Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[Cl:11][SiH:12]([Cl:14])[Cl:13]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Si:12]([Cl:14])([Cl:13])[Cl:11])=[CH:5][CH:4]=1.[Cl:11][Si:12]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Si:12]([Cl:14])([Cl:13])[Cl:11])=[CH:5][CH:4]=1)([Cl:14])[Cl:13]
Reactant: ClCc1ccc(CCl)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: c1ccccc1
Product: ClCc1ccc(C[Si](Cl)(Cl)Cl)cc1
Product: Cl[Si](Cl)(Cl)Cc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 25 %
Yield: 30 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.059 g (0.20 mmol) of tetrabutylphosphonium chloride, 0.35 g (2.0 mmol) of 1,4-bis(chloromethyl)benzene, 1.35 g (10.0 mmol) of trichlorosilane, and 10 ml of dried benzene were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 0.16 g of 1-chloromethyl-4-(trichlorosilylmethyl)benzene (yield; 30%) and 0.19 g of 1,4-bis(trichlorosilylmethyl)benzene (yield; 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=O)[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([N:30]2[CH2:34][C@H:33]([CH2:35][NH2:36])[O:32][C:31]2=[O:37])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([NH:36][CH2:35][C@@H:33]3[O:32][C:31](=[O:37])[N:30]([C:20]4[CH:21]=[CH:22][C:23]([N:24]5[CH2:25][CH2:26][S:27][CH2:28][CH2:29]5)=[C:18]([F:17])[CH:19]=4)[CH2:34]3)=[O:16])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)c(C)nc2c1
Reactant: NC[C@H]1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Product: COc1ccc2cc(C(=O)NC[C@H]3CN(c4ccc(N5CCSCC5)c(F)c4)C(=O)O3)c(C)nc2c1
Yield: 43 %

Procedure:
It was prepared following the same procedure as in Example 1, starting from 370 mg of 7-methoxy-2-methylquinoline-3-carboxylic acid and 350 mg of N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine. After similar work-up, 244 mg were obtained corresponding to the desired 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-quinolinecarboxamide (Yield=43%).
Reaction SMILES: [C:1]([NH:9][N:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[C:1]([N:9]1[CH:13]([CH3:14])[CH2:12][CH:11]=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: C/C=C/C=NNC(=O)c1cccnc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: CC1CC=NN1C(=O)c1cccnc1
Reaction time: 3 h
Yield: 42.1 %

Procedure:
Nineteen grams of this hydrazone was suspended in 50 ml of biphenyl ether, followed by stirring at 200°-220° C. (bath temperature) for 3 hours. After cooling, the reaction liquid was purified by silica gel chromatography (CHCl3 :MeOH=100:1). Thus there was obtained 8.0 g of 1-nicotinoyl-5-methyl-2-pyrazoline in the form of an oil (bp. 143°-145° C./0.3 mmHg). The yield was 42.1%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C([O-])c1cc(Br)cc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Yield: 99.4 %

Procedure:
5-bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was filtered off and dried in a heated vacuum pistol to give the title compound as a beige solid (4.7 g).
Reaction SMILES: [CH2:1]([C@H:5]([N:9]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][O:23][C:22]2=[O:32])[C:10]1=[O:33])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O.C(O)C1C=CC=CC=1>ClCCl>[CH2:1]([C@H:5]([N:9]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([N:21]2[C@@H:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][O:23][C:22]2=[O:32])[C:10]1=[O:33])[C:6]([O:8][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)O)N1C(=O)[C@@H](N2C(=O)OC[C@@H]2c2ccccc2)[C@H]1CCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)N1C(=O)[C@@H](N2C(=O)OC[C@@H]2c2ccccc2)[C@H]1CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.79 gm (1.76 mMol) 2-(S)-isobutyl-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-(phenyl)ethyl)azetidin-2-on-1-yl]acetic acid in 20 mL dichloromethane was cooled to −4° C. To this solution were added 0.26 mL (1.85 mMol) triethylamine followed by 0.26 mL (1.85 mMol) benzyl chloroformate. After 5 minutes 0.20 mL (1.93 mMol) benzyl alcohol were added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then washed sequentially with two portions each of 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane: ethyl acetate to provide the title compound as a colorless, crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11](=[O:19])[C:10]=1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(OCc2ccccc2)ccn1CC1CC1

Procedure:
A solution of intermediate D1 (3.0 g, 11.7 mmol) and N-bromosuccinimide (2.09 g, 11.7 mmol) in DCM (100 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo yielding D33 (3.56 g, 91%).
Reaction SMILES: C1[O:15][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:12][CH2:13]Cl)OC1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH:4]=[O:15])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCOc1ccccc1C1OCCO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCN(c2ccccc2)CC1
Reaction time: 18 h
Yield: 42.8 %

