treated with 200 g of triethylamine. The mixture was treated dropwise at 75° C. with 235 g of 2,3-dichloro-1,1,1,4,4,4-hexafluoro-2-butene. Stirring was continued for 2 hours at 75° C. 1200 ml of the solvent were subsequently distilled off in vacuo, and the residue was taken up in 1500 ml of water. The product was extracted using diethyl ether, and the organic phase was washed twice using 10% strength by weight aqueous sodium hydroxide solution and once with water. After drying with magnesium sulphate, the organic phase was concentrated and subjected to fractional distillation in vacuo. The yield was 258 g (=84% of theory). The boiling point was 63° C. at 12 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.8 and -79.7 ppm. 1H-NMR: 4.71 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indol-4-amine (30 mg) and 4-methylmorpholine (46 mg) in DCM (3 mL) was added methanesulfonyl chloride (16 mg) dropwise. Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20-30% ethyl acetate in hexane) to afford the title compound as a white solid. LC/MS m/z=407.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([NH2:31])=[CH:26][N:25]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:15][C:26]3[N:25]=[C:24]([Cl:23])[N:29]=[CH:28][C:27]=3[N:31]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc2nc(-c3ccc(OCc4ccccc4)cc3)oc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 298.1 %

Procedure:
A mixture of 4-(benzyloxy)benzoic acid (1.04 g) and phosphorus oxychloride (12.2 mL) was stirred at room temperature for 5 min, and 2,4-dichloropyrimidin-5-amine (500 mg) was added thereto, and the obtained mixture was stirred at 100° C. for 2 hr. The reaction mixture was added to 1M aqueous sodium hydroxide solution at 0° C., and the precipitate was collected by filtration, and dissolved in THF and ethyl acetate. The obtained solution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (3.07 g) as a mixture with impurity. A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and DMF (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. In another reaction container, A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and toluene (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. The two reaction mixtures were combined, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.4 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>CCOCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Reactant: Cc1ccccc1[Mg]Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1cccc2c1C=C(C(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-isopropylindene (9.8 g, 51 mmol) and NiCl2(PPh3)2 (1.8g, 2.8 mmol) are dissolved in 150 mL of Et2O. 2-Methylphenylmagnesium bromide (51 mmol) as an Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq) and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 6.6 g (52%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3(O)[CH2:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@H]1C3=CC[C@H](OC(=O)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 140 mg of 3β,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androstane in 7.0 ml of pyridine was added 0.14 ml of thionyl chloride. The mixture was left to stand under nitrogen for 40 minutes whereupon it was poured into 70 ml of an ice-water mixture. Extraction with ether followed by washing of the ethereal phase with water and evaporation at reduced pressure gave 3β,19-diacetoxy-17β-pivaloxy-5α-androst-14-ene as a resinous material which was used as the starting material in the reaction described in the following example.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[H-].[Na+].CS(O[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)=O.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[CH:14][N:15]([CH2:24][CH2:25][NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:16]=2)=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])#[N:7]
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1

Procedure:
2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile (1.0 g), DMF (10 ml) and sodium hydride (60% in oil, 0.24 g) were stirred for 30 min at RT. 2-(tert-Butoxycarbonyl-amino)ethyl methanesulfonate (1.45 g) in DMF (3.3 ml) was added and the mixture was microwaved for 30 min at 160° C. (Biotage Initiator Sixty operating at 2.45 GHz). After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with water and brine, dried with Na2SO4 and evaporated. The product was triturated with IPA and filtered. Yield 0.92 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 3.38 (m, 2H), 4.24 (t, 2H), 6.92 (m, 1H), 7.06 (d, 1H), 7.85 (d, 1H), 8.19 (d, 1H), 8.33 (dd, 1H), 8.70 (d, 1H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCOCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 1-piperazine-carboxylate (932 mg, 5 mmol) and triethyl amine (836 μL, 6 mmol) in dioxane (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.28 g, 5 mmol). A white precipitate begins to form almost immediately. The reaction mixture was stirred for 1 hour at room temperature and the filtered. The filtrate was concentrated in vacuo to yield the product as a shiny white solid (1.85 g, 91%). 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.01 (t, 4H, J=5.1 Hz), 3.53 (t, 4H, J=5.1 Hz), 7.64 (dt, 2H, J=2.1, 8.7 Hz), 7.70 (dt, 2H, J=2.1, 8.7).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Br)[CH:23]=[CH2:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:24][CH:23]=[CH2:22])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reactant: C=CCBr
Product: C=CCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.45 g (0.012 mol) of allylbromide, the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising syrup in a yield of 2.25 g (68.4% of theory) and with an Rf value of 0.66 (solvent mixture as specified in 4.7.1).
Reaction SMILES: [Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3](F)=[O:4].[Cl-:11].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3]([Cl:11])=[O:4]
Reactant: [Cl-]
Reactant: O=C(F)C(F)(Br)C(F)(F)Br
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Cl)C(F)(Br)C(F)(F)Br
Yield: 57 %

