Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[B:9]([O-])([O-:14])[O:10]C(C)C.[Li]CCCC>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([B:9]([OH:14])[OH:10])[CH:3]=[N:4][CH:5]=1
Reactant: Fc1cncc(Br)c1
Reactant: CC(C)OB([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(F)c1
Reaction time: 0.5 h

Procedure:
3-bromo-5-fluoropyridine (2a) (25 kg, 142 moles, 1.0 equiv.), THF (222.5 kg) and isopropyl borate (28 kg, 149.3 moles, 1.05 equiv.) were added to a 700 L low temperature reactor. The resulting mixture was cooled to −90° C.˜−80° C. while stirred. Then n-BuLi (40.2 kg, 2.5 M, 142 moles, 1.0 equiv.) was added dropwise (2 kg/h) maintaining the temperature below −87° C. After the addition was complete, the mixture was maintained at −88˜−83° C. for 2.5 h. When the reaction was deemed complete by HPLC analysis, it was quenched by addition of 9% aqueous HCl (7.7 kg). The mixture was transferred to a 1000 L glass-lined reactor and the temperature returned to −20˜−10° C. Additional HCl solution (122.3 kg) was then added until pH was adjusted to 1˜2 maintaining the temperature at 0˜10° C. The mixture was then held for 0.5 h in order to allow layers to separate. The organic layer was separated and washed with saturated brine (38 kg). It was stirred for 0.5 h and then held again for 0.5 h to allow layer separation. The aqueous layer was separated and the combined aqueous layers were extracted with EtOAc twice (51+25 kg). The organic phase was separated and pH was adjusted to a value of 6 by using 30% aqueous NaOH solution (27.4 kg). At this pH a solid precipitated out. The slurry was filtered by centrifuge and allowed to dry in a tray dryer at 40˜45° C. Title compound (2b) was obtained as a white solid (17.5 kg, 87.4%, purity: 98.6% AUC using method B).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.ClC(Cl)(Cl)C[O:38][C:39](=O)[NH:40][C:41]1[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[O:43][N:42]=1.C(N(CC)CC)C>CS(C)=O>[C:46]([C:44]1[O:43][N:42]=[C:41]([NH:40][C:39]([NH:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[N:15]4[CH:16]=[CH:17][C:18]([C:20]5[CH:21]=[CH:22][C:23]([C:26]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[O:27])=[CH:24][CH:25]=5)=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:9][CH:10]=2)=[O:38])[CH:45]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cc(C(C)(C)C)on6)cc5)cnc4c3)cc2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.2 g, 0.63 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Heat the mixture to 70° C., stir five hours, and cool to room temperature. Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.048 g, 15%). MS(ES), m/z 592 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C@:52]1([C:62]([O:64][CH3:65])=[O:63])[CH2:54][C@@H:53]1[C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1>CN(C=O)C>[Br:61][C:58]1[CH:57]=[CH:56][C:55]([C@H:53]2[CH2:54][C@:52]2([NH:51][C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@]1(NC(=O)[C@@H]2CCCCN2C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (9.05 mg) in DMF (3 mL) was added Hunig's Base (0.019 mL) followed by HATU (15 mg). The mixture was allowed to stir at room temp for 10 min. To this solution was added in one portion (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate hydrochloride (11 mg) and the mixture was stirred overnight. The mixture was evaporated to dryness, the residue extracted into diethyl ether and washed well with water and brine, then dried over sodium sulfate. The sample was passed through a small silica plug/eluting with diethyl ether to give (S)-tert-butyl 2-((1R,2R)-2-(4-bromophenyl)-1-(methoxycarbonyl)cyclopropylcarbamoyl)piperidine-1-carboxylate (6 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][NH2:7])=O.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([N:10]1[C:4]([CH2:3][O:2][CH3:1])=[N:6][NH:7][C:11]1=[O:12])[CH3:9]
Reactant: COCC(=O)NN
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCn1c(COC)n[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methoxyacetic acid hydrazide (3.0 g) was heated and dissolved in toluene (60 ml), and then ethyl isocyanate (2.56 ml) was added dropwise. After stirring for at room temperature for one day, the reaction mixture was concentrated under reduced pressure. The residue was added to a 2% aqueous solution of potassium hydroxide (100 ml) that had been heated to 95° C., and the mixture was stirred at 95° C. for 45 minutes. After cooling to room temperature, concentrated hydrochloric acid (2.9 ml) was added and the mixture was stirred at room temperature for one day. Silica gel was then added to the reaction mixture, and it was concentrated under reduced pressure and purified by silica gel column chromatography. The obtained solid was washed with diethyl ether to obtain the title compound (3.56 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].O[CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])=[O:24]
Reactant: Cc1ccccc1C(=O)O
