Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1>CC#N.C(Cl)Cl>[Br:27][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2-amine (7.49 g, 24.87 mmol) in CH3CN/DCM (100/30 mL) was added NBS (4.43 g, 24.87 mmol) in portions at 0° C. The reaction solution was stirred at 0° C. for 10 min. The precipitate was removed by filtration. The black filtrate was concentrated to give a black residue which was purified by CombiFlash (80 g silica gel column, EtOAc/Hexane) to afford 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (7.8 g, 82%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-Methoxy-ethylamine (90 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 341 (105.5 mg, yield: 20%). 1HNMR (DMSO-d6, 400 MHz): δ8.63 (s, 1H), 8.31 (s, 1H), 7.94-7.88 (m, 2H), 7.76-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.21 (s, 2H), 6.99 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.49 (s, 4H), 3.29 (s, 3H), 3.15 (s, 2H). ESI-MS: m/z=533 [M+H+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CN(C)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a mixture of 306 mg (purity: 99.0%; 1.84 mmol) of 4-hydroxy-3,6-dichloropyridazine and 830 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added dimethylaniline (2.76 g) and 331 mg (5.62 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 381 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.CC(C)([O-])C.[K+].[OH:26][C:27]1[CH:32]=[C:31]([Cl:33])[N:30]=[N:29][C:28]=1Cl>C(O)(C)(C)C>[Cl:33][C:31]1[N:30]=[N:29][C:28]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:27]([OH:26])[CH:32]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture of 1.34 g (9.05 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (7.00 mL) was added 1.20 g (9.05 mmol) of 85% potassium t-butoxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 4.97 g (purity: 96.0%; 2.89 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (35.0 g) at 170° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 701 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 88%) and 6.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]1=[O:20])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Nc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Yield: 163.7 %

Procedure:
A solution of 20.0 g of 2-isopropylaminobenzaldehyde, 29.4 g of diethyl malonate, 10 ml of piperidine, 10 ml of acetic acid and 500 ml of toluene was heated to reflux for 13 hours. The reaction solution was washed with water and then with saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 52 g of ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as the crude product.
Reaction SMILES: Cl.[CH:2]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)([CH3:4])[CH3:3].[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH:2]([N:5]1[C:6]2[C:7](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]1=[O:21])([CH3:4])[CH3:3]
Reactant: CC(C)Nc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Yield: 147.4 %

