Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[O:14][CH2:27][CH:26]=[CH2:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCBr
Reactant: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(CC)c(C)c(C(=O)OC)c1C(=O)OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 83.1 %

Procedure:
4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02 mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14 mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). The suspension was heated at 60° C. After 14 hours, the reaction was cooled to room temperature and filtered. The solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 0.976 g (83%) of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz, 1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[O:31][CH3:32].Cl>C(#N)C.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.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:31][CH3:32])[C:23]=2[F:30])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a 50 mL three-necked flask equipped with a stirring bar and a condenser were placed 4,5,6-trichloropicolinic acid (0.503 g, 90% purity, 2 mmol), triethylamine (0.607, 6 mmol), acetonitrile (5 g) and water (5 g). The mixture became a homogeneous solution which was sparged with nitrogen for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added and the mixture was heated to 50° C. In a one-necked flask were placed (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid (1.951 g, 22 wt % in methyl isobutyl ketone/dimethoxyethane, 2.1 mmol) and acetonitrile (2.5 g). The solution was sparged with nitrogen for 15 minutes, and then slowly added to trichloropicolinic acid solution by a syringe pump at 50° C. The total addition time was about two hours. The reaction mixture was stirred at 50° C. for three more hours. A sample was taken and analyzed by HPLC. The LC results indicated that the reaction was completed. The reaction mixture was allowed to cool to room temperature. To acidify the reaction mixture, hydrochloric acid (6 g, 1 N HCl in water) was added to the flask dropwise. The resulting slurry was stirred overnight. The mixture was filtered and a light brown solid was obtained. This crude product was stirred in acetonitrile at room temperature for 2 hours. After filtration and vacuum drying, the white product (0.44 g, 92% LC purity, 58% yield) was obtained. 1H NMR (400 MHz, THF-d8) δ 8.35 (s, 1H), 7.40 (dd, J=8.5, 1.7 Hz, 1H), 7.23 (dd, J=8.5, 6.9 Hz, 1H), 4.00 (d, J=1.3 Hz, 3H); 13C NMR (101 MHz, THF-d8) δ 163.62 (s), 154.81 (s), 153.03 (s), 152.31 (s), 147.36 (s), 144.64 (d, J=13.4 Hz), 143.70 (s), 133.21 (s), 129.55 (d, J=3.5 Hz), 126.34 (d, J=14.4 Hz), 125.71 (s), 125.41-125.01 (m), 60.91 (d, J=4.8 Hz); 19F NMR (376 MHz, THF-d8) δ+−128.96. ESI/LC/MS/PI (M+H)+=349.9559 (100%), 351.9531 (99.66%), 353.95 (33.59%).
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:19][N:20]1[C:24]([C:25](O)=[O:26])=[C:23]([C:28]([F:31])([F:30])[F:29])[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:21]1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50].O>C1COCC1>[Cl:55][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:25]([C:24]2[N:20]([CH3:19])[N:21]=[C:22]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])[C:23]=2[C:28]([F:30])([F:31])[F:29])=[O:26])=[CH:54][C:44]=1[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 40.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (=DMTMM, see Tetrahedron 1999, 55, 13159-13170) (1.25 g, 4.51 mmol, 1.1 eq.) was added to 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (1.28 g, 4.1 mmol; preparation according to WO2010/051926) and tert-butyl (5-amino-2-chlorobenzyl)carbamate (1.05 g, 4.1 mmol, 1.0 eq.) in THF (15 ml), and the mixture was left at room temperature for 18 h. Water (30 ml) was added, the mixture was extracted with ethyl acetate (3×30 ml) and the extracts were dried over MgSO4. After concentration under reduced pressure, the product was purified by column chromatography on silica gel (hexane/ethyl acetate), giving tert-butyl [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzyl]carbamate (924 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][NH:20][CH3:21].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[N:20]([O:19][CH3:18])[CH3:21])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 60.6 %

Procedure:
A solution of 4-[N-(tert-butoxycarbonyl)amino]-cyclohexane carboxylic acid (11.95 g, 49.0 mmol), O,N-dimethylhydroxylamine (4.88 g, 50.0 mmol), DCC (9.60 g, 50 mmol) and triethylamine (5.06 g, 50.0 mmol) in DMF (150 mL) was stirred at room temperature overnight. Water (500 mL) was added and the mixture was extracted with CHCl3. The organic phase was washed with water, dried and concentrated under reduced pressure. Purification by flash chromatography (hexane/EtOAc 1:1) gave [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (8.50 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: COCCCN
Solvent: C1CCOC1
Product: COCCCNc1cccc2nc(NC(=O)c3ccccc3)nn12

