Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)=[C:16]=[S:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([S:24][C:21]2[CH:22]=[CH:23][C:18]([N:15]=[C:16]=[S:17])=[CH:19][CH:20]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: S=C=Nc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCc1ccc(C(=O)Sc2ccc(N=C=S)cc2)cc1

Procedure:
(18). Quantities: compound 17 (4.00 g, 0.021 mol), compound 3 (2.59 g, 0.016 mol), N,N'-dicyclohexylcarbodiimide (3.95 g, 0.019 mol), 4-(dimethylamino)pyridine (0.79 g, 0.019 mol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:19]
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCCCCl)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorophenyl)-1-methylethylamine hydrochloride (4.0 g) was reacted with 5-chloropentanoyl chloride (3.0 g) in dichloromethane (15 ml) containing triethylamine (8.1 ml) in a similar manner to Example 52b, to give 5-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]pentanamide.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][CH:28]=[CH:27][C:26]=2[CH:30]=1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:28]1[O:29][C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:30][C:26]=2[CH:27]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: Clc1ccc2occc2c1
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3cc(Cl)ccc3o2)C1

Procedure:
The title compound (0.98 g) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (1.60 g) and 5-chloro-benzofuran (0.86 g, FP1.537.206) using the method of Description 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-:11].[Cs+]>C(OCC)(=O)C.CCCCCCC>[OH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Br
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1O
Yield: 83 %

Procedure:
Following general operating mode A, 2′-bromoacetophenone (199 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 83% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.C(O)(=O)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Brc1cccs1
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
2-Bromothiophene (130.4 g, 0.8 mol) was dissolved in 2-Me-THF (240 ml, 0.3 L/mole) and the resulting mixture cooled to 2° C. NiCl2(dppe) (2.11 g, 4.0 mmol) was added followed by addition, over about 40 min. at ≦30° C., of the 4-fluoro-phenylmagnesium bromide solution prepared as in STEP A above to yield a dark red solution. The solution was then stirred at 22° C. for 1.5 hrs. A solution of acetic acid (91.7 ml, 1.6 mol) in water (240 ml, 0.3 L/mol) was then added and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer was washed with water (80 ml, 0.1 L/mol), then concentrated in vacuo at 75° C. to yield 2-(4-fluorophenyl)thiophene as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:19]=3)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:57].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:57][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:19]=2)=[O:17])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCO)c3ccccc3)cc2)c2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCBr)c3ccccc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Ethyl 4-{3-[4-(1-phenyl-3-hydroxypropoxy) benzoyl]indol-1-yl}butanoate (4.00 g) obtained in Step 1 was dissolved in methylene chloride (40 ml). Triphenylphosphine (3.24 g) and carbon tetrabromide (3.24 g) were added to the resultant solution while cooling on ice bath and stirred for 30 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture to separate an organic layer. The organic layer was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), obtaining 3.97 g of ethyl 4-{3-[4-(3-bromo-1-phenylpropoxy)benzoyl]indol-1-yl}butanoate as colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 1-(3-nitrophenyl)piperazine (12.0 g; 58 mmol) in DMF (60 ml) was added sodium hydride (2.55 g; 64 mmol, 60% dispersion in mineral oil) in portions over 30 min. The mixture 20 was kept under nitrogen. Ethyl 2-bromoacetate (7.1 ml; 64 mmol) was added, the mixture was stirred at ambient temperature for one hour and then poured into water (250 ml). The oily precipitate was filtered off, re-dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6b (11.0 g; 65%).
Reaction SMILES: [CH3:1][CH:2]([NH:16][CH2:17][CH3:18])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH2:7][CH:6]=[CH:5]1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[CH2:17]([N:16]([CH:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH2:7][CH:8]=[CH:9]1)[C:19](=[O:21])[CH3:20])[CH3:18]
Reactant: CCNC(C)CC1(c2ccccc2)C=CCC=C1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Product: CCN(C(C)=O)C(C)CC1(c2ccccc2)C=CCC=C1
Reaction time: 8 h

Procedure:
1.5 g. of α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine are dissolved in a mixture of 10 ml. of acetic acid anhydride and 8 ml. of pyridine and left to stand at room temperature overnight. Then, the mixture is stirred for 2 hours with 2 N aqueous potassium bicarbonate solution and subsequently extracted with ether. The ether phase is washed with dilute aqueous hydrochloride acid and then with water, dried with sodium sulfate, filtered and concentrated to dryness. The crude product obtained is chromatographed on silica gel with ether. There is obtained N-ethyl-N-[1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)ethyl]-acetamide in the form of an oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[CH:11][C:12]([NH2:13])=[C:14]([Br:23])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Nc1cc(Cl)c(OCc2ccccc2)cc1Br
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 125.3 %