Reactant: CC(C)(C)C(=O)NCO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(CNC(=O)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Cool sulfuric acid (3.67 mL) to 0° C., and add 2-methylbenzoic acid (500 mg, 3.67 mmol, 1.0 equiv) and N-(hydroxymethyl)-2,2-dimethylpropanamide (506 mg, 3.86 mmol, 1.05 equiv). Allow the mixture to warm to room temperature, and stir overnight. Dilute with water (25 mL) and extract with EtOAc (50 mL). Dry the organic layer over MgSO4, filter, and concentrate under reduced pressure to give the crude compound. Purify the material by reverse-phase HPLC on an XBridge Prep C18 5 μM OBD 30×75 mm column, eluting with a gradient of 5-50% (0.1% TFA in acetonitrile) in (0.1% TFA in water) to give the title compound (255 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): δ 12.76 (s, 1H), 8.09 (t, 1H, J=6.0 Hz), 7.67 (d, 1H, J=1.6 Hz), 7.25 (dd, 1H, J=8.0, 1.6 Hz), 7.21 (d, 1H, J=8.0 Hz), 4.22 (d, 2H, J=6.0 Hz), 2.46 (s, 3H), 1.10 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([OH:16])=O)[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([Cl:19])=[O:16])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2(C(=O)O)CC2(C)C)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(4-methoxyphenyl)-2,2-dimethylcyclopropanecarboxylic acid (44 mg, 0.20 mmol), thionyl chloride (44 μL, 0.60 mmol) and DMF (1 drop) was stirred at room temperature for 30 minutes. The mixture was concentrated and the resultant acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][C:29](=[O:31])[CH3:30])[CH2:25][CH3:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[CH3:34][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][C:29]([OH:31])([CH3:34])[CH3:30])[CH2:25][CH3:26])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCC(C)=O)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-oxoheptan-3-yl)piperidin-2-one prepared above in Step C (78 mg, 0.16 mmol) in THF (1.6 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (344 μL, 0.481 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 33% and 43% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([O:16][C@@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C>ClCCl>[CH2:25]([O:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[CH:12][C:11]([C:14]([O:16][C@@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:15])=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[O:45])=[CH:47][CH:48]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCC[C@H](C)OC(=O)c1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ncc(C(=O)O[C@@H](C)CCCCCC)cn3)cc2)cc1
Yield: 28.5 %

Procedure:
--The hydroxy ester 60 (410 mg, 1.25 mol), 4-tetradecyloxybenzoic acid (417 mg, 1.25 mmol), DCC (257 mg, 1.25 mmol) and dimethylaminopyridine (cat.) in dry dichloromethane (15 ml) were stirred for 48 h at room temperature. Flash silica was added and the solvent was removed in vacuo and the residue was purified by flash chromatography (10% ethyl acetate-light petroleum) to give the ester 61 (230 mg, 28%) (from EtOH/MeOH), transitions/° C. I TGB(fog) TGB(C or A) SC 88 SCferri1 81.4 SCferri2SCanti 69 K (m.p. 85.4° C.); [α]D19 +20.2° (c 1.9 in CHCl3); νmax /cm-1 (KBr) 2880, 1705 (CO), 1690 (CO), 1610, 1460, 1290, 1240, 1195, 1110 and 830; δ 0.88 (6H, m), 1.20-1.60 (33H, m), 1.60-1.90 (4H, m), 4.05 (2H, t, J 6, OCH2), 5.22 (1H, sext, J 6, OCHMe), 6.98 (2H, J 8, 3'- and 5'-H), 7.37 (2H, d, J 8, ArH), 8.16 (2H, d, J 8, ArH), 8.60(2H, d, J8, 2'- and 6'-H) and 9.31 (2H,s,); m/z 642 (M+ -2), 419,317,265 and 121.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CCc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 200 ml reactor equipped with a reflux condenser and a stirrer, 60 ml of carbon tetrachloride and 10 g of the above mentioned fraction containing 3-ethylbenzophenone were introduced. While stirring the resultant mixture at room temperature, 8.6 g of N-bromosuccinimide and 0.14 g of benzoyl peroxide were added thereto, and reflux was perfomed for 8 hours while stirring the reaction solution. After the reaction solution had been cooled to room temperature, the succinimide was filtered out, and carbon tetrachloride was distilled off from a filtrate under a reduced pressure. The spectrum data of the obtained product were in accord with those of 3-(1-bromoethyl)benzophenone.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Cl:5][C:6]1[C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:8][C:9]([F:13])=[CH:10][C:11]=1F.O>CN(C)C=O>[NH2:1][C:11]1[CH:10]=[C:9]([F:13])[N:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[C:6]=1[Cl:5]
Reactant: COC(=O)c1nc(F)cc(F)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
