Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCCOC1C=C2C(C=CC(=O)N2)=CC=1.[Na+].[I-].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:49]=[C:48]3[C:43]([CH2:44][CH2:45][C:46](=[O:50])[NH:47]3)=[CH:42][CH:41]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:49]=[C:48]3[C:43]([CH:44]=[CH:45][C:46](=[O:50])[NH:47]3)=[CH:42][CH:41]=2)[CH2:30][CH2:29]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Agent: [I-]
Solvent: CC#N
Product: O=c1ccc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A mixture of intermediate 15 (120 mg, 0.41 mmol) and NaI (123 mg, 0.82 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 2 (175 mg, 0.62 mmol) and anhydrous K2CO3 (226 mg, 1.64 mmol) were added to the mixture. The resulting mixture was heated to reflux overnight. The mixture was evaporated under reduced pressure and the residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)quinolin-2(1H)-one (compound 4) (50 mg, 26%). 1H NMR (300 MHz, CDCl3) δ 11.54 (br., 1H), 7.71 (d, J=6.9 Hz, 1H) 7.44 (d, J=8.1 Hz, 1H), 7.09-7.07 (m, 2H), 7.01-6.97 (m, 1H), 6.82-6.78 (m, 2H), 6.53 (d, J=9.3 Hz, 1H), 4.10 (t, J=6.6 Hz, 2H), 3.30 (d, J=5.1 Hz, 4H), 2.87-2.81 (m, 4H), 2.62 (t, J=7.5 Hz, 2H), 2.01-1.99 (m, 2H), 1.92-1.82 (m, 2H), 1.76-1.68 (m, 2H). HPLC: 99%, RT 2.461 min. MS (ESI) m/z 460.2 [M+H]+. mp: 55-57° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])[C@@:11]([CH3:14])([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[CH:12]=[CH2:13])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: C/C=C(\C)C(=O)N1C(=O)OC[C@H]1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 73.2 %

Procedure:
Residual moisture in (R)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (458.9 mg, 2.172 mmol) was removed by azeotroping with anhydrous toluene. A cooled (−78° C.) solution of dried (R)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one in anhydrous toluene (10 mL) was treated dropwise with a solution of sodium bis(trimethylsily)amide in toluene (0.6 M, 5.4 mL, 3.258 mmol). After stirring the yellow solution at −78° C. for 35 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.1 mL, 6.516 mmol) was added. After stirring at 0° C. for 3.5 h, the reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to afford the title compound (543.3 mg, 73%) as a colourless oil and as a 5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 0.77-0.99 (m, 8H), 1.49 (s, 3H), 2.36 (d of heptet, J=6.9, 3.8 Hz, 1H), 3.42-3.60 (m, 3H), 4.15-4.31 (m, 3H), 4.49-4.57 (m, 1H), 5.00 (d, J=17.6 Hz, 1H), 5.10 (d, J=10.7, 1H), 6.19 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 364.1 [M+Na], Tr=3.32 min.
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)[CH2:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1cccc(C2CC(N)=NN2c2ccccc2)c1
Solvent: Cc1ccccc1
Product: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of the crude product of 1-phenyl-5-(3-propylphenyl)-4,5-dihydro-1H-pyrazol-3-ylamine (18.6 g) in toluene (185 ml) was added activated carbon (pH5 to 8, 9.29 g), and the mixture was stirred overnight under oxygen atmosphere at reflux. This reaction solution was cooled to room temperature, and then the activated carbon was filtered off through Celite, and eluted with ethyl acetate. This filtrate was concentrated under reduced pressure, the resulting residue was dissolved in toluene (185 ml), and to the solution was added fresh activated carbon (pH5 to 8, 9.29 g), and the mixture was stirred overnight under oxygen atmosphere at reflux. This reaction solution was cooled to room temperature, and then the activated carbon was filtered off through Celite, and eluted with ethyl acetate. This filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/1) to give the titled compound (8.68 g).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[N:23]([CH2:24][C:25](O)=[O:26])[N:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:26])[N:22]=[C:21]([C:28]([F:30])([F:29])[F:31])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 4.65 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.50 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]1[C:14]2[CH:15]=[C:16]([CH2:19][NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11]1>>[O:10]1[C:14]2[CH:15]=[C:16]([CH2:19][N:20]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)[S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ccoc3c2)cc1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3ccoc3c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-(benzofuran-6-ylmethyl)sulfamoyl)benzoate (step-1 of Example 2). LC-MS (method-C) m/z: M+1 obs 490.91; tR=2.75 min.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:33][CH:34]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1Nc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-(3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (53.0 mg, 0.257 mmol) (prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.023 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.09 (dd, J=4.6, 1.5 Hz, 1H), 8.05 (d, J=6.5 Hz, 1H), 7.78 (dd, J=8.1, 1.4 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.28-7.23 (m, 1H), 7.13 (d, J=7.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.74 (t, J=7.2 Hz, 1H), 6.69 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.33 (s, 3H), 3.10 (s, 3H), 2.09 (t, J=6.0 Hz, 2H), 2.67-2.57 (m, 4H), 1.87-1.77 (m, 4H). MS=523 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:11][CH2:10][CH:2]=[CH2:3])[C:2]([Br:1])=[C:3]([O:12][CH2:6][CH:5]=[CH2:4])[CH:4]=1)[CH:20]=[CH2:21]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cc(OCC=C)c(Br)c(OCC=C)c1
Reaction time: 15 h
Yield: 194.8 %

