Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:24][CH2:23]4)[CH:21]=3)=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]>C(O)C.O.Cl.[Fe]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:24][CH2:23]4)[CH:21]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
Iron powder (1.010 g, 18.09 mmol) was added to a solution of isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.86 g, 1.81 mmol) in ethanol (12 mL) and water (2.4 mL). 1 N aqueous HCl (1 drop) was added, and the reaction was heated at 90° C. for 2 h. The mixture was cooled to rt and filtered through a pad of Celite, washing with ethanol. The filtrate was concentrated, and ethyl acetate was added. The solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 398 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][NH:7]2.C(OC(=O)CNC1C=CC=C(Br)C=1N)C.[OH-].[Na+].OO>Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[N:7]2
Reactant: O=C1CNc2cccc(Br)c2N1
Agent: CCOC(=O)CNc1cccc(Br)c1N
Agent: Cl
Agent: OO
Product: O=c1cnc2cccc(Br)c2[nH]1
Temperature: 95 °C

Procedure:
A sealable tube is charged with 4.99 g (39.549 mmol) of a mixture of 8-Bromo-3,4-dihydro-1H-quinoxalin-2-one with (2-Amino-3-bromo-phenylamino)-acetic acid ethyl ester (as obtained in step 1.2). 50 mL of a 1M NaOH solution and 12.1 ml of a 30% H2O2 aqueous solution are added. The tube is sealed and heated to 95° C. for 1 h. After cooling, 50 mL of 1M HCl solution are added slowly and the brown solid is collected by filtration, to afford, after drying in HV at 50° C., the title compound which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)Cl)cc1
Yield: 380.5 %

Procedure:
In a 55-L reactor, 2.5 kg of 4-methoxycinnamic acid and 11 kg of ethyl acetate were placed to give a suspension. The suspension was combined with 1.75 kg of thionyl chloride (1.05 times the mole of 4-methoxycinnamic acid) added dropwise while maintaining the reactor inside temperature at 65° C. to 70° C. After the dropwise addition, a reaction was performed until the conversion from 4-methoxycinnamic acid reached 99% or more. After the completion of reaction, about 5 kg of ethyl acetate was distilled off together with unreacted thionyl chloride and an acidic gas at 60° C. under reduced pressure. After the concentration, the resulting mixture was combined with ethyl acetate in an amount equal to the distilled-off amount and yielded 15.2 kg of a 4-methoxycinnamoyl chloride/ethyl acetate solution (2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Temperature: 100 °C
Yield: 79.1 %

Procedure:
Compound 121a was synthesized using the same procedure as example 112a, except using tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (0.83 g, 3.0 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (0.88 g, 3.3 mmol), cesium carbonate (1.27 g, 3.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.275 g, 0.3 mmol), Xantphos (0.26 g, 0.45 mmol) and 1,4-dioxane (30 mL). The reaction mixture was heated at 100° C. overnight. Work-up and purified by flash column chromatography (silica, ethyl acetate/hexanes) to give a 80% yield (1.1 g) of 121a as a solid: MS (ESI+) m/z 465.0 (M+H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14](#N)C>[Pt](=O)=O.CO>[CH3:14][N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[S:1][C:5]=2[CH2:6]1
Reactant: COC(=O)c1cc2ccncc2s1
Reactant: CC#N
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1cc2c(s1)CN(C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of methyl thieno[2,3-c]pyridine-2-carboxylate (370 mg, 1.9 mmol) and acetonitrile (7.3 mL) was stirred at 42° C. for 6 h over which time the formation of a precipitate was observed. Upon cooling to room temperature, the solvent was removed in vacuo. To the material thus obtained was added methanol (10 mL) and platinum dioxide (100 mg, 0.4 mmol). The mixture was stirred under a balloon H2 atmosphere pressure for 4 h. The solvent was then removed under reduced pressure and the residue obtained was partitioned between EtOAc and saturated aqueous NaHCO3. Upon separation, the aqueous layer was extracted with EtOAc three additional times. The combined organic phases were further washed with saturated aqueous NaHCO3, water and brine, dried over anhydrous MgSO4 and concentrated to give methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.4 g, 95%) as an off-white solid. LCMS: (FA) ES+ 212; 1H NMR (CDCl3, 300 MHz) δ7.50 (s, 1 H ), 3.85 (s, 3 H ), 3.64 (m, 2H), 2.73 (m, 4 H ), 2.48 (s, 3 H ).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:22])[CH2:6][CH:7]([CH3:21])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=1>O.CO>[C:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:7]([CH3:21])[CH2:6][C:5]([OH:22])=[O:4])=[CH:11][CH:12]=1)([OH:19])=[O:18]
Reactant: COC(=O)Cc1ccc(CCC(C)CC(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CCc1ccc(CC(=O)O)cc1)CC(=O)O

