Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Br:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Br:46][CH2:47][CH2:48][C:49]([O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: O=C(Cl)CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCBr
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of dilinoleylmethanol (II, 560 mg, 1 mmol) and dry triethylamine (0.44 g, 4.2 mmol) in 50 mL of anhydrous CH2Cl2 was added dropwise 3-bromopropionyl chloride (technical grade, 0.34 mL) under nitrogen. The resulting mixture was stirred at room temperature for 3 days. The organic phase was diluted with 50 mL of dichloromethane and washed with water (3×50 mL), brine (50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 610 mg of brownish oil as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-3% ethyl acetate gradient in hexanes as eluent. This resulted in 540 g of a mixture of III as a major product and a by-product. The mixture was used in the following step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH3:18])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.[N:32](OCCC(C)C)=O>C(Cl)(Cl)Cl>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]([CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:2](=[N+:1]=[N-:32])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)[CH3:18]
Reactant: CC(C)CCON=O
Reactant: COC(=O)C(N)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]

Procedure:
A mixture of methyl 2-amino-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoate (5.00 g), acetic acid (4.4 mL) and chloroform (1.60 mL) was treated dropwise with isoamyl nitrite (3.2 mL). The mixture was heated at reflux for 1.5 hrs, cooled, diluted with chloroform (200 mL) and washed successively with dilute hydrochloric acid (200 mL), water (2×200 mL) and brine (200 mL). The chloroform solution was dried over MgSO4, evaporated and the residue chromatographed on silica gel using 3% ethyl acetate in dichloromethane as eluent to afford the title compound, a gum.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:15][S:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:17])[CH:8]2[C:6]([OH:7])=[O:5])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonyl amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (29 mg, 0.054 mmol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester: Cal. 479.5 found (M−H)+ 478.6. Cal. 498.6, found (MNH4)+498.1; 1H NMR (DMSO, 400 MHz), ppm: 7.85 (d, 2H), 7.38 (m, 5H) 7.01 (d, 2H), 5.5 (m, 2H) 4.45 (d, 2H), 4.30 (d, 2H), 4.15 (m, 2H), 4.00 (m, 1H), 3.90 (dd, 1H), 3.83 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[O:8][C:7](=[O:11])[C:6](=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:13])[C:5]=1[OH:22])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:30]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12](=[C:6]2[C:5]([OH:22])=[C:4]([C:1](=[O:3])[CH3:2])[C:9](=[O:10])[O:8][C:7]2=[O:11])[CH3:13])=[CH:20][CH:19]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)cc2)C(=O)OC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a solution of 3.03 g. (0.01 m.) of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, 1.0 g. (0.01 m.) of triethylamine in 150 ml. of tetrahydrofuran is added 0.78 g. (0.01 m.) of acetyl chloride. The resulting mixture is refluxed for two hours, cooled and filtered. The solid is recrystallized to give 3-[1-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 199°-201° C.
Reaction SMILES: [O:1]([C@@H:9]([CH2:14][CH2:15][OH:16])[C:10]([O:12][CH3:13])=[O:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl>[CH2:29]([O:28][CH2:27][O:16][CH2:15][CH2:14][C@H:9]([O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])[C:10]([O:12][CH3:13])=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
(Step 2) To methyl (S)-2-(tert-butyldimethylsiloxy)-4-hydroxybutanoate (220 mg, 0.886 mmol) obtained in Step 1, dichloromethane (0.89 mL), diisopropylethylamine (0.464 mL, 2.66 mmol), and {(chloromethoxy)methyl}benzene (0.30 mL, 2.21 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80), whereby methyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (191 mg, 59%) was obtained,
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)(=O)C>[CH3:25][CH:10]1[CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC1n1c(=O)ccc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CNCCC1N1C(=O)CCc2ccccc21
Yield: 65.4 %

