Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](Cl)=[O:7])[CH:2]=[CH2:3].[C:9]([O:12][CH2:13][CH:14]([NH:20][C:21]([C:23]1[C:28]([I:29])=[C:27]([NH2:30])[C:26]([I:31])=[C:25]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:24]=1[I:46])=[O:22])[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>CN(C)C(=O)C>[C:43]([O:42][CH2:41][CH:35]([NH:34][C:32]([C:25]1[C:26]([I:31])=[C:27]([NH:30][C:6](=[O:7])[CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[C:28]([I:29])=[C:23]([C:21]([NH:20][CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][O:12][C:9](=[O:11])[CH3:10])=[O:22])[C:24]=1[I:46])=[O:33])[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:45])[CH3:44]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: C=CCOCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCOCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Temperature: 5 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
Allyloxyacetyl chloride (9.0 g, 67 mmol) was added dropwise to a stirred solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (30.0 g, 34 mmol) in N,N-dimethylacetamide (70 ml) at 0°-5° C. The reaction mixture was stirred at 5° C. for 30 minutes and at room temperature for 20 hours. It was then slowly added dropwise to a well stirred mixture of ice-water (1.5 L), when a white solid separated out. This was collected by filtration, washed with water, and dried in vacuo to obtain N,N'-Bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2-propenyloxy)acetyl]amino-2,4,6-triiodo-1,3-benzenedicarboxamide as a white amorphous solid (32.1 g, 97% yield), m.p. 214°-16°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:32][C:29]([F:30])([F:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: FC(F)(F)c1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: FC(F)(F)c1ccccc1CC[C@H]1CNCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Combine (S)-1,4-dibenzyl-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (2.66 g, 6.06 mmol), ammonium formate (1.91 g, 30.31 mmol), 5% Pd/C (293.3 mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3 hrs, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 1.46 g (93%) of the title compound as a white solid: mp 43°–47°; mass spectrum (ion spray): m/z=259.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.CCOC(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:21](=[O:22])[NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)Cc1c(C(=O)NC(C)(C)C)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Step I (I): To a solution of methyl 2-(5-bromo-1H-indol-3-yl)acetate ( 268 mg, 1.0 mmol) and tert-butyl isocyanate (149 mg, 1.5 mmol) in dichloromethane was added boron trifluoride diethyl etherate dropwise at −5° C. under nitrogen. The mixture was stirred from −5° C. to rt and at rt overnight. 100 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give 340 mg of the crude methyl 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetate (yield 92.6%). MS (ESI) (M+H)+=369.05. 1H NMR (500 MHz, CDCl3) δ ppm 1.51 (s, 9 H) 3.74 (s, 3 H) 3.86 (s, 2 H) 7.26 (d, J=8.55 Hz, 1 H) 7.35 (dd, J=8.55, 1.83 Hz, 1 H) 7.79 (d, J=1.53 Hz, 1 H) 8.01 (s, 1 H) 9.17 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:10](I)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCO>[F:1][C:2]1[C:10]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(I)c(F)c(C(=O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a solution of 2-fluoro-3-iodo-5-methoxy-benzoic acid (3.0 g 10.14 mmol, 1.0 eq) in a mixture of water (30 mL), EtOH (30 mL) and DMF (60 mL), was added 3-fluorophenylboronic acid (1.56 g 11.15 mmol, 1.1 eq) and Na2CO3 (4.3 g, 40.56 mmol, 4.0 eq). The mixture was stirred at room temperature under N2 for 10 mins then Pd(PPh3)4 (1.17 g, 1.01 mmol, 0.1 eq) was added. The mixture was heated at 100° C. for 5 h then cooled to room temperature and acidified with 1M HCl. The aqueous layer was extracted with EtOAc and the combined extracts were washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:3) to give the title compound as a yellow solid (2.2 g, 81%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:13]=[C:14]([O:18][NH2:19])[CH:15]=[CH:16][CH:17]=1)([OH:11])=[O:10]>>[C:9]([C:12]1[CH:13]=[C:14]([O:18][N:19]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:17]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: NOc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(ON=Cc2ccccc2)c1
Yield: 58.1 %