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 3-methoxypropylamine (195 μl; 1.91 mmol; 10.0 eq.) in THF (3.0 mL), 90° C., 12 h, as white needles (35 mg; 56%). HPLC, Rt: 1.95 min. (purity 99.3%). LC/MS, M+(ESI): 326.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14](CS(N3CCC[C@@H]3C(O)=O)(=O)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40].C([N:46](CC)CC)C.CC(N(C)C)=O>ClCCl.C(OCC)(=O)C>[CH3:37][N:38]([CH3:43])[S:39](=[O:41])(=[O:40])[NH:46][CH:14]1[CH2:15][CH2:16][C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH2:12][CH2:13]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)S(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate R (102 mg, 0.26 mmol) in dichloromethane (3 ml) was treated with N,N dimethylsulfamoyl chloride (112 μL, 0.80 mmol) followed by triethylamine (74 μl, 0.52 mmol) and dimethylacetamide (1 ml). After 2 hours stirring at room temperature the reaction was diluted with ethyl acetate and washed with H2O and brine, dried (MgSO4) and evaporated to an oil which crystallised on standing. 1H NM (360 MHz, CDCl3) δ 7.39–7.31 (4H, m), 7.09–7.04 (2H, m), 6.89–6.87 (1H, m), 4.56–4.54 (1H, d, J=7.2 Hz), 3.55–3.49 (1H, m), 2.82 (6H, s), 2.61–2.35 (4H, m), 2.06–1.97 (2H, m), 1.57–1.44 (2H, m). m/z=491, 493 [MH]−
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].Cl.[F:27][C:28]([F:37])([F:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH2:29][C:28]([F:36])([F:37])[F:27])[CH2:35][CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(CC(F)(F)F)CC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 76.6 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and commercially available 1-(2,2,2-trifluorethyl)piperazine hydrochloride (CAS 13349-91-2) (87 mg, 0.422 mmol) in acetonitrile (1 ml) with diisopropylethyl amine (0.24 ml, 1.405 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (105 mg, 77%), MS (ISP) m/e=488.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2)[CH3:2].Cl[C:19]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]([S:30][CH3:31])[N:20]=1.C(N(CC)CC)C>C(O)CCC>[CH2:28]([O:27][C:25]([C:24]1[C:19]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)=[N:20][C:21]([S:30][CH3:31])=[N:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of 3-(indan-5-ylamino)-propionic acid ethyl ester (5 g, 21.4 mmol) and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5 g, 21.4 mmol) in 40 mL of n-butanol was added triethylamine (3 mL, 21.4 mmol). The solution was stirred at rt for 2 days. The solvent was removed under vacuum. The residue was extracted into EtOAc, washed with water, brine and then dried with Na2SO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:10-1:6, v/v), gave 8.2 g (90%) of the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.35 (t, 2H), 3.55 (q, 2H), 2.82 (m, 4H), 2.69 (t, 2H), 2.58 (s, 3H), 2.06 (m, 2H), 1.20 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]([OH:13])=O.[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][N:24]([C:11]([C:3]2[C:4]3[O:8][CH2:7][O:6][C:5]=3[CH:9]=[CH:10][C:2]=2[Br:1])=[O:13])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1c(Br)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A suspension of 5-bromo-1,3-benzodioxole-4-carboxylic acid (0.50 g), 4-benzyl-4-hydroxypiperidine (0.59 g), HATU (1.2 g) and triethylamine (1.4 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.85 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12]1[C:13]([I:27])=[C:14]([C:18]([I:26])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:20]=1[I:21])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][NH:34][CH3:35])[CH3:30]>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:36])[CH2:33][N:34]([C:15](=[O:16])[C:14]1[C:13]([I:27])=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:18]=1[I:26])[CH3:35])[CH3:30]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
840 ml (6.1 Mol) triethylamine is added to a solution of 759 g (1.2 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 276 g (1.8 Mol) sarcosine ethyl ester hydrochloride in 7600 ml N,N-dimethylformamide and stirred for 1 hr. at 60° C. The reaction mixture is cooled to room temperature, the crystallized triethyl ammonium chloride is filtered, washed with N,N-dimethylformamide and reduced under vacuum in a rotary evaporator. The residue is dissolved in 650 ml methanol and added dropwise to 3 l ethyl acetate. The precipitate is crystallized overnight, filtered to a dry state and finally washed with water, 1N hydrochloric acid, cold saturated sodium bicarbonate, water and dried under vacuum at 60° C. Yield: 685 g (80%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11].CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>O.C1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([S:14]([Cl:25])(=[O:17])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)O)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)Cl)cc1Cl
Yield: 74.7 %