Procedure:
A suspension of 2.29 g of 2-(2-chloroethyloxy)benzaldehyde ethyleneacetal, 1.73 g of N-phenylpiperazine, 1.50 g of anhyrous potassium carbonate and 15 ml of dimethylformamide is stirred at 70°-80° C. for about 18 hours under argon atmosphere. The reaction mixture is concentrated under reduced pressure to remove dimethylformamide. Water is added to the residue, and the aqueous mixture is extracted with ether. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is dissolved in 10 ml of methanol, and 10% hydrochloric acid is added thereto. The mixture is heated at 60° to 70° C. for 10 to 20 minutes, and then is made alkaline with 10% sodium hydroxide solution and extracted with ether. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:chloroform=2:8). 1.33 g of 2-[2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde are obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1cccc(F)c1
Product: N#Cc1cccnc1-c1cccc(F)c1
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloro-3-cyanopyridine and 3-fluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.9 (M+H)+; 1H NMR (CDCl3) δ 7.19-7.26 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 7.47-7.54 (m, 1H), 7.65 (ddd, J=9.7, 2.2, 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.10 (dd, J=8.1, 1.9 Hz, 1H), 8.89 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[H][H].F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1>CS(C)=O>[C:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2nc[nH]c12
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1cccc2c1ncn2-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Acetylbenzimidazole (4.4 g, 27.5 mmol) was dissolved in dry DMSO (40 ml) and cooled. Sodium hydride (0.91 g, 80% suspension in oil) was added and the mixture was allowed to warm to room temperature. When the evolution of hydrogen had ceased 1-fluoro-3-nitrobenzene was added and the mixture was heated to 120° C. overnight. After cooling the reaction mixture was poured into ice-water and the crude product was filtered off. Purification was achieved by column chromatography on silica gel with ethyl acetate/petroleum ether (1:1) as the eluent. Yield 2.09 g, mp 175°-177° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:26])[C:21]([O:24][CH3:25])([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:44])[C@@H:15]2[CH2:27][CH2:28][C@H:29]2[O:34][C:33](=[O:35])[CH2:32][C@H:31]([O:36][Si](C(C)(C)C)(C)C)[CH2:30]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:26])[C:21]([O:24][CH3:25])([CH3:22])[CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:44])[C@@H:15]2[CH2:27][CH2:28][C@H:29]2[O:34][C:33](=[O:35])[CH2:32][C@H:31]([OH:36])[CH2:30]2)=[CH:10]1
Reactant: COC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(C)(C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 98.1 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 814 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-methoxy-2-methylpropionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 148, above] and 17.5 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 518 mg of the title compound as colorless needle-like crystals, melting at between 150° and 152° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11a, and 1-methyl-1H-imidazole-4-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.99 (d, 1H), 8.63 (m, 1H), 8.50 (d, 1H), 7.88 (d, 2H), 7.55 (s, 1H), 7.42 (s, 1H), 7.32 (d, 2H), 7.13 (m, 1H), 7.04-6.97 (m, 3H), 4.47 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 506 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 71.5 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.33 g, 1.2 mmol) (prepared according to Example 1, step A), 1,4-dioxane (20 mL), 2-(3-aminophenyl)ethanol (0.22 g, 1.6 mmol), and p-toluenesulfonic acid monohydrate (0.080 g, 0.42 mmol). The mixture was heated at 105° C. for 3 hours and then an aqueous solution of NaHCO3 (saturated) was added. The organic solvent was removed under vacuum followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The crude was purified by silica gel column chromatography to provide the desired product as a white solid (0.33 g, 74% yield). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[Br:7][C:6]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: Cc1onc(N)c1Br
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-amino-4-bromo-5-methylisoxazole (2.58 g, 14.6 mmol) and DMAP (893 mg, 7.3 mmol) in 60 mL dichloromethane at −78° C. was added pyridine (6 ml, 74.1 mmol) followed by 2,2,2-trichloroethyl chloroformate (8 ml, 58 mmol). The reaction was allowed to warm to room temperature while stirring over ca. 4 hours. Ice water was added, the aqueous phase neutralized with saturated aq. NaHCO3, and the product extracted with ether (3×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:15]2)=[O:11])[S:6][CH:7]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][N:16]1[CH2:17][CH2:18][O:19][C@@H:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][S:8][C:5]2[S:6][CH:7]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[N:4]=2)[CH2:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2nnn[nH]2)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
The resultant product (457 mg) of (22-1), sodium azide (78 mg) and ammonium chloride (525 mg) were suspended in dimethylformamide (3 mL), and the mixture was heated under reflux for 4 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (193 mg) as an orange powder.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.[CH3:15][O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][C:17](=[O:29])[C@@H:18]([NH:28][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH2:11])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 4-iodo-2-nitrobenzoic acid (0.35 g, 1.20 mmol) dissolved in SOCl2 (5 mL) was heated at reflux for 2 h. The mixture was concentrated and the resulting liquid was dissolved in DMF (5 mL). DMAP (161 mg, 1.32 mmol) and 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (0.37 g, 1.32 mmol) were added and the solution was stirred overnight at rt. The mixture was poured into water and extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), and concentrated to provide the crude product as a yellow oil. The oil was purified by flash chromatography (hexanes/EtOAc) to provide the product as a colorless oil (50%, 313 mg). 1H NMR (400 MHz, CDCl3): 7.59 (d, J=8.1, 2H), 7.37 (d, J=8.2, 1H), 7.28 (d, J=2.0, 1H), 7.18 (d, J=8.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.49 (d, J=7.4, 1H), 5.10-5.04 (m, 1H), 3.81 (s, 3H), 3.33-3.17 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16](=[O:19])(=[O:20])[CH2:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCS(=O)(=O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenyl]-amide (as prepared in the previous step, 145 mg, 0.261 mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2 mL of TFA. The resulting solution was stirred at RT for 3 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-25% EtOAc/DCM) gave 83 mg (90%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.34 (s, 1H), 9.60 (s, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.75 (s, 1H), 7.30 (dd, 1H, J=8.4, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.86 (m, 1H), 3.11-3.23 (m, 4H), 2.80 (dddd, 1H, J=12.2, 12.2, 2.8, 2.8 Hz), 2.40-2.57 (m, 2H), 2.17-2.35 (m, 6H), 1.74-1.91 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O3S, 425.2 (M+H). found 425.6.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:37][CH2:38][CH3:39])([CH2:34][CH2:35][CH3:36])[C:7](=[O:33])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=4[S:15](=[O:32])(=[O:31])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:8]3[C:7](=[O:33])[C:6]([CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH3:39])[C:5]4[C:10]([C:9]=3[OH:12])=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)=[N:14][S:15](=[O:31])(=[O:32])[C:16]=2[CH:22]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2cc(F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
The compound of Example 17B (76 mg, 0.14 mmol) was added to trifluoroacetic acid (6 mL) and stirred at ambient temperature for 30 min. The solution was concentrated in vacuo and the residue was stirred with ethyl acetate and saturated sodium bicarbonate solution for 30 min. The organic layer was extracted with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo to afford the title compound (69 mg, 100%) as a foam. 1H NMR (300 MHz, DMSO-d6): δ 0.62 (m, 8 H) 0.86 (dd, J=12.32, 6.43 Hz, 2 H) 2.00 (s, 2 H) 2.16 (m, 2 H) 6.96 (m, 2 H) 7.43 (d, J=8.82 Hz, 1 H) 7.63 (m, 1 H) 7.82 (m, 2 H) 13.48 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:26]([OH:28])=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(CCc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(CCc1ccccc1)C(=O)O
Yield: 77 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-homophenylalanine to provide the title compound in 77% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:9][CH:10]=1)(=O)C.[CH3:25]O>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:25])=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: CC(=O)Nc1cccc(C(=CCCCC(=O)O)c2cccnc2)c1
Agent: Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1