Procedure:
To a suspension of 4-benzyloxy-3-chloroaniline (674 mg) and potassium carbonate (1.14 g) in dichloromethane (32 mL) was added dropwise a solution of bromine (1.25 g) in dichloromethane (16 mL) at −15° C. in one hour, and the mixture was stirred at −15° C. for 75 minutes. Water was added to the reaction mixture and this resulting mixture was stirred vigorously for additional 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.13 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
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: [Na+]
Product: Cc1c(-c2ccccc2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (150 mg, 0.704 mmol), phenylboronic acid (86 mg, 0.704 mmol), sodium carbonate (149 mg, 1.408 mmol) and Pd(PPh3)4. Product used without further purification in the next step. Mass Spectrum (ESI) m/e=255.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.32 mmol), 1,1-dimethylethyl (4-hydroxyphenyl)carbamate (0.0737 g, 0.35 mmol) and ADDP (0.121 g, 0.48 mmol) in THF (3.5 mL) at rt was added tri-n-butylphosphine (0.12 mL, 0.48 mmol). The resulting mixture was stirred 1 hour at rt and diluted with EtOAc until homogeneous. The resulting solution was extracted with 1 N NaOH (×2), washed (water, brine), dried over Na2SO4 and filtered. The filtrate was adsorbed onto a minimal amount of silica gel and purified by flash chromatography (EtOAc/hexanes), affording 0.133 g of the title compound as a colorless gum: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=9.0 Hz, 1H), 7.26 (app. d, J=8.3 Hz, 2H), 7.16 (d, J=2.3 Hz, 1H), 6.98 (dd, J=9.0, 2.5 Hz, 1H), 6.80-6.75 (m, 2H), 6.38 (bs, 1H), 4.24-4.14 (m, 4H), 3.97 (t, J=5.1 Hz, 2H), 1.50 (s, 9H); MS (ESI) m/z 502 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of 4-Isopropoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.31 (d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz), 6.73 (d, 2H, J=6.8 Hz), 7.39 (m, 3H), 7.63-7.70 (m, 4H), 8.82 (d, 2H, J=6.0 Hz), 9.99 (s, 1H). MS: m/z 476.0 (M++1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[N:22]1([CH2:21][C:20]2[C:13]3[O:12]/[C:11](=[CH:10]\[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)/[C:15](=[O:16])[C:14]=3[CH:17]=[CH:18][C:19]=2[OH:36])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCCNCC1
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-1,4-diazepane-1-carboxylate (0.141 g, 0.288 mmol) in methylene chloride (1.5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (1.5 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting solid was washed with methylene chloride to obtain (Z)-7-[(1,4-diazepan-1-yl)methyl]-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.0843 g, 75%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCOB1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2cccnc2)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.06 g, 4.56 mmol), 3-(1,3,2-dioxaborinan-2-yl)pyridine (0.743 g, 4.56 mmol), dioxane (14 mL), and tetrakis(triphenylphosphine)palladium(0) (0.527 g, 0.456 mmol), and K3PO4 (2.90 g, 13.68 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-60% EtOAc/hex, 1.5 L) to the product (0.39 g, 37%). LC/MS: Rt=1.07 min. LC/MS (Condition A): 231.09/233.09.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8]C)=O.Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Cl)(C)C>C1COCC1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: CNOC
Reactant: COC(=O)CCC(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(CCC(=O)N(C)OC)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of methyl 4,4-dimethoxy-butyrate (4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl (4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride (46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide (5.9 g, 99%) as pale liquid. M/Z=191.0
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.Cl.C(OCC)(=O)C>[C:11]([N:19]1[CH2:24][CH2:23][C:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A stirred solution of 176 mL of commercial 1M lithium bistrimethylsilylamide in tetrahydrofuran was diluted with 100 mL of tetrahydrofuran and cooled to -78° C. under inert atmosphere. A solution of 44 g of ethyl 1-benzoyl-4-piperidinecarboxylate in 200 mL of tetrahydrofuran was added dropwise keeping the temperature below -60° C., followed by 21 mL of benzyl bromide. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of 1N hydrochloric acid, 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of 1N hydrochloric acid, dried over MgSO4, and concentrated. The residue was dissolved in 300 mL of toluene, filtered and concentrated under reduced pressure. Drying under reduced pressure gave 56.3 g of ethyl 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylate as a viscous oil homogeneous by thin layer chromatography, eluting with 1:1 ethyl acetate: hexane, 1H NMR (300 MHz, CDCl3) 1.20 (t, 3H), 1.40 (m, 1H), 1.60 (m, 1H), 2.07 (m, 1H), 2.22 (m, 1H), 2.85 (d, 2H), 3.08 (m, 1H), 3.65 (m, 1H), 4.12 (q, 2H), 4.65 (m, 1H), 7.04 (m, 2H), 7.24 (m, 3H), 7.38 (m, 5H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-])=O.[Cl:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:13][CH2:14][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(OCCCl)cc1
Temperature: 100 °C