Procedure:
To a solution of 4-Bromo-3,5-dihydroxybenzoic acid (20.43 g, 87.5 mmol, 1.0 equiv) in DMF (120 mL) at room temperature was added solid K2CO3 (60.5 g, 438 mmol, 5 equiv). To the suspension was added allylbromide (31 ml, 358 mmol, 4.1 equiv) dropwise over 25 minutes. After 15 hours, water (150 mL) was added and the slurry was poured into water (300 mL). The precipitate was separated by filtration, washed with water, and dissolved in ether. The solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford 16 as a white powder (30.1 g, 97%). Rf=0.52 (15% EtOAc/hexane); FTIR (neat, cm−1) 3088, 2900, 1717, 1649, 1582, 1424, 986; 1H NMR (400 MHz, CDCl3) δ, 7.24 (s, 2H), 6.12-5.98 (m, 3H), 5.51 (dd, J=17.6, 1.6 Hz, 2H), 5.40 (dd, J=17.2, 1.2 Hz, 1H), 5.32 (dd, J=10.2, 1.2 Hz, 2H), 5.30 (dd, J=8.4, 1.6 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 4.66 (d, J=3.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ132.2, 132.0, 129.9, 118.4, 117.9, 107.9, 106.9, 69.9, 65.7; MS EI+ calculated for C16H17BrO4 (M−H+): 351, found: 351.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH3:8])=[O:6]>CO.O>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:7]([C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[CH3:8])=[CH:10][CH:11]=1)([OH:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CN(C(=O)NCCCl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CO
Solvent: O
Product: CN(C1=NCCO1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 86.3 %

Procedure:
Dissolve 10.0 g (26 m.mole) of N-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methyl-urea in a mixture of 50 ml of methanol and 100 ml of water. Heat for one hour on a steam bath. Concentrate, and partition between 1N aqueous sodium bicarbonate solution and ether (diethyl) and then extract with 200 ml of 1N hydrochloric acid. Add sodium bicarbonate and then extract with 200 ml of ether. Dry the ether extract and concentrate to obtain 7.8 g of the title compound as a white solid, m.p. 188°-190° C. The salts may be prepared by standard techniques such as by treatment of a solution of the free base in a suitable organic solvent, e.g. ether, with the desired acid, e.g. hydrochloric, and then filtering off the precipitated salt. The hydrochloride salt melts at 147°-149° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C.Br>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Agent: Br
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1F
Reaction time: 0.29 h

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (1.0 g) in acetic acid (30 ml) was treated dropwise with a solution of bromine (0.736 g) in acetic acid (4.5 ml) at 50° in the presence of a few drops of 48% hydrogen bromide in acetic acid. After stirring for 15-20 minutes, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with 8% sodium bicarbonate (50 ml) and water (50 ml). The organic layer was then dried (MgSO4) and concentrated to give a pale brown oil which crystallised from benzene/acetone, 1.2 g, m.p. 129-132°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:40])[NH2:39])=[CH:34][CH:33]=1.Cl[C:42]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:43]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH:40][C:42]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:43])=[CH:36][CH:37]=1
Reactant: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OC1CCCCC1
Product: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[(4-amidino-phenyl)-oxymethyl]-5-[N-(methoxycarbonylmethyl)-quinoline-8-sulphonylamino)-benzimidazole and cyclohexyl chloroformate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:25])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[CH:13][CH:12]=3)[C:9]=2[CH:10]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([OH:25])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(F)cc2c1ccn2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(-n2ccc3c(O)cc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-fluoro-1-{4-[(phenylmethyl)oxy]phenyl}-1H-indol-4-ol (D20) (75 mg) and palladium on charcoal (75 mg) in ethanol (3 mL) was stirred under hydrogen at room temperature for 3 hours. The mixture was filtered and the filtrate was evaporated and chromatographed on silica gel (0-50% ethyl acetate in hexane). The product containing fractions were concentrated and then re-evaporated from ether (3×) to give the title compound (E10) as a white solid, (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=O)=[O:4].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccncc1C(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccncc1C(=O)Cl
Temperature: 25 °C

