Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:35][CH2:36][CH2:37]O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:40].C([O-])(O)=O.[Na+]>ClCCl>[Br:40][CH2:37][CH2:36][CH2:35][S:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:29][CH:30]=1
Reactant: OCCCSc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (7.90 g, 30.0 mmol) was added to a solution of 3-(4-benzyloxy-phenylsulfanyl)-propan-1-ol (CAB02032, 4.12 g, 15.0 mmol) and carbon tetrabromide (4.98 g, 18.0 mmol) in dichloromethane (120 mL) at 0° C. (ice/water bath). The reaction mixture was allowed to warm up to room temperature and was stirred for another hour. The solution was transferred into a separation funnel and conc. NaHCO3-solution (50 mL) was added. The organic layer was separated, dried over sodium sulphate ad concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and hexane (100 mL) was added with stirring. The precipitated triphenylphosphine oxide was filtered off and washed with more EtOAc/hexane-mixture (1:4, 100 mL). The organic solutions were concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:10, Rf: 0.48). Yield: 4.96 g (98%) colourless oil, which becomes a solid after a couple of days. 1H-NMR (400 MHz, CDCl3) δ=2.07 (tt, J=7.0, 7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 3.50 (t, J=7.0 Hz, 2H), 5.04 (s, 2H, —OCH2Ph), 6.92 (d, J=9.0 Hz, 2H), 7.27-7.44 (m, 7H). 13C-NMR (100.5 MHz, CDCl3) δ=32.30, 32.50, 34.41, 70.44, 115.84, 126.15, 127.72, 128.31, 128.86, 133.65, 136.89, 158.43.
Reaction SMILES: [Cl-].[S:2]([C:6]1[CH:15]=[C:14]([S:16]([OH:19])(=[O:18])=[O:17])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([NH2+:20]N)=[CH:11]2)([OH:5])(=[O:4])=[O:3].[CH3:22][CH:23]([C:32](=O)[CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C(O)(=O)C>[CH3:22][C:23]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:11]2[C:12]3[CH:13]=[C:14]([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=[C:6]([S:2]([OH:5])(=[O:4])=[O:3])[C:7]=3[CH:8]=[CH:9][C:10]=2[N:20]=[C:32]1[CH3:33]
Reactant: N[NH2+]c1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC1=Nc2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)cc3c2C1(C)CCCCCC(=O)O

Procedure:
(5,7-Disulfo-2-naphthyl)hydrazinium chloride (2.0 g), 7-methyl-8-oxononanoic acid (1.5 g) and acetic acid (15 ml) were heated from 80-140° C. for a total of 24 hrs. After evaporation of the solvent under vacuum, the residue was triturated with 2-propanol to give a pink solid. This solid was collected by filtration, washed with 2-propanol, then excess diethyl ether and dried under vacuum over phosphorus pentoxide. Yield of crude product=1.96 g. This was purified as required by preparative HPLC (RPC18. Water/MeCN/TFA) to give pure product. 1H-nmr (D2O) δ 0.25-0.4 (1H, broad m), 0.5-0.65 (1H, broad m), 1.00 (2H, m), 1.25 (2H, m), 1.78 (3H, s), 2.06 (2H, t), 2.35-2.5 (1H, broad m), 2.65-2.8 (1H, broad m), 2.90 (3H, s), 8.05 (1H, d), 8.58 (1H, d), 8.70 (1H, d) and (8.97 (1H, d). MS (LCMS) MH+ 470. Acc. Mass: MH+ 470.0931 (−2.6 ppm for C20H24NO8S2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:17].[H-].[Na+].[CH3:20][N:21]([CH2:23][C:24](Cl)=O)[CH3:22].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][C:23]([N:21]([CH3:22])[CH3:20])=[O:31])=[CH:4][C:3]=1[CH3:17]
Reactant: CN(C)C=O
Reactant: Cc1cc2c(C(=O)C(F)(F)F)c[nH]c2cc1Cl
Reactant: CN(C)CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc2c(C(=O)C(F)(F)F)cn(CC(=O)N(C)C)c2cc1Cl
Yield: 60 %

Procedure:
To a stirred solution of 1-(6-chloro-5methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.38 g) in 10 ml of DMF at 0° C., were added 64 mg (1.1 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. before 0.16 ml (1.1 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 300 mg (60%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[C:19](=[N:32][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OCC(=O)N[C@]1(C)c1cc(Br)ccc1F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OCC(=O)N[C@]1(C)c1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Temperature: 105 °C