Procedure:
42 grams (1.05 mole) of sodium hydroxide were dissolved in 75 milliliters of water, and 139 grams (1 mole) of 4-nitrophenol and 235 grams (1 mole) of β-chloroethyl-p-toluene sulfonate were added, while stirring. Subsequently the reaction mixture was heated at 100°C for 4 hours. After cooling, the mixture was made alkaline by means of a solution of sodium hydroxide of 33 % strength and was diluted with about 5 liters of water. The precipitated crystalline product was filtered off with suction, washed with water and dried.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:43])[NH:24][C:25](=[O:42])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH2:34][C@H:35]3[CH2:39][O:38]C(C)(C)[O:36]3)[CH:28]=2)=[CH:14]1>CO.O>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:43])[NH:24][C:25](=[O:42])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH2:34][C@H:35]([OH:36])[CH2:39][OH:38])[CH:28]=2)=[CH:14]1
Reactant: Cn1cc(C2=C(c3cccc(SC[C@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: O
Product: Cn1cc(C2=C(c3cccc(SC[C@H](O)CO)c3)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Yield: 86 %

Procedure:
Toluenesulfonic acid (10 mg) was added to a solution of 3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (60 mg) in methanol (10 mL) and water (1 mL) and the reaction mixture was heated at 50° C. for 2 h. The volatiles were removed and the residue was partitioned between water and EtOAc. The organic layer was washed with NaCl (sat.) and dried over sodium sulfate. The crude product was purified on a silica gel column with 10/45/45 of MeOH/CH2Cl2/hexane and further purified by recrystallization from CH2Cl/hexane to give 3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (47 mg). MS (EI): M+ 408.
Reaction SMILES: [OH-].[Li+].[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([O:19]C)=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C@H:6]([OH:32])[CH2:5]1.Cl>O.C1COCC1>[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C@H:6]([OH:32])[CH2:5]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCCC[C@@H](C)O)[C@H](O)C[C@H]2Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)CCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Reaction time: 24 h
Yield: 83.6 %

Procedure:
Lithium hydroxide (1.2 mL of a 0.5N solution in H2O, 0.605 mmol) was added to a solution of the ester 31 (111 mg, 0.242 mmol) in THF (0.5 mL) at 23° C. After stirring for 24 h the reaction mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 4:1 CH2Cl2/MeOH) provided 90 mg (84%) of the free acid 33 (see Scheme 5).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CC(O)=O>[CH3:16][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
4-(piperazin-1-yl)phenol 2 g (11.24 mmol) and formaldehyde 4.5 ml (37% in water, 56 mmol) were suspended in a mixture of THF/AcOH 5/1 and stirred at room temperature. After 30 minutes, sodium triacetoxyborohydride 4.7 g (22.5 mmol) was added portion-wise. The reaction was let stir a few hours and evaporated down. The crude was purified on silica gel with ethyl acetate/ethanol/NH3 7 N in methanol 8/2/0.2 to give 2.3 g of pink solid as a free base. LC/MS (254 nm) HPLC method 2 Rt 2.4 min. 1H NMR (401 MHz, DMSO-d6) δ 8.78 (s, 1H), 6.71-6.84 (m, 2H), 6.56-6.69 (m, 2H), 2.85-3.03 (m, 4H), 2.46 (br. s., 4H), 2.23 (s, 3H). HRMS (ESI) calcd for C11H16N2O [M+H]+ 193.1336 Found 193.1328.