Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:18][CH2:19][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:25]=2[CH2:26]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCOCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCOCC3)c(F)c2)c1
Yield: 39.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-morpholin-4-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.2 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[C:24](Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC(=O)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.6 %

Procedure:
1-Amino-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (50 mg, 0.16 mmol) prepared in Example 20 was dissolved in dichloromethane (10 mL), and propionyl chloride (150.38 mg, 0.14 mL, 1.62 mmol) and triethylamine (180.12 mg, 0.25 mL, 1.78 mmol) were added thereto in order at 0° C. The mixture was stirred for 24 hrs at RT, and an excess amount of propionyl chloride (2 mL) was further added thereto to be stirred for 15 hrs. The resulting mixture was washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 29 mg of the titled compound (yield: 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.[ClH:24].C(O)C>C(O)C>[ClH:24].[N:1]1([C:17]2[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[S:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Reactant: C1CNCCN1
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Piperazine (53.6 g) was added to the resulting toluene solution, reflux was conducted for 1 hour, and the resulting solution was cooled to room temperature. Washing was carried out with water (125 ml×3) to remove remaining piperazine, and an organic layer was vacuum distilled to produce oil. The oil was dissolved in ethanol, and a hydrochloric acid-ethanol solution was added thereto, to produce 11-piperazinyl-dibenzo[b,f][1,4]thiazepine hydrochloride (46.4 g).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:21])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]>O1CCCC1>[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:1][NH2:2])=[O:21])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]
Reactant: NN
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)NN)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrazine (0.041 ml, 1.30 mmol) was added dropwise with stirring to a solution of 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one (0.500 g, 1.08 mmol) in tetrahydrofuran (3 ml). The mixture was stirred at r.t. for 2 h, and the heavy white precipitate filtered, washed with ether, and dried under vacuum. Yield 0.295 g (88%). MS (m/z): [M+H]+=311.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[S:16])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Solvent: c1ccncc1
Product: S=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Yield: 187.1 %

Procedure:
A mixture of 3.0 g of 6-(4-chlorophenyl)-pyridazinone, 50 ml of dry pyridine and 3.2 g of phosphorus pentasulfide was refluxed for 1 hour, evaporated to dryness and extracted with 200 ml of ether. The ether extract was washed with water (3×100 ml), brine (100 ml), dried over magnesium sulfate and evaporated to yield 3.0 g of 6-(4-chlorophenyl)-pyridazinthione as a yellow solid.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2/[C:23](/Cl)=[N:24]/[OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:3]=[C:2]([C:1]([NH2:5])=[O:4])[O:25][N:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2/C(Cl)=N/O)N1OCc1ccccc1
Reactant: C#CC(N)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Propiolamide (0.30 g, 4.37 mmol) was added to a solution of (2S,5R,Z)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbimidoyl chloride (3.64 mmol) in dry DCM (10 mL), followed by the addition of TEA (0.56 mL, 4.0 mmol) in DCM (2 mL) over a 30 minute period. The reaction mixture was stirred at rt overnight. Then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 5:1 to 1:2, petroleum ether/EtOAc containing 1% TEA) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.4 g, 32%) as a yellow solid. ESI-MS (EI+, m/z): 343 [M+H]+.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].C(O)C.S(O[CH:42]([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:48])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)OCC)cc1

Procedure:
To a warm mixture of 7 g. (18.3 m moles) sodium 4-(hexadecylamino)benzoate in 100 ml. ethanol is added 4.7 g. (18.3 m moles) ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (2.22 g, 6 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as a white solid (2.70 g, 86%, 92% purity). MS (ISP) 484.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)[NH:8][CH:7]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]2=[O:29].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH2:16][CH2:17]3)[N:10]=2)[C:5](=[O:29])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]1)[CH3:31]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)C(F)(F)F)CC3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(=O)C(F)(F)F)CC3)c(F)cc2c1=O

Procedure:
Ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate was treated with ethyl iodide and potassium carbonate in dimethyl formamide by the same procedure as described in Example 1 to form ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate. This product was hydrolyzed by treating with aqueous potassium carbonate in a mixture of chloroform and methanol to give ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate, m.p. 150°-151° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.CO.[NH2:15][OH:16]>C1C=CC=CC=1>[OH:16][N:15]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: NO
Solvent: CO
Solvent: c1ccccc1
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
A mixture of 3-hydroxyphenylglyoxylic acid (3.32 g.) and 1N-methanol solution of hydroxylamine (45 ml.) was refluxed with stirring, for 25 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in 1N-sodium hydroxide aqueous solution (50 ml.) and the solution was washed with ether, acidified with hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried and concentrated to give yellow oil. To the oil was added benzene and benzene was distilled off. The residue was crystallized with petroleum ether and the crystals were collected by filtration, washed with petroleum ether and dried to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>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.C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:38]([Si:39]([CH3:42])([CH3:40])[CH3:41])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A resealable tube was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone 3 (5.000 g, 11.98 mmol), acetonitrile (100 mL), and triethylamine (6.06 g, 8.35 mL, 59.9 mmol). Dichlorobis(triphenylphosphine)palladium (II) (0.841 g, 1.20 mmol) and 1-phenyl-2-(trimethylsilyl)acetylene were added and argon was bubbled through the solution. The tube was sealed and the mixture stirred at 100° C. for 4 h. The reaction mixture was concentrated to afford 7-benzyl-3-phenyl-2-(trimethylsilyl)furo[2,3-b]pyridin-4(7H)-one 4d as a brown oil. MS (MH+) 374.2; Calculated 373 for C23H23NO2Si.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][CH:34]1[CH2:36][O:35]1>[I-].[K+].CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:33][CH:34]5[CH2:36][O:35]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCC4CO4)cc32)nc1-c1cccc(Cl)c1
Yield: 75 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.5 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.012 mL (0.15 mmole) of 2-chloromethyl-oxirane was heated at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, diluted with 20 mL of water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.032 g of 4-(3-chloro-phenyl)-2-(6-oxiranylmethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.39a) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][CH:46]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][CH2:46][N:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCNC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Product: CC(C)(C)[Si](C)(C)OCCCN(CCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)C1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 46 %