Reaction time: 20 h
Yield: 112.5 %

Procedure:
In a sealed tube a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one (1.0 g, 3.2 mmol) in toluene (8 ml) was treated consecutively with sodium tert-butylate (912 mg, 9.5 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl-x-phos) (134 mg, 10 mol %) and tris(dibenzylideneacetone)-dipalladium chloroform complex [Pd2(dba)3.CHCl3] (98 mg, 5 mol %). Benzophenone imine (1.06 ml, 6.3 mmol) was added finally via syringe. The tube was sealed under argon and the mixture was stirred at 105° C. for 20 h. For the workup, the brown solution was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated at reduced pressure to give brown oil (1.5 g). The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one was obtained as a light yellow foam (1.13 g, 86% of theory). Mass (calculated) C26H25FN2O2 [416.493]; (found) [M+H]+=417.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([P:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[Br-:1].[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][P+:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCP(CCCC)CCCC
Reactant: BrCc1cccs1
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1cccs1
Product: [Br-]
Temperature: 90 °C
Yield: 92.3 %

Procedure:
2-bromomethylthiophene (72 g, 0.41 mol) was dissolved into toluene (400 mL). To this solution, tributylphosphine (82 g, 0.41 mol) was added. This mixture was heated to 90° C. overnight. This mixture was cooled to room temperature and the solid was filtered. The solid was washed by ethyl ether (200 mL) to give 142.3 grams, (92.3% yield).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:20])[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:12][C:6]2=[CH:5][N:4]=1.ClN1C(=O)CCC1=O.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>CN1CCCC1=O.O>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:3]2[N:8]=[C:7]3[NH:9][C:10](=[O:20])[N:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])[CH2:12][C:6]3=[CH:5][N:4]=2)[CH2:31][CH2:32]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CSc1ncc2c(n1)NC(=O)N(c1ccccc1C)C2
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1N1Cc2cnc(N[C@H]3CC[C@H](O)CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sulfide 10.2 (2 g) in 4 mL 1-methyl-2-pyrrolidinone was combined with N-chlorosuccinimide (1.03 g) in 4 mL 1-methyl-2-pyrrolidinone and 0.125 g water, and the mixture was stirred for 1.5 hours at 25° C. To this solution was added trans-4-aminocyclohexanol (2.65 g). The mixture was heated to 60° C. for 48 hours, cooled to 20-25° C. and treated with 10 mL water. This mixture was cooled to 5° C. and stirred for 2 hours. The solid was collected by filtration, washed with water, hexanes and dried in vacuo. The solid was purified by flash column chromatography using 95/5-90/10 dichloromethane/methanol as eluant to give 614 mg of 7-(trans-4-hydroxycyclohexylamino)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. The resulting solid was converted to the hydrochloride salt by the action of ethereal hydrochloric acid/ethyl acetate on the free base.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH3:2])[CH3:22]
Reactant: C[C@@H]1CCCN1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN1CCC[C@H]1C
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(R)-2-methyl-pyrrolidine hydrochloride (1.0 g, 8.2 mmol, 1.1 eq) was dissolved in 2-butanone (25 mL) and potassium carbonate (2.2 g, 15.7 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (1.07 mL, 7.5 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and solid was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.5 g of the title compound (yield 99%) which was used in the next step without further purification.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].[C:22]([O-:25])(O)=[O:23].[Na+]>C(Cl)Cl>[C:22]([CH:14]([C:7]1[CH:6]=[CH:18][CH:10]=[CH:9][CH:8]=1)[C:15]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([OH:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:16])([OH:25])=[O:23]