Procedure:
65 g of 6-(3-acetylaminophenyl)-6-(3-pyridyl)hex-5-enoic acid are refluxed for 4 hours in a mixture of 400 ml of methanol and 200 ml of methanolic hydrochloric acid. The solvent is removed and the residue is taken up in water. The aqueous phase is washed with ethyl acetate and adjusted to pH 8-9 by the addition of 4N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The organic phase is washed, dried and evaporated down.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15](OC)=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH3:20].Cl>O>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([NH2:20])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: N
Agent: Cl
Solvent: O
Product: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reaction time: 11 h
Yield: 73.1 %

Procedure:
Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (37 g) was added to saturated methanolic ammonia solution (1850 ml) at 25-30° C., the mixture was stirred for 6 to 16 hours at the same temperature. The reaction mass was distilled under vacuum to remove the solvent after completion of the reaction. Water (148 ml) was added to the resulting residue, followed by adjusting the pH to 2-4 with concentrated HCl and then filtering the aqueous layer. The pH of the resulting aqueous layer was adjusted to 9-10 with ammonium hydroxide solution. The separated solid was filtered, washed with water (100 ml) and then dried to produce 25.5 g of 5-(1-piperazinyl)benzofuran-2-carboxamide (Purity by HPLC: 99%; Yield: 73.1%).