Procedure:
Benzaldehyde (21.0 μL, 0.207 mmol) was subjected to the representative coupling procedure with 3 (31.8 mg, 0.208 mmol) as outlined above (method 2), yielding 3a as a white solid (29.0 mg, 58%). 1H-NMR (500 MHz, 1:1 CD3OD:d6-DMSO) δ 7.39-7.45 (m, 5H), 7.59-7.64 (m, 1H), 7.71-7.78 (m, 3H), 8.58 (s, 1H); 13C-NMR (125 MHz, d6-DMSO) δ 114.5, 118.8, 123.3, 127.7, 129.1, 129.3, 130.8, 131.1, 132.3, 153.3, 158.9, 166.9; MALDI-FTMS (DHB) 242.0812 m/z [MH]+, C14H12NO3 requires 242.0812. RP-HPLC: 98% pure.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:24]([Zn+])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)C>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:24]([C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:5]=[CH:4][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=N)Nc1cccc(Cc2ccccc2)n1
Yield: 39.4 %

Procedure:
The preparation was carried out analogously to Example 67, using 0.200 g (0.548 mmol) N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine and 2.74 mL (1.369 mmol) of the benzyl zinc bromide solution (0.5 M in tetrahydrofuran) under Pd catalysis with 20 mg (0.055 mmol) [1,1′-bis-(diphenylphosphino)ferrocene]palladium(II) chloride-methylene chloride. The mixture was likewise heated under reflux under a nitrogen atmosphere, first for 4 hr, and then after repeated additions of 2.43 mL (1.213 mmol) of the 0.5 M benzyl zinc bromide solution and 20 mg (0.055 mmol) Pd catalyst for an additional 8 hr, i.e., for a total of 12 hr of heating. After appropriate workup and purification via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid), 95 mg (0.216 mmol, 40%) pure N-(6-benzylpyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CCC(CO)CC1

Procedure:
To a solution of 5.76 g (0.05 mol) of 4-piperidinemethanol and 4.75 g (0.06 mol) of pyridine in 50 mL of methylene chloride cooled to 0° add dropwise a solution of 10.4 g (0.055 mol) of 4-chlorobenzeneacetyl chloride in 25 mL of methylene chloride. When the addition is complete stir the reaction overnight at room temperature. After this time add 25 mL of 2N hydrochloric acid. Separate the layers and wash the methylene chloride layer with two 50 mL portions of saturated sodium bicarbonate solution and 25 mL of saturated sodium chloride solution then dry the methylene chloride layer over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:12]=1[NH2:13].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.CO>[CH3:7][N:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([O:10][CH3:9])[CH:17]=2)=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cc1ncc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2cnc(C)n2C)ccc1N
Temperature: 150 °C
Yield: 42.2 %