Procedure:
Acetic acid (30 ml) and 1-(1-benzyl-3-methyl-4-piperidinyl)carbostyril (2.1 g) are added to 10 % palladium-carbon (0.5 g) and the mixture is subjected to catalytic reduction at 80° C. under atmospheric pressure. After the catalytic reduction, 10 % palladium-carbon is filtered off and the filtrate is concentrated under reduced pressure. Water is added to the residue and the mixture is basified with aqueous sodium hydroxide solution and then extracted with dichloromethane. After washed with water, the extract is dried with magnesium sulfate and the solvent is distilled off under reduced pressure to give 1-(3-methyl-4-piperidinyl)-3,4-dihydrocarbostyril (1.01 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:8][C:7](C)(C)[O:6][C:5]1=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1.O.CO>C1(C)C=CC=CC=1>[CH3:7][O:6][C:5](=[O:11])[CH:4]([OH:8])[CH2:3][CH2:2][Br:1]
Reactant: CC1(C)OC(=O)C(CCBr)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(O)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 5-(2-bromo-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (synthesized as instructed in Tetrahedron Letters, 1997, 38, 28, 4935) (93 mg, 0.416 mmol) in toluene (0.5 mL) were added p-TsOH.H2O (8 mg, 0.0415 mmol) and methanol (0.5 mL), followed stirring overnight at room temperature. The solution was concentrated in a vacuum, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was dried over sodium sulfate and filtered. The filtrate was concentrated to produce 68 mg of the compound as an oil. 1H NMR (300 MHz, CDCl3) δ 1.98 (1H, m), 2.34 (1H, m), 2.96 (1H, d), 3.56 (2H, m), 3.82 (3H, s), 4.37 (1H, pentet).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(OC([O-])=O)(OC(C)(C)C)=O>CN(C=O)C>[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: NCCCCO
Reactant: Clc1cccc2nccn12
Agent: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCOc1cccc2nccn12
Yield: 41 %

Procedure:
To a suspension of 60% sodium hydride (oily; 1.32 g, 33 mmoles) in DMF (60 ml) was added a solution of 5-chloroimidazo[1,2-a]pyridine (4.59 g, 30.1 mmoles) and 4-aminobutanol (2.68 g, 30.1 mmoles) in DMF (60 ml) at room temperature with stirring and the mixture was stirred at the same temperature for 5 hours. Tert-butyl dicarbonate (9.83 g, 45 mmoles) was added to the reaction solution, which was stirred at room temperature for 13 hours. After the solvent was distilled off, water was added to the residue, which was extracted with ether twice, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was dissolved in methanol (20 ml), followed by the addition of conc. hydrochloric acid (20 ml) and stirring at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with 3N NaOH. After drying over anhydrous potassium carbonate, the solvent was distilled off. The residue was purified by column chromatography (eluent:methanol/chloroform=1:5) to obtain 2.53 g of the desired product (40.9%, light brown oily product).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8](O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]1([NH2:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH2:21])[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[NH:22][C:11]3[C:20]4[C:15]([CH:14]=[CH:13][CH:12]=3)=[CH:16][CH:17]=[CH:18][C:19]=4[NH:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2cccc(N)c12
Reactant: OB(O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Product: Brc1cccc(B2Nc3cccc4cccc(c34)N2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 3-bromobenzene boronic acid (20 g, 0.1 mol) and naphthalene-1,8-diamine (17.3 g, 0.11 mol) in anhydrous toluene (600 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether:EtOAc 5:1 to afford the title compound as a grey solid in 54% yield, 23 g.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:35]=[CH:34][C:18]([C:19]([N:21]4[CH2:26][CH2:25][N:24](C([O:29][C:30]([CH3:33])(C)C)=O)[CH2:23][CH2:22]4)=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=[O:38])C>>[C:30]([OH:38])(=[O:29])[CH3:33].[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])=[CH:34][CH:35]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2n1
Reactant: CC(=O)Cl
Product: CC(=O)O
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCNCC4)cc3)n2n1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
The solution of tert-butyl 4-(4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoyl)piperazine-1-carboxylate (65 mg, 0.14 mmol) was cooled to 0° C. and treated with acetyl chloride (320 mg, 4.07 mmol). The reaction was maintained at room temperature for overnight. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (neutral) to afford (4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)phenyl)(piperazin-1-yl)methanone acetic acid salt (52 mg, 76% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.34 (d, J=8.3 Hz, 2H), 7.87 (s, 1H), 7.64 (d, J=9.6 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 6.75 (d, J=9.6 Hz, 1H), 3.40 (t, J=7.2 Hz, 2H), 3.04 (br. s., 3H), 1.92-2.02 (m, 7H), 1.73 (t, J=7.2 Hz, 2H), 1.41-1.59 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 379.2 [(M+H)+, calcd for C21H27O 379.2].
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:46]/[O:47]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:45])[N:26]([C@@H:29]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[O:39][C:40](=[O:44])[O:41][C:42]=5[CH3:43])=[O:35])[CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[CH3:43][C:42]1[O:41][C:40](=[O:44])[O:39][C:38]=1[CH2:37][O:36][C:34]([N:31]1[CH2:30][C@H:29]([N:26]2[C:25](=[O:45])/[C:24](=[CH:23]/[C:15]3[CH2:14][S:13][C@@H:12]4[C@H:11]([NH:10][C:8](/[C:7](/[C:4]5[N:3]=[C:2]([NH2:1])[S:6][N:5]=5)=[N:46]/[OH:47])=[O:9])[C:18](=[O:19])[N:17]4[C:16]=3[C:20]([OH:22])=[O:21])/[CH2:28][CH2:27]2)[CH2:33][CH2:32]1)=[O:35]
Reactant: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N/O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1