Sodium azide (0.0086 mol, 0.60 g) was added to a solution of methyl 3-chloro-4,6-difluoropyridine-2-carboxylate (0.0072 mol, 1.5 g) in 15 mL dimethyl formamide (DMF). The solution was stirred 10 min at ambient temperature before pouring into 350 mL water and extracting the aqueous mixture with EtOAc (2×100 mL). The organic phase was dried (Na2SO4) and then treated with excess NaBH4 for 30 min. The excess NaBH4 was quenched with aqueous EtOH and the mixture was diluted with water (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic layers were dried (Na2SO4) and concentrated to an off-white powder which was purified by reversed-phase HPLC to give methyl 4-amino-3-chloro-6-fluoropyridine-2-carboxylate (0.0059 mol, 1.2 g). 1H NMR(CDCl3): δ 3.95 (3H, s), 5.2-5.1 (2H, bs), 6.36 (1H, s). 19F NMR {1H}: δ −72.7.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C.[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51](O)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]>C1COCC1>[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51]([O:23][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=2)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCCCCCOC(=O)c1cc(O)ccc1O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOC(=O)c1cc(OC(=O)c2ccc(OCCCCCCOC(=O)C=C)cc2)ccc1O
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of mesyl chloride (3.44 g) in 50 ml of dry THF was added dropwise under argon to a cooled (−25° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (8.35 g) and triethylamine (6.07 g) in 100 ml of dry THF. After complete addition (15 min), the reaction mixture was stirred for a further 30 min at −25° C., treated with a solution of 2,5-dihydroxybenzoic-6-acryloyloxyhexyl ester in 50 ml of dry THF and further stirred at −25° C. for 4 h. The reaction mixture was then filtered through celite and the solvent was removed by evaporation. The filtrate was purified by flash chromatography using a short silica-gel column and dichloromethane/diethylether (39/1) as eluent to give 10.8 g of 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-hydroxybenzoic acid 6-acryloyloxyhexyl ester as a slightly beige oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH:22](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:22]=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1
Reactant: CCOC(OCC)OCC
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=CCc1nncn1-2

Procedure:
In analogy to Example 16(b), by reacting 7-chloro-5-(2-chlorophenyl)-2-hydrazino-3H-1-benzazepine with triethyl orthoformate there is obtained 8-chloro-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 189°-190°.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=3)[N:34]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:33]=2)[CH:29]=[CH:28][N:27]=1.[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH2:79])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH:79][C:41]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:33]=[C:32]4[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[O:42])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1
Reactant: NC1CCCC(Cn2ncc3ccccc32)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-((1H-indazol-1-yl)methyl)cyclohexanamine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])=[O:3].[Cl:16][C:17]1[C:18]([OH:26])=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH:20]=O.O>CN(C)C=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[S:15])[NH:13][N:14]=[CH:20][C:19]2[CH:22]=[C:23]([Cl:25])[CH:24]=[C:17]([Cl:16])[C:18]=2[OH:26])=[CH:9][CH:10]=1)([OH:4])=[O:3]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2cc(Cl)cc(Cl)c2O)cc1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
Concentrated aqueous hydrochloric acid (1 mL) was added to a stirred solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (213 mg, 1.00 mmol) and 3,5-dichloro-2-hydroxybenzaldehyde (198 mg, 1.04 mmol) in dimethylformamide (20 mL). The mixture was stirred for 18 h, water was added and the precipitate filtered, washed (water) and dried to give the title compound (212 mg, 55%) as a solid. MS (ES−) m/e 382, 384 [M−H]-.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:36][C:37]1[N:42]=[C:41]([C:5]2[CH:4]=[C:3]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 97 °C
Reaction time: 3 h

Procedure:
1.32 g of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanylethoxy-methyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid, 583 mg of 2,4-dichlorpyrimidine and 3,3 g of cesium carbonate are dissolved in 17 ml of a 1:4 mixture of water and dioxane, and argon is passed through the solution for degassing. After addition of 125 mg of (1,1′-bis(diphenyl-phosphine)ferrocene)palladium(II) chloride-dichloromethane complex, the solution is stirred at 97° C. for 3 hours. For workup, it is diluted with 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH3:20][C:21]([Mg]Br)=[CH2:22]>C1COCC1>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[C:21]([CH3:22])=[CH2:20])[N:3]=[CH:2]1
Reactant: C=C(C)[Mg]Br
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Solvent: C1CCOC1
Product: C=C(C)C(O)(c1ccc2cc(OC)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.80 g) with 2-propen-2-ylmagnesium bromide in THF (1.0 M, 9.5 ml) was carried out to give the titled compound (0.76 g) as a colorless powder.