Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:52])[C@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][C@H:47]([C:46]([OH:45])=[O:52])[CH:49]([CH3:51])[CH3:50])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 234B and L-valine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.15-12.77 (br.s, 1 H), 8.94 (s, 1 H), 7.92 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.15 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.23 (m, 2 H), 2.04 (m, 1 H), 1.67 (m, 4 H), 0.88 (dd, 6 H); MS (ESI+) m/z 688 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Cl:28][C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:15]2[CH:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH:32]=[CH:31][N:30]=1
Reactant: OB(O)C1(Cl)C=CC=CN1
Reactant: COc1cc(-c2cc(C)nc(OS(=O)(=O)C(F)(F)F)c2)ccc1C(F)(F)F
Product: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-pyridin-2-yl ester (example A.59) (2.0 g, 5.0 mmol) and commercially available 2-chloropyridine boronic acid (0.758 g, 5.0 mmol) according to the general procedure IVb. Obtained as an off-white solid (1.50 g, 82%). MS (ISP) 379.2 [(M+H)+] and 381 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N-:13]=[C:14]=[O:15].[K+]>O.C(O)(=O)C>[NH:1]([C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]([NH2:13])=[O:15]
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(/C=C/C(=O)O)cc1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
A stirred solution of (E)-3-(4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100° C. for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid. MP>350° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 4-bromo-3-fluorophenol (89 g, 465.9 mmol) in a mixture of CH2Cl2 (940 mL) and H2SO4 (52.1 mL, 978 mmol) at 0° C., HNO3 (65%) (32.9 ml, 468 mmol) was added dropwise (the mixture turned from colourless to black). The resulting mixture was stirred at 0 ° C. for 1 h and then poured into water. The organic layer was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to afford the crude compound which was purified by flash chromatography (SiO2, heptane/toluene 1:3) to give 4-bromo-5-fluoro-2-nitrophenol (49.5 g, 45%). 1H-NMR (400 MHz, CDCl3) 6.95 (d, J=9.0, 1H), 8.38 (d, J=6.2, 1H), 10.69 (s, 1H).
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>C(#N)C.O>[CH:1]1([S:6][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: SC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(SC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.1 %

Procedure:
Cyclopentanethiol (1.0 g) (available from Aldrich) was dissolved in acetonitrile (10 ml) and potassium carbonate (1.35 g) was added. After 5 min, 1-fluoro-4-nitrobenzene (1.38 g) (available from Aldrich) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The organic layer was washed with 1M aqueous sodium hydroxide (20 ml), water (20 ml), and 1M aqueous hydrochoric acid (20 ml). The organic layer was separated and the solvent evaporated in vacuo to give the title compound as a yellow liquid (0.7 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Br:25])[NH2:21].C(=O)(O)[O-].[Na+]>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(Br)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Yield: 31.9 %