Procedure:
90 mg of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]-thiadiazol-3-yl)-2-triphenylmethyloxyiminoacetyl-amino]-8-oxo-3-[(E)-(R)-2-oxo-1′-(5-methyl-2-oxo-1,3-dioxol-4-ylmethoxycarbonyl)-[1,3′]bi-pyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 10 ml of dichloromethane, 0.5 ml of triethylsilane and 2 ml of trifluoroacetic acid and stirred at room temperature. After 30 minutes the mixture is added dropwise to 150 ml of diethyl ether. The precipitate is filtered, washed with diethyl ether and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(N)c1OC
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1OC

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,3-dimethoxyaniline by a procedure similar to Example 28 (84% yield). 1H NMR (CDCl3): 8.57 (s, broad, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.77-7.86 (m, 3H), 7.55-7.61 (m, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.73-6.75 (m, 1H), 4.00 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][NH2:33].C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[N:33]=[CH:3][CH:4]=2)=[N:8]1
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Reactant: NNCC(F)(F)F
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2CC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of 2,2,2-trifluoroethylhydrazine (0.0483 mL) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.[OH2:36]>O1CCCC1>[F:13][C:14]1[C:19]([CH:1]=[O:36])=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Nc1ccc(F)cc1F)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)NC(C)C
Reactant: O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask containing N,N-diisopropylamine (2.692 mL, 19.21 mmol) in 50.0 mL or tetrahydrofuran, n-butyllithium (2.50 M in hexane, 7.684 mL, 19.21 mmol) was added at −78° C. under an atmosphere of nitrogen. After stirring at −78° C. for 30 minutes, N-(2,4-difluoro-phenyl)-4-trifluoromethyl-benzenesulfonamide (3, 2.09 g, 6.20 mmol) was added, with continued stirring at −78° C. under nitrogen for one hour. The reaction was allowed to come to room temperature over 15 minutes, then poured into water, acidified with 1 N aqueous hydrochloric acid to pH=1, and extracted with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, the appropriate fractions were combined, and the solvents removed to provide the desired compound (4, 1.02 g). MS (ESI) [M−H+]−=364.1.
Reaction SMILES: C(OC([NH:8][CH:9]([C:37]([OH:39])=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:19]([OH:36])=[C:20]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24])(=[O:17])=[O:16])=O)(C)(C)C>FC(F)(F)C(O)=O>[ClH:24].[NH2:8][CH:9]([C:37]([OH:39])=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:19]([OH:36])=[C:20]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24])(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O)C(=O)O
Yield: 139 %