Procedure:
A 163-g (0.56 mole) sample of 2,3-dibromo-2,3,3-trifluoropropionyl fluoride was added dropwise to a mechanically stirred suspension of 76 g (0.56 mole) of aluminum chloride in 282 ml of methylene chloride. The reaction mixture warmed spontaneously to 40°. After cooling, the volatile portion of the reaction mixture was distilled under reduced pressure into a Dry Ice-cooled trap. Redistillation gave 97.5 g (57%) of 2,3-dibromo-2,3,3-trifluoropropionyl chloride as a colorless liquid: bp 128°-129°; nD25 1.4436; ir (liquid) 5.57 μ (COCl); 19F nmr (CCl3F) δ 55.7 ppm (d, J = 175 Hz to d, J = 14.5 Hz, 1F), 57.9 ppm (d, J = 175 Hz to d, J = 16 Hz, 1F) and 116.5 ppm (d, J = 16 Hz to d, J = 14.5 Hz, 1F).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][C:4](=[O:14])[C:3]=1[S:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH:15]([CH3:17])[CH3:16]
Reactant: O=C1C=C(O)CC(c2ccccc2)N1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)ccc2C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)NC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method III using 95.6 mg of 5,6-dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone, 180 mg of toluene-4-thiosulfonic acid S-(2-isopropyl-5-methylphenyl) ester (prepared as per Ranasinghe and Fuchs, Synthetic Communications 18: 227, (1988)) and 0.08 ml of triethylamine in 5 ml of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2 /isopropanol (99/1 to 95/5) as eluent gave a solid (m.p. 184°-186° C.). 1H NMR (CDCl3) δ1.28 (d, 3H), 1.29 (d, 3H), 2.23 (s, 3H), 2.98 (d, 2H), 3.52 (qn, 1H), 4.85 (t, 1H), 5.63 (s, 1H), 6.78 (s, 1H), 6.96 (m, 1H), 7.14 (d, 1H), 7.35-7.44 (m, 5H), 7.55 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:81]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
12.8 mg (13.9 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 10.9 mg (41.8 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 10.8 mg (59% of theory) of the title compound were obtained as a solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccn1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.080 mL, 0.6 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (193 mg, 0.50 mmol) in DCM (10 mL) and stirred at RT for 30 minutes. 2-Aminopyridine (57 mg, 0.6 mmol) and pyridine (0.082 mL, 1 mmol) were added and the reaction stirred for a further 16 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (50 mL). The organic phase was washed with water (2×20 mL), 1N citric acid (10 mL), water (10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (100 mL), then dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-80% ethyl acetate in isohexane, to give the desired compound as a white foam (42 mg). 1H NMR δ (CDCl3): 1.28 (d, 3H), 2.31 (quin, 2H), 3.34 (s, 3H), 3.43-3.56 (m, 2H), 4.19 (t, 2H), 4.57 (q, 1H), 4.62 (t, 2H), 6.90 (s, 1H), 7.03 (t, 1H), 7.20 (s, 1H), 7.36 (s, 1H), 7.71 (t, 1H), 8.23 (d, 1H), 8.28 (s, 1H), 8.30 (d, 1H), 8.64 (s, 1H), 8.79 (s, 1H); m/z 464 (M+H)+