Procedure:
A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of ethanol was refluxed under N2 for 5 h. Saturated sodium bicarbonate was added and volatile material was removed. The residue was slurried with hexane, collected, washed with hexane and water and dried. The insoluble material was repeatedly extracted with boiling ethyl acetate and the solution was then filtered through silica gel. The solvent was removed to give 3.80 g of green solid: mass spectrum (electrospray, m/e): M+H 449.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 7-bromo-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.10 mmol) in concentrated H2SO4 (0.5 mL) at 0° C. was added KNO3 (11 mg, 0.109 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 12 h and it was poured into ice water (2 g). The precipitate was collected by filtration, affording 32 mg (91.4%) of crude title compound. It was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH 2 with 4N HCl to give a brown precipitate, which was collected by filtration, and dried at 50° C. for 4 h, affording pure title compound (28 mg, 79.3%) as a yellow powder. Mp: 292°-94° C., IR (KBr, cm-1): 3412, 3068, 3937, 1718, 1556, 1387. 1H NMR (DMSO-d6): δ7.644 (s, 1H), 11.721 (s, 1H), 12.423 (s, 1H). HRMS: calcd for C9H3ClF3N3O4 (M+) m/z: 352.9258, found: 352.9259.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7].[OH-].[Na+]>CO>[NH2:7][C@H:6]([C:5]([OH:13])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COC(=O)[C@@H](N)CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
1.16 Gram (5 mmol) of L-lysine methyl ester dihydrochloride was dissolved in 4.5 ml of methanol, and 2.5 ml of 2 N aqueous sodium hydroxide solution was added thereto to prepare a treating agent solution. An untreated cotton cloth (160 mm×170 mm, 5.0 g) was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for an hour at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and then washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently was washed with 0.05 N aqueous hydrochloric acid solution and rinsed three times with water, and finally washed with a JAFET standard detergent solution for household washing machine, rinsed with water and air-dried. A part of this cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1749 cm−1. As a result of determination for the amount of the bonded L-lysine, it was 0.10 mmol based on 1 g of the cloth. The degree of esterfication was 0.016.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)=[O:4].[C-:11]#[N:12].[K+]>C(O)C>[Br:10][C:7]1[S:6][C:5]([C:3](=[O:4])[CH2:2][C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1ccc(Br)s1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: N#CCC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
2-Bromo-1-(5-bromothiophen-2-yl)ethanone (5 g, 17.6 mmol) dissolved in ethanol (100 mL) was treated with an aqueous solution (10 mL) of potassium cyanide (6.19 g, 96.8 mmol) and stirred at ambient temperature overnight. The volatiles were removed in vacuo and crushed iced added to the residue which was acidified to pH 4 with acetic acid. The yellow precipitate that formed was collected by suction filtration and purified by flash chromatography on silica gel using a gradient of 10-30% of ethyl acetate in hexanes to yield a light gray solid (3 g).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:24](O)[CH3:25]>>[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH2:24][CH3:25])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)Nc1ccccc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Thionyl chloride was dropped to ethanol and the mixture was stirred for 2 hours. Then, N-n-octanoylanthranilic acid was added to the mixture and reaction was allowed to proceed for 3 days at the room temperature. After the reaction, the solvent was removed and ethyl N-n-octanoylanthranilate was obtained from the remaining reactant after the purification by column chromatography with the yield of 89.2 %.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.5 %

Procedure:
Methyl thiosalicylate (1.0 g, 6.1 mmol) and tert-butyl 3-[3-(6-cyano-2-pyridyl)propoxy]propanoate (1.6 g, 5.5 mmol) were dissolved in toluene (5.0 ml). Triethylamine (1.35 ml, 9.7 mmol) was added to the mixture and the mixture was refluxed for 14 hrs. The reaction mixture was subjected to a silica gel (110 g) column chromatography and eluted with hexane-ethyl acetate (3:2, v/v) to give the titled compound (1.7 g, 67%) as white crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:11]2=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:11]2=[O:16])(=[O:4])=[O:3]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (0.3 g, 2.62 mmol) was added to a stirred suspension of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl]isoindoline-1,3-dione (0.55 g, 1.31 mmol) and triethylamine (0.4 g, 3.93 mmol) in methylene chloride (60 mL) and the resulting mixture stirred for 24 hours. The mixture was then washed with sat. Sodium bicarbonate (25 mL), 1N hydrogen chloride (25 mL), H2O (25 mL), brine (25 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried in methanol:tetrahydrofuran (2:1) to give after isolation by filtration 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.53 g, 70%) as a white solid: mp 277-279 ° C.; 1H NMR (DMSO-d6) δ 8.05-7.95 (m, 3H), 7.11-6.92 (m, 3H), 5.78-5.74 (dd, J=5.5, 9.1 Hz, 1H), 4.31-4.22 (m, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.55 (s, 6H), 2.95 (s, 3H), 1.31 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 166.11, 165.35, 148.96, 147.88, 138.63, 136.05, 132.60, 129.64, 129.31, 129.27, 125.26, 119.89, 112.33, 111.76, 63.73, 55.46, 53.38, 47.92, 43.50, 43.44, 41.15, 14.61; Anal. Calcd. for C22H26N2O10S3: C, 45.95; H, 4.56; N, 4.87; S, 16.74. Found: C, 45.90; H, 4.40; N, 4.75; S, 16.55.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:24])=O>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[Cl:24])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Temperature: 110 °C
Yield: 84 %