Procedure:
Following the general procedure for Boc deprotection in example 36, N-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′(2-chlorophenyl) urea (104 mg, 0.17 mmol) was stirred in 1 mL of trifluoroacetic acid to form the desired product (64 mg, 61%). LC-MS (m/z) 505.0 (M+).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH2:65])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 21 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of biotin (0.59 g, 2.42 mmol, 1.5 eq), HBTU (0.79 g, 2.10 mmol, 1.3 eq) and DIEA (0.45 mL, 2.60 mmol, 1.6 eq) in DMF (15 mL) was stirred for 20 min at 21° C. before being added dropwise to a solution of tert-butyl-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (400 mg, 1.61 mmol, 1 eq) in DMF (10 mL). The reaction mixture was stirred for 2 h at 21° C., after which the DMF was removed in vacuo to give a yellow residue. The crude product was purified by column chromatography (gradient 2-10% MeOH/CH2Cl2) to yield the desired compound as a white solid (0.61 g, 1.29 mmol, 80% yield). m.p. 106-108° C.; [α]D20.0+23.0 (c 0.6, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.55 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 4.36 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 3.62 (bs, 6H, OCH2), 3.59-3.55 (m, 2H, OCH2), 3.46 (m, 2H, NCH2), 3.31 (m, 2H, NCH2), 3.17 (dt, 3.0, 5.0 Hz, 1H, SCH), 2.92 (dd, J=5.0, 13.0 Hz, 1H, SCHH), 2.79 (d, J=13.0 Hz, 1H, SCHH), 2.27 (t, J=7.0 Hz, 2H, NHC(O)CH2CH2CH2), 1.71 (m, 4H, NHC(O)CH2CH2CH2CH2), 1.47 (br, 11H, C(CH3)3 & NHC(O)CH2CH2CH2CH2); 13C NMR (125 MHz, CDCl3) δ 173.69 (s), 163.92 (s), 155.99 (s), 79.14 (s), 70.03 (t), 69.69 (br t), 61.58 (d), 60.06 (d), 55.19 (d), 40.16 (t), 39.96 (t), 38.91 (t), 35.44 (t), 28.09 (q), 27.80 (t), 27.67 (t), 25.23 (t), * 2 t absent; IR (neat) 3307, 2933, 1691 cm−; HRMS (ES) calcd for C21H38N4O6NaS [M+Na]+ 497.2410, observed 497.2423.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Yield: 94.4 %

Procedure:
2a-(4-Bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (220 mg, 0.72 mmol), 4-(2-methoxyphenyl)piperazine (150 mg, 0.79 mmol) and potassium carbonate (150 mg, 1.1 mmol) were stirred in anhydrous N,N-dimethylformamide (5 ml) at 50° C. for 4 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 280 mg of the title compound (0.68 mmol, 94% in yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(N(CC)CC)C.[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](Cl)=[O:27].O>C1COCC1>[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)=[O:27]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.76 g (18.4 mmol) of ethyl 5-amino-1H-indole-2-carboxylate from Example LXI and 2.05 g (2.82 ml, 20.3 mmol) of triethylamine are added to 40 ml of THF. The mixture is cooled to 0° C., and a solution of 2.48 g (2.56 ml, 18.4 mmol) of 3,3-dimethylbutyryl chloride in 20 ml of THF are added. The mixture is stirred at RT for 2 h and, for work-up, poured into water. The pH is adjusted to 7 and the mixture is extracted 3 times with ethyl acetate. The combined organic phases are dried with sodium sulphate, filtered and dried under reduced pressure.