Procedure:
A solution of 20 g of potassium hydroxide in 40 cc of water is added to a solution of 19.3 g of 5-(4-carbomethoxymethylphenyl)-3-methylvaleric acid methyl ester in 200 cc of methanol and the mixture is heated at reflux for 2 hours. The solution is subsequently concentrated, diluted with water, acidified with 2 N hydrochloric acid and extracted with ether. The crude 5-(4-carboxymethylphenyl)-3-methylvaleric acid obtained after concentrating the ether extract, is recrystallized from ether/hexane. M.P. 100°-102°.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29]C)=[O:27])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]3[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Product: COC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Yield: 81.8 %

Procedure:
The title compound was prepared 3-chloro-2-[4-(3-chloro-propoxy)-phenyl]-2H-indazole (0.5 g, 1.6 mmol) and ethyl isonipecotate (0.37 g, 2.3 mmol) using the procedure of step 4 of the Example 4 to provide the title compound (0.56 g, 75%) as a hydrochloride salt.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[C:24]([CH:32]2[CH2:34][CH2:33]2)=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:29]=2)[C:24]([CH:32]2[CH2:33][CH2:34]2)=[N:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: Oc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCOc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzyl 2-bromoethylcarbamate (1.0563 g) which can be prepared according to the method described in Reference example 40, etc. was dissolved in dehydrated DMF (5 mL), added with 1-benzyl-3-cyclopropylindazol-6-ol (533.4 mg) which can be prepared according to the method described in Reference example 3, etc. and potassium carbonate (879.1 mg), and stirred overnight at 50° C. under nitrogen atmosphere. After cooling to room temperature, the reaction solution was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the resulting reside was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=81:19→60:40) to obtain the title compound as a crude product (508.2 mg).
Reaction SMILES: [OH:1][CH:2]1[C:7]2([CH2:26][OH:27])[O:8][CH:9]([N:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][C:11]3=[O:25])[CH:3]1[O:4][N:5]([C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:6]2.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)(C2C=CC=CC=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>N1C=CC=CC=1>[CH3:52][O:51][C:48]1[CH:47]=[CH:46][C:45]([CH:44]([C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[O:27][CH:26]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]23[CH:2]([OH:1])[CH:3]([CH:9]([N:10]4[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[N:12][C:11]4=[O:25])[O:8]2)[O:4][N:5]([C:28](=[O:37])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:6]3)=[CH:50][CH:49]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ccn(C2OC3(CO)CN(C(=O)COc4ccccc4)OC2C3O)c(=O)n1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C23CN(C(=O)COc4ccccc4)OC(C(n4ccc(NC(=O)c5ccccc5)nc4=O)O2)C3O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 165.1 %

Procedure:
To a solution of Compound 67 (1.80 g, 3.54 mmol) in anhydrous pyridine (15 mL) was added 4-N,N-dimethylaminopyridine (65 mg, 0.53 mmol) and 4,4′-dimethoxytrityl chloride (2.04 g, 6.02 mmol). After stirring at room temperature for 6 hours the reaction mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 mL), washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (2% methanol in CH2Cl2) yielded 2.37 g (82%) of Compound 68 as a pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:16]1([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:21]2)[CH2:18][CH2:17]1
Reactant: Nc1ncn(CC2CC2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(CC4CC4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-cyclopropylmethyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish foam (Yield=45%). MS ISP (m/e): 320.1 (100) [(M+H)+].
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1)#[N:2].[CH2:21]([Mg]Br)[CH3:22].[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:2][C:1]1([C@@H:3]2[CH2:7][CH2:6][N:5]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:4]2)[CH2:22][CH2:21]1
Reactant: N#C[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC1([C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)CC1
Reaction time: 18 h
Yield: 48 %