Procedure:
6-Nitro-2-(3-fluoro-phenyl)-quinolin-4-ol, 5.2 g (16.3 mmoles), was placed in a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water was cautiously added dropwise until all of the POCl3 was consumed. The product crystallised from the water and solids were collected by filtration. The solids were washed with water, placed in a 250 mL Erlenmeyer and triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of 2-(2-fluorophenyl)-ethanol (4.00 g, 28.5 mmol) and triethylamine (6.36 mL, 45.7 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (2.88 mL, 37.1 mmol) at −5° C. The mixture was stirred for 4 hours and was allowed to slowly warm to room temperature. The mixture was diluted with dichloromethane and extracted with 1 M HCl and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography, using dichloromethane as eluent, to afford 5.88 g (94.4%) the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37]OS(C)(=O)=O)=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45].[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH2:36][CH2:37][N:48]=[N+:49]=[N-:50])=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
The mesylate from Step 5 (0.115 g, 0.17 mmol) was dissolved in DMF (5 mL). NaN3 (0.065 g, 1.0 mmol) was added and the mixture was heated to 60° C. and stirred for three hours. Reaction was cooled to room temperature and water was added. Extracted with EtOAc and washed organic layer with brine. Dried organics over sodium sulfate and filtered and concentrated by rotary evaporation. Dried further under a strong vacuum. Obtained 0.100 g of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in 94% yield.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[C:29](=[O:39])[C:30]5[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32]4=[O:34])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)c5ccccc5C4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and phthalimide as starting compounds.
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[S:12][CH:11]=[N:10][C:9]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([C:36]2[CH:45]=[C:44]([O:46][CH3:47])[C:39]3[O:40][CH2:41][CH2:42][O:43][C:38]=3[C:37]=2[F:48])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=C(C(F)(F)F)O[N:28]=3)=[CH:23][CH:22]=2)=[N:14]1)=[O:7])C.[OH-].[Na+]>[Fe].C(O)(=O)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH:19]([C:36]2[CH:45]=[C:44]([O:46][CH3:47])[C:39]3[O:40][CH2:41][CH2:42][O:43][C:38]=3[C:37]=2[F:48])[C:15]2[NH:16][C:17](=[O:18])[N:13]([C:9]3[N:10]=[CH:11][S:12][C:8]=3[C:6]([OH:7])=[O:5])[N:14]=2)=[CH:22][CH:23]=1)(=[NH:28])[NH2:31]
Reactant: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2 ml of a methanol solution containing 57 mg of 4-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid ethyl ester, 0.2 ml of a 5 N sodium hydroxide aqueous solution was added. The resulting mixture was stirred at room temperature for 18 hours, and then 2 ml of methanol, 2 ml of acetic acid, and 38 mg of iron powder were added thereto. The mixture was stirred at 60° C. for 18 hours and then at 65° C. for 6 hours, under a nitrogen atmosphere. After cooling, the reaction mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:18]>C1(C)C=CC=CC=1>[C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][Br:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc(C=Cc2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: BrCc1cccc(C=Cc2ccccc2)c1
Yield: 227.9 %

Procedure:
21 g (0.1 mol) of 3-(2-phenyl-vinyl)-benzyl alcohol were dissolved in 200 ml of anhydrous toluene, and 10 g of phosphorus tribromide were added dropwise at 0°-10° C., whilst stirring. The mixture was then stirred at 10° C. for 2 hours and at room temperature for a further 2 hours. The reaction mixture was then extracted by shaking twice with 500 ml of water each time, the organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by subjecting the product to brief incipient distillation at a bath temperature of 60° C./2 mm Hg. 23 g (84.2% of theory) of 3-(2-phenyl-vinyl)-benzyl bromide were obtained as a yellow oil with the refractive index nD22 : 1.6376 (isomer mixture with a cis proportion of about 90%). ##STR63##
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[C:10]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1.C(N(CC)CC)C>O>[CH2:6]([O:5][C:3]([C:2]1[N:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([Br:8])[C:10]2=[N:16][C:17]=1[S:18][CH3:19])=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CSC(=Nc1ncc(C)cc1Br)SC
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(SC)nc2c(Br)cc(C)cn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Ethyl bromoacetate (5.4 g) was added to methyl N-(3-bromo-5-methyl-2-pyridyl)(methylsulfanyl)methaneimidothioate, and the mixture was stirred at 60° C. for 4 hours. After cooled to room temperature, triethylamine was added to treat the material, and water was further added thereto. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:9) to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (2.4 g) as a white powder.