Procedure:
Sodium salt of 3-chloro-4-methylsulfonyloxybenzene sulfonic acid (453 g: 1.47 moles), N,N-dimethylformamide (21.1 g: 0.288 mole) and benzene (2000 cc) were mixed and heated with stirring until the mixture was refluxed. Phosphorus oxychloride (237 g: 1.55 moles) was added dropwise to the mixture for 1 hour. The resultant mixture was refluxed with stirring for an additional 3 hours and then water (1000 cc) was added to the resultant mixture under the temperature 20° C.-30° C. with cooling. The mixture was stirred for 1 hour under the same temperature and then the layer of benzene was separated from the mixture. The benzene solution separated was washed with water two times and dried over anhydrous sodium sulfate. Benzene was removed from the benzene solution by distillation to obtain crude white crystals (335. g) of 3-chloro-4-methylsulfonyloxybenzene sulfonylchloride. The crude white crystals were recrystalized from benzene. Yield: 74.7%. Melting point: 100°-100.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Br:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23]C(O)=O>>[Br:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][C:3]1[C:4](=[O:5])[C:6]2[C:11]([C:12](=[O:13])[C:2]=1[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Product: COc1ccc(CC2=C(C)C(=O)c3ccccc3C2=O)c(Br)c1
Yield: 57 %

Procedure:
As starting materials for the coupling reaction menadione and 2-Bromo-4-methoxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 857 mg (2.31 mmol, 57% yield) of P_TM102 were isolated as yellow oil.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(F)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (10 mL). Add trifluoracetic acid (3 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-fluoroindole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)CCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-indan-1-one (21.1 g, 0.118 mol, see preparation in J. Org. Chem. 57, 1992, 589-594) and N,N-diisopropylethylamine (21.6 mL, 0.124 mol) in CH2Cl2 (200 mL) was added SEMCl (21.3 mL, 0.121 mol). The mixture was stirred at room temperature for 2 hours and diluted with NaHCO3 solution. After separation, the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc/hexane (3:7 to 1:1) to give 26.3 g (72%) of the desired product as brown oil. MS (ESI) m/z: 309.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm −0.01 (s, 9H) 0.96 (t, J=8.25 Hz, 2H) 2.66 (t, J=5.70 Hz, 2H) 3.03 (t, J=5.70 Hz, 2H) 3.80 (t, J=8.25 Hz, 2H) 3.90 (s, 3H) 5.36 (s, 2H) H) 7.20 (s, 1H) 7.22 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[CH:28]=2)[NH3+:23])=[CH:18][CH:17]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[CH:28]=2)[NH:23][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Reactant: Cn1cc([C@@H]([NH3+])c2ccc(Br)cc2)nn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1cc([C@@H](NC(=O)Cc2ccc(C3CC3)cc2)c2ccc(Br)cc2)nn1
Reaction time: 24 h
Yield: 88.3 %

Procedure:
To a solution of 0.075 g (0.426 mmol) (4-cyclopropylphenyl)acetic acid in 0.850 ml DMF was added 0.194 g (0.638 mmol) (S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methanaminium chloride 0.063 g (0.468 mmol) HOAT, 0.090 g (0.468 mmol) EDC, and 0.186 mL (1.06 mmol) triethylamine. After 24 hr at room temperature, the reaction mixture was purified by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.160 g (88%) N-[(S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-(4-cyclopropylphenyl)acetamide. 1H NMR (CDCl3, 400 MHz) 7.43-7.40 (m, 2H); 7.39 (m, 1H); 7.14 (m, 4H); 7.03 (d, 2H, J=8.25 Hz); 6.73 (d, 1H, J=7.41 Hz); 6.20 (d, 1H, J=7.50 Hz); 4.04 (s, 3H); 3.56 (s, 2H); 1.91-1.84 (m, 1H); 0.98-0.94 (m, 2H); 0.70-0.66 (m, 2H). HRMS (ES) [M+1]+ calcd for C21H21BrN4O: 425.0977. Found: 425.0979.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CC(C)C(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and isobutyryl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.13 (d, J=6.82 Hz, 6H) 1.27-1.37 (m, J=7.42, 7.42, 7.42, 7.42, 7.20 Hz, 2H) 2.20 (t, J=7.20 Hz, 2H) 2.65 (dt, J=13.58, 6.73 Hz, 1H) 6.73 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.34 Hz, 2H) 7.83-7.93 (m, 4H) 8.13 (d, J=8.08 Hz, 1H) 10.22 (s, 1H); ESI-MS: m/z calc'd for C25H26N4O2S 446.56. found 447.1 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[O:43]1[C:44]2[CH:45]=[CH:46][C:38]([CH2:37][NH:47][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([CH3:34])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:39][C:40]=2[O:41][CH2:42]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCO5)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and piperonylamine, m.p. 149-151° C. MS [(+)ESI, m/z]: 568 [M+H]+ Anal. Calcd for C36H31N3O4: C, 75.90; H, 5.49; N, 7.38. Found: C, 75.77; H, 5.36; N, 7.19.