Reactant: CCN(CC)CC
Reactant: O=C([O-])O
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
56 ml. (0.4 moles) or triethylamine are added to a suspension of 42 g. (10.2 moles) of 6-APA in 600 ml. of methylene chloride. The obtained solution is cooled to 0° C., and 136 g. (0.2 moles) of phenylmalonic acid di-pentachlorophenylester are added to the solution at such a rate that the temperature should not rise above +5° C. Thereafter 28 ml. (0.2 moles) of triethylamine are added to the mixture, upon which the phenylmalonic acid di-pentachlorophenylester immediately dissolves. The mixture is stirred for 30 minutes, then 200 ml. of a 8% aqueous sodium hydrocarbonate solution is added. The pH of the mixture is adjusted to 7, and the methylenechloride phase is separated. The aqueous phase is covered with 200 ml. of ethyl acetate, and is acidified to pH=2 with 10% aqueous phosphoric acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].Br[C:12]1[O:16][CH:15]=[C:14]([CH:17]=[O:18])[CH:13]=1.C([Li])(C)(C)C.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.CCCCC>[OH:18][CH:17]([C:14]1[CH:13]=[C:12]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCBr
Reactant: O=Cc1coc(Br)c1
Agent: [Li]C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of 1-bromooctane (1.33 g, 6.9 mmol) and magnesium turnings (174 mg, 7.3 mmol) in tetrahydrofuran (8 ml) was refluxed under argon for 60 minutes. After cooling to 0°, a solution of 5-bromo-3-furaldehyde (1.21 g, 6.9 mmol) in THF (1 ml) was added and conditions maintained for 60 min. The mixture was further cooled to -78° and tert-butyl lithium (a 1.7M solution in pentane, 4.26 ml, 7.3 mmol) was added dropwise, followed by chlorotrimethylsilane (2.63 ml, 20.7 mmol) after 1 hour. Stirring was continued overnight while the cooling bath attained room temperature. The mixture was quenched with saturated aqueous ammonium chloride, diluted with water (15 ml) and extracted with ether. Evaporation of the dried (magnesium sulfate) extract gave a brown oil, which was subjected to flash chromatography on silica using 15% ethyl ether/petroleum ether. Fractions with Rf of about 0.2 on evaporation gave the captioned compound as a yellow oil.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1)=O.CI.[OH-].[K+]>CC(C)=O>[CH3:3][NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: O=C(Nc1ccc2ncsc2c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: CNc1ccc2ncsc2c1
Yield: 19 %

Procedure:
To 6-Trifluoroacetamidobenzothiazole (1.97 g, 8 mmol) in 40 ml dry acetone was added methyl iodide (4.54 g, 32 mmol) and then KOH (2.1 g, 32 mmol). The mixture was refluxed for 40 min. and concentrated in vacuo. The product was taken up in 40 ml H2O, refluxed for 40 min. and extracted with methylene chloride. The organic phase was washed with water, dried over Na2SO4 and concentrated in vacuo. The product was purified by flash chromatography (silica gel, methylene chloride) to give 250 mg 6-methylamino-benzothiazole.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>CCOCC.CCCCCC>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 8.28 g of 2-bromothiazole in 100 ml of ether at -78° C., under argon, was added 21.7 ml of n-butyl lithium in hexane. The mixture was stirred at -78° C. for 45 minutes then 6.8 ml of trimethylsilyl chloride was added. This mixture was stirred at -78° C. for 1 hour, warmed to -30° C. over 1 hour, then 0° C. over 1/2 hour and kept at 0° C. for 1 hour. The reaction was quenched with 50 ml of 50% saturated sodium bicarbonate and then diluted with 50 ml of ether. The ether solution was washed with 50 ml of brine, dried, filtered and evaporated, giving 10.81 g of 2-trimethylsilylthiazole as an amber colored oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].[ClH:13].[CH3:14][N:15]([CH3:27])[C:16]1[CH:17]=[C:18]([NH:22]S(C)(=O)=O)[CH:19]=[CH:20][CH:21]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.CO>[Cl-:13].[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:6]([CH:5]=1)=[NH+:22][C:18]1[C:19](=[CH:20][CH:21]=[C:16]([N:15]([CH3:27])[CH3:14])[CH:17]=1)[N:10]=2)[CH3:12]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Cl