Procedure:
(3R)-3-Cyano-1-(1,1-diphenylmethyl)pyrrolidine (0.70 g) was dissolved in tetrahydrofuran under an argon atmosphere. Titanium(IV) tetraisopropoxide (0.86 mL) and ethylmagnesium bromide (1.78 mL, 3 mol/L ether solution) were added to the solution at room temperature. After 05 h, trifluoroboron-diethyl ether complex (0.67 mL) was added dropwise to the mixture, and the resultant mixture was stirred at room temperature. After 18 h, 2 mol/L aqueous sodium hydroxide (30 mL) was added to the reaction mixture, and the resultant mixture was stirred for 0.25 hours. The product that precipitated was collected through filtration and then extracted. The formed aqueous layer was again extracted with ethyl acetate, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystals. The residue was subjected to silica gel chromatography, to thereby give the target compound (0.374 g, yield 48%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.P([O-])(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]2[O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:2]=1)=[O:7]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (12.7 g., 100 mmole) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (55.4 g., 110 mmole) was heated in an oil bath maintained at 160-165°. After the sugar had melted, bis(p-nitrophenyl) phosphate (400 mg.) was added with stirring and the mixture was heated under diminished pressure at 160-165° for 15-20 min. Crystallization of the residue from ethyl acetate-ethanol provided 42.5 g. (74.5%) of product with M.P. 137-139°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH2:21]NCCC2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:74][CH2:75][CH2:76][C:77]1[CH:121]=[CH:120][C:80]([O:81][CH2:82][CH2:83][N:84]([CH3:119])[C:85]([C:87]2[CH:88]=[C:89]([S:93]([C:96]3[CH:97]=[C:98]4[C:103](=[C:104]([CH3:106])[CH:105]=3)[N:102]=[CH:101][C:100]([C:107]([NH2:109])=[O:108])=[C:99]4[NH:110][C:111]3[CH:116]=[CH:115][CH:114]=[C:113]([O:117][CH3:118])[CH:112]=3)(=[O:95])=[O:94])[CH:90]=[CH:91][CH:92]=2)=[O:86])=[CH:79][CH:78]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si:67]([C:70]([CH3:71])([CH3:73])[CH3:72])([CH3:69])[CH3:68])[CH2:21][NH:74][CH2:75][CH2:76][C:77]2[CH:121]=[CH:120][C:80]([O:81][CH2:82][CH2:83][N:84]([CH3:119])[C:85]([C:87]3[CH:88]=[C:89]([S:93]([C:96]4[CH:97]=[C:98]5[C:103](=[C:104]([CH3:106])[CH:105]=4)[N:102]=[CH:101][C:100]([C:107]([NH2:109])=[O:108])=[C:99]5[NH:110][C:111]4[CH:116]=[CH:115][CH:114]=[C:113]([O:117][CH3:118])[CH:112]=4)(=[O:94])=[O:95])[CH:90]=[CH:91][CH:92]=3)=[O:86])=[CH:79][CH:78]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCN)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 140, using Intermediate 95 in place of Intermediate 94. ES/MS calcd for C60H67N6O9SSi+ 1075.45. Found m/z=1075.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12](Cl)=[CH:13][C:14]=1[Cl:15]>O.C(O)C>[N+:17]([C:11]1[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[C:14]([Cl:15])=[CH:13][C:12]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: NCP(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
3.3 g (30 mmol) of aminomethanephosphonic acid in 120 ml of water and 120 ml of ethanol are introduced together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene, and it is refluxed for 4 hours at 120° C. bath temperature. After removing the ethanol in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is adjusted acidic with 4 N hydrochloric acid to pH 1 and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid of melting point 207.3° C. is obtained.
Reaction SMILES: C[CH2:2][CH2:3][CH:4]([OH:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:16]CCCC(O)CCCCCCCCC.CCCCCC(O)CCCCCCCC>>[CH3:2][CH2:3][CH:4]([OH:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:16]
Reactant: CCCCCCCCCC(O)CCCC
Reactant: CCCCCCCCCCC(O)CCC
Agent: CCCCCCCCC(O)CCCCC
Product: CCCCCCCCCCCC(O)CC

Procedure:
4-tetradecanol; 5-tetradecanol; 6-tetradecanol;
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)CC1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (33.0 g, 115 mmol) was treated with 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperazine (26.4 mL, 115 mmol) according to the method described in Part E of Example 1. The reaction was stirred overnight. The crude product was triturated with diethyl ether and isolated by filtration to provide 33.05 g of tert-butyl 4-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)C.[Pd]>[C:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2ccc(N)cc21
Yield: 89 %

Procedure:
6-Nitroindoline (15.63 g, 0.095 mol) was refluxed for 0.25 h in acetic anhydride (100 ml), cooled, and the precipitate filtered and washed with water, before drying in vacuo. This material (16.6 g, 0.08 mol) was hydrogenated in ethanol (500 ml) over 10% palladium on charcoal (3.4 g of 50% paste in water). The catalyst was removed by filtration and the filtrate was evaporated to leave the title compound as an off-white/cream powder (12.59 g; 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][CH2:31][NH:30][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:15][N:14]=1)=[O:17])([CH3:37])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCCNC(=O)OC(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.1 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (374 mg, 0.888 mmol) obtained in Example 12 in methylene chloride (10 ml), tert-butyl (2-aminoethyl)carbamate (170 μl, 1.07 mmol), 1-hydroxybenzotriazole (120 mg, 0.888 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (206 mg, 1.07 mmol) and 4-methylmorpholine (116 μl, 1.07 mmol) were added, and the mixture was stirred for 19 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethylacetate (=1:1) was concentrated under reduced pressure, to obtain the title compound (491 mg, 0.871 mmol, 98%) as an amorphous substance.