Procedure:
A solution of 133.7 g of 2-isopropylaminobenzaldehyde hydrochloride, 200 g of diethyl malonate, 70 ml of piperidine, 70 ml of acetic acid, 50 g of potassium carbonate and 1.5 liter of toluene was heated to reflux for 10 hours. The reaction solution was washed with water and then with saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 256 g of ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as the crude product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](O)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:22][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of phosphoryl chloride (2.0 mL, 21.2 mmol) and quinoline (1.30 mL, 10.8 mmol) was added solid powder 3-nitro-5-(trifluoromethyl)pyridin-2-ol (4.00 g, 18.3 mmol) (95% purity). The resulting dark brown thick suspension was heated to reflux for 4 h and gradually turned into a very cloudy dark brown solution. After cooling to 100° C., water (11 mL) was slowly added to the mixture which was further cooled to room temperature and neutralized carefully with Na2CO3. The resulting solution was extracted with EtOAc three times. The extracts were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes 30:70) to afford 2.28 g of desired product.
Reaction SMILES: [OH-:1].[Na+].[N+]([C:6]1C=CC=C[C:7]=1[C:8]([O-:10])=O)([O-])=O.[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([NH:32][C@@H:33]([CH2:41][SH:42])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>CC(O)(C)C>[CH:24]1[C:25]2[CH:26]([CH2:28][O:29][C:30]([NH:32][C@@H:33]([CH2:41][S:42][CH2:6][C@H:7]([OH:1])[CH2:8][OH:10])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[O:31])[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (2S)-(+)-glycidyl-4-nitrobenzoate (9, 1.1 eq) and 1M NaOH (1.1 eq) in tBuOH (0.1 M) was stirred at room temperature until complete hydrolysis of the nitrobenzoate (30 minutes). To the resulting mixture, a solution of (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1 eq) in tBuOH (1 M) was introduced. The reaction was stirred at room temperature for 15 hours. The reaction mixture was concentrated en vaccuo to remove tBuOH and dissolved in EtOAc. The EtOAc solution was washed three times with water, and once with brine. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-90% EtOAc/Hex to give the title product as colorless viscous oil.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(C(C)C)CC)(C)C.[Si:19]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Si:19]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([C:32]([CH3:34])([CH3:35])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Heptanoic acid (2.06 g, 15.86 mmol), and diisopropylethylamine (2.72 mL, 21.14 mmol; DIPEA) were added to a stirring solution of the amine 4 (4.00 g, 10.57 mmol) in anhydrous DMF (20 mL) under an argon atmosphere. After 5 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.04 g, 15.86 mmol; EDCI) was added as a solid. After stirring for 12 h at room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with water (2×30 mL), and brine (20 mL). The combined aqueous layers were back-extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by SiO2 column chromatography using 30% EtOAc/hexanes as eluent to give amide 5 (4.75 g, 91%) as a viscous oil. TLC: EtOAc/hexanes (3:7), Rf˜0.60; 1H NMR (400 MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 and 3.96-4.80 (m, 1H, rotamers), 3.62 and 3.68 (t, J=4.8 Hz, 2H, rotamers), 3.02 and 3.16 (t, J=5.2 Hz, 2H, rotamers), 2.38 and 2.24 (t, J=5.3 Hz, 2H, rotamers), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18 and 1,12, (d, J=7.3 Hz, 6H, rotamers), 1.03 and 1.04 (s, 9H, rotamers), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, 1:1 mixture of rotamers) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47, 14.33, 14.28.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.O>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.0 g) in tetrahydrofuran (100 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.6 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CN(C=O)C.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>CCOC(C)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:16][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoroethanol (6.15 mL, 84.4 mmol) was placed into a flask with DMF (141 mL). To the reaction mixture was added NaH (3.4 g, 84.4 mmol) in portions. The reaction was then stirred for 30 min at 25° C. At this point, 2,5-dibromopyridine was added and the mixture was heated to 90° C. and stirred at that temperature overnight. The reaction was cooled to rt and diluted with EtOAc (100 mL). The organic layer was washed with H2O (3×150 mL), brine (2×100 mL), dried (MgSO4), filtered, and concentrated. This material was purified by column chromatography (15:1 hexane:EtOAc) to give 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine as an oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:23][C@@H:19]([CH2:18][CH:15]3[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]3)[C:20]([NH:34][CH2:33][CH2:32][NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:22])[S:3][C:4]=2[CH:10]=1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: NCCNc1ccc(F)cc1
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared from 2,6-dichlorobenzothiazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=8.0 Hz), 8.17 (t, 1H, J=5.6 Hz), 7.72 (d, 1H, J=2.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.15 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 6.84(m, 2H), 6.50(m, 2H), 4.40(m, 1H), 3.16(m, 2H), 2.97(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28ClFN4OS (M+H+)475.17. found 475.3.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
DMF and KOH (3.3 g, 58 mmol) were stirred together at rt for 5 minutes before adding 1,2,4-triazole (1 g, 14.5 mmol). After a further 30 minutes, the reaction mixture was cooled to 0° C. and 1-bromo-4-bromomethyl-benzene (7.2 g, 29 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to 60° C., then cooled to It, extracted with ethyl acetate and water, and subsequently dried over K2CO3. The solvent was evaporated to yield yellow-white crystals, which, upon repeated recrystallisation, (ethylacetate/isohexane) yielded 0.60 g of the sub-title compound as white crystals (62% isolated yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCI (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15; found 451.04.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1.N1C=CN=CC=1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CCC(=O)C4CCCCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1cnccn1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ccc(C4CCCCC4)n23)cc1
Reaction time: 6 h

Procedure:
To a solution of 1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one (0.050 g, 0.12 mmol) in THF (2 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.071 g, 0.13 mmol, TCI). After about 6 h at ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of 40-90% EtOAc in heptanes to provide 8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2;3′-e]pyrazine as a tan solid (0.020 g, 42%). LC/MS (Table 2, Method a) Rt=3.39 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[CH3:2].[N:22]1([CH2:28][CH2:29][CH2:30][Cl:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[ClH:31].[ClH:31].[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Reactant: ClCCCN1CCCCC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCn1c2ccc(C(=O)OCCCN3CCCCC3)cc2c2cc(C(=O)OCCCN3CCCCC3)ccc21
Product: Cl

Procedure:
By the procedure of Example 2, one equivalent of 9-ethylcarbazole-3,6-dicarboxylic acid is allowed to react with two equivalents of 3-piperidinopropyl chloride in the presence of a catalytic amount of benzyltrimethylammonium chloride to give the product.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[C:13](=[O:15])=[O:14]>CCOCC.CCCCC>[Br:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: O=C=O
Reactant: Brc1cscc1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: O=C(O)c1cscc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL ether under a positive nitrogen atmosphere was added dropwise 75 mL 1.7M t-BuLi in pentane at below -73° C. and the resulting reaction solution was stirred at -78° C. for 0.5 h. After that, the ether solution was poured into dry ice and extracted with water. The aq solution was washed with ether and then acidified with concentrated HCl. The solid was filtered and air-dried to give 9 g of 4-bromo-3-thiophene-carboxylic acid, yield 70.3%.