Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-(5-indanoxy)benzaldehyde (6.2 g) in ethanol (100 mL) was added a solution of semicarbazide hydrochloride (3.2 g) and sodium acetate (2.3 g) in water (50 mL) at room temperature. The mixture was stirred for 1 h, and the resulting solid was collected by filtration, washed with water (3×100 mL) and dried in vacuo to yield the title compound as a pale yellow solid (7.5 g, 97%), mp: 218-220° C. 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 7.24 (d, J=8.1, 1H), 6.94 (d, J=8.7, 2H), 6.92 (s, 1H), 6.82 (d, J=8.1, 1H), 6.45 (s, 2H), 2.84 (t, J=7.5, 4H), 2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])=[CH:8][CH:7]=1)[CH3:5]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: COC(=O)C(C)c1ccc(N)cc1
Product: COC(=O)C(C)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using 2-(4-amino-phenyl)-propionic acid methyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded 2-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-propionic acid methyl ester, which was hydrolyzed to 2-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-propionic acid in step 4, MS (ISP): m/e=526.2 (M−H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.OS(C(F)(F)F)(=O)=O>>[I:1][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[C:10]([F:9])([F:22])[F:23])[NH:17][C:16](=[O:20])[C:15]2=[O:21]
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1Nc2cc(C(F)(F)F)c(I)cc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.8 %

Procedure:
N-Iodosuccinimide (25.0 g, 119.5 mmol) was added to a stirred mixture of 6-trifluoromethylisatin (10.3 g, 47.8 mmol) and triflic acid (75 g) at 0° C. under nitrogen. The ice bath was removed and stirring at room temperature was continued for 7 h. The mixture was poured into ice-water and was extracted with EtOAc. The combined organic extracts were evaporated under reduced pressure and the residue was triturated with CHCl3 to produce a yellow-orange solid. Filtration of the crude solid and purification by recrystallization from CHCl3 gave 5-iodo-6-trifluoromethylisatin xxxiii (10.4 g) as an orange solid. 1H NMR (DMSO-d6) δ 7.17(s, 1 H), 8.08(s, 1 H), 11.27(s, 1 H); ms 340.0 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[C:4]([Br:31])[CH:3]=1.Cl.N1C=CC=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[C:4]([Br:31])[CH:3]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(N)cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(N)cc4Br)oc23)[C@@H]1CO

Procedure:
Compound of example 146 (0.150 g, 0.3 mmol) was demethylated using pyridine hydrochloride (1.5 g, 13 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 17.5 g (84 mmol) of (R)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 150 ml of dry pyridine was cooled to 5° and treated dropwise with 11.5 g (0.1 mol) of methanesulfonyl chloride keeping the temperature at 5°. The reaction mixture was stirred at 5° for two hours and stored at 5° for 18 hours. The reaction mixture was allowed to warm to room temperature over three hours and the solvent was then removed in vacuo. The residue was partitioned between ethyl acetate/water (500 ml each) and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4) and evaporated in vacuo to give 21.2 g of the title compound.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CCCCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCC)n1

Procedure:
A mixture of 6.3 g. 3-n-butylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 4 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-butylthio-1,2,4-triazole, b.p. 157° C./0.6 mm. (95.0% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:3][Cl:4].[Mg].[CH2:14]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])Cl)[CH3:15]>O1CCCC1>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH2:3][Cl:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(CCl)Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1ccc(CC(C)CCl)cc1

Procedure:
a solution of 24.7 parts of 2-methyl-3-(4-bromophenyl)-propyl chloride in 20 parts of tetrahydrofuran (THF) were added dropwise to 2.4 parts of magnesium in 25 parts of THF. The reaction was maintained at from 50° to 52° C., and the mixture was then refluxed for a further 30 minutes. 16.5 parts of triethylchlorosilane were added dropwise at room temperature and the mixture was then refluxed again for 6 hours, cooled and filtered. The solution was concentrated and the residue was distilled to give, at a boiling point of 115°-120° C./0.01 mm Hg, 20.3 parts of 2-methyl-3-(4-triethylsilylphenyl)-propyl chloride of n24 1.5080.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
0.67 ml of 4-tert-butylbenzaldehyde (3.99 mmol) and 600 mg 2-(4-trifluoromethyl-phenyl)-ethylamine (2.66 mmol) were dissolved in 9 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 151 mg (3.99 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 1 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 2:1) to give 673 mg dark red oil (75%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:7]([NH2:8])=[N:19][C:17]3[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=3[CH:20]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: COc1cccc(CC#N)c1
Product: COc1cccc(-c2cc3cnc(N)nc3nc2N)c1