Procedure:
To a microwave vial was added 5-bromo-1,2-dimethyl-1H-imidazole (230 mg, 1.31 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (393 mg, 1.58 mmol), Pd(PPh3)4 (152 mg, 0.13 mmol), CsF (599 mg, 3.94 mmol) and DME/MeOH 3/1 (4 mL). The mixture was heated in a microwave at 150° C. for 1 hour. The reaction mixture was then filtered and concentrated onto silica gel and purified by Biotage silica gel column chromatography eluting with (EtOAc/MeOH 100/0 to 96/4) to give the title product as a light brown oil (120 mg, 42%). 1H NMR (500 MHz, CDCl3): δ 2.43 (s, 3H), 3.48 (s, 3H), 3.87 (s, 3H), 6.73-6.78 (m, 3H), 6.87 (s, 1H). LC (Method A)-MS (ESI, m/z) tR 0.49 min, 218 [(M+H+), 100%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Fc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
4-fluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give 4-acetyl-4'-fluoro-2-nitrobiphenyl, m.p. 88°-90° C. (from methanol). This compound was reduced with stannous chloride in concentrated hydrochloric acid to give 4-acetyl-2-amino-4'-fluorobiphenyl, m.p. 88°-91° C. (from methanol). The amino group in this compound was converted to methoxy in the following way:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15]C2CCCCO2)[C:11]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[NH:26][C:27](=[O:44])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:15][CH2:14][C:12]1[C:11]([C:22]([F:24])([F:23])[F:25])=[CH:10][C:9]2[NH:26][C:27](=[O:44])[CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=4)[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(COC4CCCCO4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(CO)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(tetrahydro-pyran-2-yloxymethyl)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M241) (156 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (50 mg, 42%).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:49]2[CH2:54][CH2:53][C:52](=O)[CH2:51][CH2:50]2)[CH:44]=[C:45]([F:48])[C:46]=1[F:47]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:52]1[CH2:51][CH2:50][CH:49]([C:43]2[CH:44]=[C:45]([F:48])[C:46]([F:47])=[C:41]([F:40])[CH:42]=2)[CH2:54][CH2:53]1
Reactant: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(C2CCC(=CCC3OCCCO3)CC2)cc(F)c1F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (200 ml), suspending it, stirring under ice cooling till the liquid temperature reached 10° C., adding potassium t-butoxide (3.0 g, 27 mmols) to the reaction mixture, further elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(3,4,5-trifluorophenyl)cyclohexanone (5.7 g, 25 mmols) from the dropping funnel over 30 minutes, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(3,4,5-trifluorophenyl)cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 178.8 %

Procedure:
tert-Butyl {[1-[(2-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:5 to give the title compound as colorless crystals (yield 78 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[C:32]([CH:33]=[O:34])=[CH:31][CH:30]=[N:29]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:33]([OH:34])[C:32]4[N:28]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][O:22]5)[N:29]=[CH:30][CH:31]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: O=Cc1ccnn1C1CCCCO1
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 43 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 2-tetrahydropyran-2-ylpyrazole-3-carbaldehyde to afford 329 mg (43% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:30][CH:31]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenyl-thiophenol.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][S:6][C:5]1=[N:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:20][C:7]1[S:6][C:5](=[N:9][C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[N:4]([CH2:3][O:2][CH3:1])[CH:8]=1
Reactant: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCn1cc(Br)sc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
6.38 g (20.6 mmol) of methyl 6-(3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridine-2-carboxylate was dissolved in 60 ml of 1,4-dioxane and 3.67 g (20.6 mmol) of N-bromosuccinimide was added thereto at room temperature. The reaction mixture was heated under reflux for 30 minutes, cooled to room temperature, diluted with 200 ml of ethyl acetate and washed with 150 ml of water for three times. After that, the reaction mixture was washed with 150 ml of brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give 7.10 g (19.8 mmol) of the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([C:37](Cl)=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:32]3[S:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added thenoyl chloride (0.71 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.88 g, yield 64%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([O:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([O:25][CH2:26][CH2:27][C:28]([F:30])([F:29])[F:31])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCCC(F)(F)F)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-(3,3,3-trifluoropropoxy) pyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (53 mg) in methanol (1.0 mL) was added 2N aqueous sodium hydroxide (235 μL) solution at room temperature, and the mixture was stirred for 20 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (10 mM NH4HCO3-containing system)), and the obtained fraction was evaporated under reduced pressure to give the title compound (32 mg) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH:16]([CH3:18])[CH3:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6].[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[C:25]([O:26][CH3:27])[CH:24]=1>C1(C)C(C)=CC=CC=1>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH2:2][CH2:3][N:4]([CH:16]([CH3:18])[CH3:17])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)(=[O:7])=[O:6])[CH:32]=[CH:31][C:28]=1[O:29][CH3:30]
Reactant: CC(C)N(CCCl)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN(C)CCN(C(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reaction of N-β-chloroethyl-N-(1-methylethyl)-3,4-dichlorobenzenesulfonamide with N-methylhomoveratrylamine in xylene containing inorganic carbonate acid scavengers by heating for five days.