Procedure:
Starting from the compound of Example 13 and 3-(tert-butyldimethylsilyloxy)-propionaldehyde and using procedure E, the title compound was obtained as a yellow foam (62 mg; 46% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=401 (M+ of free base). α[D]589 =-14.17 (c=0.45, methanol).
Reaction SMILES: [C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH2:29][C:30]1[S:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH2:39])=[CH:32][C:31]=1[CH3:40])[CH3:28]>>[C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8]([NH:39][CH2:38][CH2:37][S:36][CH2:35][C:33]1[S:34][C:30]([CH2:29][N:27]([CH3:26])[CH3:28])=[C:31]([CH3:40])[CH:32]=1)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(CSCCN)sc1CN(C)C
Reactant: CSC(=C[N+](=O)[O-])NCC(O[SiH](C)C)(c1cccc(C)c1)C(C)(C)C
Product: Cc1cccc(C(CNC(=C[N+](=O)[O-])NCCSCc2cc(C)c(CN(C)C)s2)(O[SiH](C)C)C(C)(C)C)c1
Yield: 80 %

Procedure:
In the same manner as in Example 6-(2), 3.8 g of 1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)-ethyl]amino}-1-methylthio-2-nitroethene and 2.6 g of 2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamine were reacted and treated to obtain 4.6 g (yield 87%) of oily N-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.3 %

Procedure:
tBuOK (434 mg; 3.87 mmol; 1.1 eq.) was added to a solution of 2,4-difluoro-benzaldehyde (500 mg; 3.52 mmol; 1 eq.) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (779 mg; 3.87 mmol; 1.1 eq.) in 1,4-dioxane (3 mL) and reaction mixture was stirred at room temperature for 15 minutes. The solution was diluted with water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (208 mg, 18%) as white solid. HPLC (max plot) 92.8%; Rt 4.46 min.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:15]([O:17]C(Cl)=O)[CH3:16]>ClCCl>[CH2:15]([O:17][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])[OH:7])[CH3:16]
Reactant: CCCC[PH](=O)O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCP(=O)(O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butylphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butyl-phosphonic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:9]2)=CC=1.ClC(OCCCl)=O.CO>ClCCCl>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2
Reactant: COCCOCCOc1cccc2c1CN(Cc1ccc(OC)cc1)C2
Agent: O=C(Cl)OCCCl
Solvent: ClCCCl
Solvent: CO
Product: COCCOCCOc1cccc2c1CNC2
Reaction time: 17 h

Procedure:
A solution of 2-(4-methoxy-benzyl)-4-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-isoindole (45 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) was treated with -chloroethyl chloroformate (0.1 mL, 0.93 mmol). After 17 hours, methanol (5 mL) was added and the mixture stirred for 3 hours. The solvents were removed in vacuo to afford the title compound as a greenish-black solid, which was used without further purification. 1H NMR (methanol-d4) 7.36 (1H, t), 6.98 (2H, d), 4.60 (2H, s), 4.57 (2H, s), 4.23-4.21 (2H, m), 3.85-3.83 (2H, m), 3.69-3.67 (2H, m), 3.57-3.54 (2H, m), 3.36 (3H, s). MS: [M+H]+ 238.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N+:3]=1[O-].[CH3:16][C:17]([O:19]C(C)=O)=[O:18]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]([O:19][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1)(=[O:18])[CH3:16]
Reactant: Cc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1nccc(OCC(F)(F)F)c1C
Temperature: 92.5 °C
Yield: 94 %

Procedure:
40 ml of 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (0.078 mole) in methylene chloride were dropwise added to a solution of 28.7 ml acetanhydride and 0.182 g 4-dimethylaminopyridine, then methylene chloride was distilled off and the residue was heated to a temperature of from 90 to 95° C. for 4-5 hours. At the end of the reaction, 3.6 ml of water were added and acetic acid was removed by vacuum distillation to obtain an oil product. The yield was 94-96%, determined by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24]C(=O)C)[CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46](Cl)=[O:47])(=[O:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46]([NH:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([OH:28])[CH2:23][OH:24])[CH2:10][CH:11]([OH:17])[CH2:12][OH:13])=[O:8])=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(CCCCl)C(=O)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CC(COC(C)=O)OC(C)=O)CC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(CCCCl)OC(C)=O)c(I)c(C(=O)N(CC(O)CO)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Amino-3-acetoxymethyl-N,N-bis-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide g, 6.85 mmol) was dissolved in dry N,N-dimethylacetamide (10 ml) and the mixture was cooled in an ice-bath. 2-Acetoxy-5-chloropentanoyl chloride (4.36g, mmol) was then added dropwise. The mixture was stirred at room temperature for 24 h, and then added slowly to aqueous sodium hydrogen carbonate (5%, 600 ml) with efficient stirring. A precepitate was formed and filtered off, redissolved in methylene chloride (250 ml) which was washed with water (6×70 ml), dried (Na2SO4) and concentrate in vacuo. The residue was chromatographed on a column of silica gel using heptane/ethyl acetate (3/7) as the eluent Yield: 7.30 g (97%).