Procedure:
The title compound was prepared according to Example 1, starting from 3-methoxybenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 284-286° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.O[N:11]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:11])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of 2-morpholinoethanol (5 g, 38 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindoline-1,3-dione (9.3 g, 57 mmol) and triphenylphosphine (15 g, 57 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11 ml, 57 mmol) was slowly added drop wise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc—Hexane). The resultant clear oily compound was dissolved in CH2Cl2 (50 ml). Hydrazine hydrate (5.8 mL, 76 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil of O-(2-morpholinoethyl)hydroxylamine (3.5 g, 24 mmol). [M+H] calc'd for C6H14N2O2, 147; found, 147.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:10]1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 57.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (260 mg, 1.2 mmol), 2-nitrobenzene-1-sulfonyl chloride (597 mg, 2.69 mmol), DMAP (cat) and pyridine (0.3 ml, 3.67 mmol) in DCM (5 ml) gave the title compound (275 mg, 56%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>ClCCl>[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:5])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methanesulfonyl chloride (3.069 g, 26.791 mmol) was added to a solution of 4-butylbenzyl alcohol (4.000 g, 24.355 mmol) in dichloromethane (120 mL) at 0° under argon atmosphere. Triethylamine (2.711 g, 26.791 mmol) was added dropwise at a slow speed to this mixture, and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane) to give the title compound (3.64 g, 82%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1I.C(NC(C)C)(C)C>C(Cl)Cl.Cl[Pd](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.[Cu]I>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Clc1ccc(C#Cc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A mixture of 1-chloro-4-ethynyl-benzene (2.71 g, 0.020 mol), 2,4-dichloro-1-iodo-benzene (3.23 mL, 0.024 mol), PdCl2(PPh3)2 (0.10 g, 1.4 mmol), CuI (1.44 g, 7.6 mmol), and diisopropylamine (7 mL) in DCM (i.e., dichloromethane) (100 mL) was stirred at room temperature for 16 h. The mixture was filtered through CELITE. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, hexane) to afford 2,4-dichloro-1-(4-chloro-phenylethynyl)-benzene as a white solid (3.23 g, 87%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:30][C:31]([C@@H:33]([NH:40][C:41]([C@@H:43]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:34][C:35]2[N:36]=[CH:37][NH:38][CH:39]=2)=[O:32])[C@@H:9]([OH:29])[CH2:10][C@@H:11]([CH:26]([CH3:28])[CH3:27])[CH2:12]/[CH:13]=[CH:14]/[C:15](=[O:25])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([NH:30][C:31]([C@@H:33]([NH:40][C:41]([C@@H:43]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:57])[CH3:56])[CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:42])[CH2:34][C:35]2[N:36]=[CH:37][NH:38][CH:39]=2)=[O:32])[C@@H:9]([OH:29])[CH2:10][C@@H:11]([CH:26]([CH3:28])[CH3:27])[CH2:12][CH2:13][CH2:14][C:15](=[O:25])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[C@@H](C/C=C/C(=O)NCCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](CCCC(=O)NCCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 79.9 %

Procedure:
80 mg (0.10 mmol) of t-butyl [(S)-[[(S)-1-[[(1S,2S,4S,E)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-7-(phenethylcarbamoyl)-6-heptenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate are dissolved in 1 ml of methanol and, after the addition of 0.015 g of palladium on charcoal (5%), hydrogenated for 7 hours at room temperature and atmospheric pressure. After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated under reduced pressure, whereby there are obtained 64 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-7-(phenethylcarbamoyl)heptyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 801 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16]Cl>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[C:11]([Cl:16])=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCl
Reactant: CC(=O)Nc1cc(-c2ccccc2)no1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1onc(-c2ccccc2)c1Cl
Yield: 60.4 %