Reactant: CN(C)c1cccc(NS(C)(=O)=O)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc2nc3ccc(N(C)C)cc3[nH+]c2c1
Product: [Cl-]
Yield: 22 %

Procedure:
N,N-diethyl-1,4-phenylenediamine (1.00 g, 6.17 mmol) was added slowly to dilute HCl (700 μl, 32%) in H2O (100 cm3). The mixture was stirred until it was homogeneous. N-[3-(dimethylamino)phenyl]methanesulphonamide (1.32 g, 6.17 mmol) in methanol (60 cm3) was added, followed by a saturated aqueous solution of potassium dichromate (2 cm3). The mixture refluxed for 15 min. The mixture was cooled and diluted with water (200 cm3), acidified with hydrochloric acid (1M) and then extracted with chloroform (6×30 cm3). The combined extracts were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. Column chromatography (1:9 methanol/dichloromethane) gave the target material as a green solid (451 mg, 22%).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].C1COCC1.Cl[C:22]1[C:31]2[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:3]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([O:15][C:22]2[C:31]3[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:5])[CH3:4]
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.1 g, 30 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.93 g, 5 mmol). THF (anhydrous, 20 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4,8-Dichloro-quinoline (1 g, 0.5 mmol) was then added in one portion. The mixture was stirred overnight under N2 at 80° C. and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Purification by column chromatography gave 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.97 (m, 2H), 2.05 (m, 2H), 3.58 (m, 2H), 3.73 (m, 2H), 4.82 (m, 1H), 4.94 (m, 1H), 6.81 (d, 1H), 7.42 (t, 1H), 7.84 (d, 1H), 8.16 (d, 1H), 8.87 (d, 1H). Exact mass calculated for C18H21ClN2O3 348.12, found 349.2 (MH+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C(C)(C)C)CC4)nc12
Yield: 105.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.014 g pivaloyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.047 g (88%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-2,2-dimethyl-propan-1-one as yellow solid; MS (ISP): m/e=470 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]1[CH2:16][O:17][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[O:8]1
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: [N-]=[N+]=NCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
4-Azidobutyrophenone (100.0 mg, 0.53 mmol) was dissolved in toluene (5 ml) at room temperature, and thereto were added ethylene glycol (0.06 ml, 1.06 mmol) and p-toluene sulfonic acid mono hydrate (10.1 mg, 0.05 mmol) in sequential order at the same temperature, and thereafter, the mixture was refluxed using a Dean Stark tube for 24 hours. The reaction solution was cooled to room temperature and added to water thereafter, followed by the extraction using ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target compound was thus obtained as a colorless oil (133 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)(=O)C>ClCCl>[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][CH:5]=1)=[O:9]
Reactant: Nc1cccc(C=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (10.73 mmol) of 3-aminobenzenecarbaldehyde were initially charged in 30 ml of dichloromethane. 849 mg (10.73 mmol) of pyridine and 1.3 g (10.73 mmol) of methanesulfonyl chloride were added, and the mixture was then stirred at RT overnight. Ethyl acetate was added, and the reaction solution was washed in each case once with 1 N hydrochloric acid, water and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 100/0→50/1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (294 mg, 1.14 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (409 mg, 1.22 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (645 mg, 1.38 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (534 mg, 0.92 mmol, 81%): LC-MS (ES) m/z=537 (M+H)+.