Procedure:
3-Chlorocarbonyl-isonicotinic acid methyl ester was prepared by refluxing a mixture of pyridine-3,4-dicarboxylic acid 4-methyl ester (100 mg) and thionyl chloride (75 μl) in chloroform (5 ml) for 3 h. After cooling to room temperature, volatiles were evaporated, and the residue was dried under high vacuum to give the product (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CCCCCn1c(-c2ccc(Cl)cc2O)nc2cc(F)c(F)cc21
Product: CCCCCn1c(-c2ccc(Cl)cc2OCc2ccc(C#N)cc2F)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(5,6-difluoro-1-pentyl-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown powder (41%). MS (Turbo Spray): m/z=484.4 (M+H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O>ClCCl>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CC[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 81.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 162e by using the (1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (290 mg, 0.966 mmol) prepared in Example 163d, 2,6-lutidine (0.136 mL, 1.17 mmol), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269 mL, 1.17 mmol) and dichloromethane (5.0 mL), to yield the title compound (327 mg, 82%) as a colorless oil.
Reaction SMILES: Cl([O-])=O.[Na+].O.P([O-])(O)(O)=O.[Na+].[CH2:12]([O:15][C:16]1[C:17]([CH:48]=[O:49])=[C:18]([CH:41]=[CH:42][C:43]=1[C:44]([F:47])([F:46])[F:45])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:29][CH:28]=2)=[CH:23][C:22]=1[F:40])[CH:13]=[CH2:14].CC(=CC)C.S([O-])([O-])(=[O:57])=S.[Na+].[Na+].Cl>C(O)(C)(C)C.O1CCOCC1>[CH2:12]([O:15][C:16]1[C:43]([C:44]([F:46])([F:47])[F:45])=[CH:42][CH:41]=[C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:31][CH:32]=3)=[CH:23][C:22]=2[F:40])[C:17]=1[C:48]([OH:57])=[O:49])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C=O)c(F)c2)cc1
Reactant: O=S([O-])([O-])=S
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
After an aqueous solution (1.1 ml) of sodium chlorite (125 mg, 1.38 mmol) and sodium dihydrogenphosphate monohydrate (125 mg, 0.91 mmol) was added dropwise to a solution of allyl (4′-{[3-(allyloxy)-2-formyl-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate obtained in Example (12-5) in a mixture of tert-butyl alcohol (2.4 ml), 1,4-dioxane (0.8 ml) and 2-methyl-2-butene (0.8 ml), the mixture was stirred at room temperature for 2 hours. After a 5% aqueous sodium thiosulfate solution was added to the reaction mixture, the mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate (twice). The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoic acid (135 mg, yield: 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.[CH3:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[CH:25]2)[S:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:6]([N:27]1[C:28](=[O:29])[N:24]([C:22]2[S:21][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([CH3:18])[CH:23]=2)[CH:25]=[N:26]1)[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccccc3)c2=O)cc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with benzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 82% yield: 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.43-7.31 (m, 5H), 6.94 (s, 1H), 5.01 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 344.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:38])(=[O:37])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:37])(=[O:38])[N:25]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-chloro-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 24).
Reaction SMILES: [O:1]=[C:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCCCCCCCCC(=O)OCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCCCCCCCCCC(O)CCCO1
Yield: 97.9 %

Procedure:
A solution of 480 g (1.89 mol) of 12-oxo-15-pentadecanolide (VI) in 735 ml of methanol is cooled to 10°-15° C. 26.2 g of sodium borohydride are added in portions at this temperature. The mixture is allowed to after-react at 15° C. for a further 2 hours. After addition of water, excess methanol is distilled off. The organic content of the reaction mixture is extracted with toluene, the toluene phase is washed neutral and dried, the toluene is stripped off and the residue is subjected to fractional distillation. 470 g (1.85 mol) of 12-hydroxy-15-pentadecanolide are obtained;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (for preparation see: Askew, B., et al., US 20033225106) (0.3 g, 1.60 mmol) in DCM (3 mL) was added Et3N (1 mL, 7.17 mmol), followed by methanesulfonyl chloride (0.5 mL, 6.46 mmol) and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in DCM and the organic phase washed with saturated sodium bicarbonate (aq.). The organic layer was dried (MgSO4), and concentrated in vacuo to give 3-methanesulfonyloxymethylazetidine-1-carboxylic acid tert-butyl ester (0.36 g, 1.40 mmol, 85%) as an oil which was used in the next step without further purification.