Procedure:
3-Phenyl-5-acetylaminoisoxazole (7) (2.022 g) was dissolved in tetrahydrofuran (50 ml), a solution of chlorine (850 mg) in carbon tetrachloride (8.8 ml) was added dropwise thereto, and the mixture was kept to react at room temperature and under ice-cooling for 30 minutes, respectively. After evaporation the resulting residue was subjected to column chromatography on silica gel (20 g) to give crystals (1.43 g) of 3-phenyl-4-chloro-5-acetylaminoisoxazole (8) from the ether fractions; mp. 141°-141.5° C. (recrystallized from ether-hexane).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:26]=[CH:25]2>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:32]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=3)[CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
To a stirring solution of N-Boc-piperazine (400 mg, 2.1 mmol) and triethylamine (1 mL, 7 mml) in methylene chloride (5 mL) was added 6-chloro-2-naphthalenesulfonyl chloride (500 mg, 1.9 mmol). After 2 h the solution was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on a (Biotage) silica column eluting with ethyl acetate:hexanes (2:8) to give 300 mg (38%). 1H-NMR (CDCl3): δ (s, 9H, 1.4), (m, 4H, 3.07), (m, 4H, 3.55), (dd, 1H, 7.55, J=1,12), (dd, 1H, 7.75, J=1,12), (m, 4H, 7.9), (s, 1H, 8.3), MS (FD) 410.1 M+; IR (chloroform) carbonyl 1691 cm−1. Anal. Calcd: C, 55.54; H, 5.64; N, 6.82; Cl, 8.63; Found: C, 55.71; H, 5.76; N, 6.85; Cl, 8.76.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21](=[O:23])[CH3:22])=[CH:19][N:18]=[C:17]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]OC(OC)N(C)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:20](=[CH:19][N:18]=[C:17]4[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:25]=[CH:26][C:16]4=3)[C:21](=[O:23])[CH:22]=[CH:35]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
1-{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}ethanone (343 mg, 0.720 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 170° C. for 6 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 M hydrochloric acid (3 mL) at 80° C. for 1 hour. After addition of saturated aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound (299 mg, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[CH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.I[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[C:27]2[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29](=[O:34])[CH:28]=[C:27]4[CH3:35])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(=O)[nH]c2ccc(I)cc12
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(=O)[nH]c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g (8.42 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine and 2.34 mL (16.84 mmol) of triethylamine are added to a suspension of 3.0 g (8.42 mmol) of 6-iodo-4-methyl-1H-quinolin-2-one in 20 mL of DMF and the mixture is evacuated three times and gassed with argon. Then 40.1 mg (0.21 mmol) of CuI and 153.9 mg (0.21 mmol) of PdCl2(dppf)-DCM complex are added and the mixture is evacuated again and gassed with argon. The reaction mixture is stirred overnight at RT, combined with EtOAc, and the precipitated product is filtered off and with washed EtOAc. The residue is stirred with a THF/water mixture (1:1), filtered, washed with THF, and dried in the circulating air dryer at 50° C. until the weight is constant. Yield: 3.10 g (99% of theoretical); C23H15ClN2O (M=370.831); calc.: molpeak (M+H)+: 371/373 (Cl); found: molpeak (M+H)+: 371/373 (Cl).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].O1CCCC1.[C:13](Cl)([Cl:15])=[O:14]>C1(C)C=CC=CC=1>[Cl:15][C:13]([NH:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: NN1CCNC1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)NN1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.01 g. (0.01 mol.) of 1-amino-2-imidazolidinone are dissolved in 20 ml. of anhydrous tetrahydrofuran and 20 ml. of a 1M solution of phosgene in toluene are added at 0°. The solution is stirred overnight at room temperature. The almost clear solution is filtered and evaporated to dryness. The 1-(chlorocarbonylamino)-2-oxoimidazolidine is obtained as an oily residue which is used without further purification.