Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].ClC(Cl)(Cl)C(=N)O[C:23]([CH3:26])([CH3:25])[CH3:24].C1CCCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]([F:17])([F:18])[CH2:3][CH:4]([CH3:16])[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:6]([O:8][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C(=O)O)C(C)CC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(C)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 3.79 g (14.5 mmol) of 5,5,5-trifluoro-3-methyl-2-(4-methylphenyl)pentanoic acid were dissolved in 60 ml of THF at room temperature, and 27 μl (0.22 mmol) of a 1 M boron trifluoride/diethyl ether complex solution were added. 3.828 g (17.48 mmol) of tert-butyl 2,2,2-trichloroethanimidoate were then metered in a little at a time, and the mixture was stirred at room temperature overnight. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 2:1), 2 g of solid sodium bicarbonate were added with vigorous stirring of the reaction solution. The reaction mixture was then filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). This gave 3.25 g (10.27 mmol, 71% of theory) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.O.C([O-])([O-])=O.[Na+].[Na+].S(Cl)([Cl:25])=O>CN(C)C=O.ClCCl>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
A 6,7-dimethoxyquinazolin-4(3H)-one suspension (2a) (0.79 g, 3.83 mmol) in thionyl chloride (7.0 mL) containing 10 drops of N,N-dimethylformarnide (DMF) was agitated and heated under reflux for three hours, until a solution was obtained. The reaction mixture was left cooling at room temperature. The reaction environment was diluted in dichloromethane and water (160 mL) and left in ice bath. The material was treated under agitation with 30 mL of saturated Na2CO3 solution. Na2CO3 was carefully added until pH was adjusted to 7-8 range. Then, the aqueous phase was extracted with CH2Cl2 (2×30 mL), and the organic phase compound was washed with salt solution (2×10 mL), dried over magnesium sulfate, filtered, and the solvent was evaporated in a rotatory evaporator in order to provide 6,7-dimethoxy-4-chloroquinazoline (3a) as a yellow solid (0.68 g, 3.03 mmol, 79%), which was used without purification in the next stage: melting point 185-187° C.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH2:10]=[O:11].C(O)(=O)C(O)=O>O>[OH:11][CH2:10][C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1
Reactant: C=O
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC1=C(O)C(=O)C(C)(CO)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10 g of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone, 20 ml of a 37% formaldehyde aqueous solution, 50 ml of water and 0.7 g of oxalic acid was stirred for 18 hours at room temperature. After working up the reaction mixture, the crude reaction product was purified by column chromatography over polyamide. Elution with pentane-dichloromethane 80/20 yielded the pure 2-hydroxymethyl-2,5-dimethyl-4-hydroxy-3-(2H)-furanone, which was recrystallized from ethyllactate; m.p. 124°-125°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[Cl:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: ClCCCNCc1ccc(Cl)nc1
Yield: 86.9 %

Procedure:
16.20 g (100 mmol) of 2-chloro-5-(chloromethyl)pyridine, 16.90 g (130 mmol) of 3-chloropropan-1-amine hydrochloride and 36.24 ml (260 mmol) of triethylamine in 200 ml acetonitrile stirred at 60° C. for 20 hours. After addition of 30.67 g (230 mmol) of 30 percent strength aqueous sodium hydroxide solution, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Concentration of the extract under reduced pressure gives 19.03 g (87% of theory) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine which can be used without further purification for the next reaction (cf. Ex. II-2).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].C([Li])CCC.[N+:12]([C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>O1CCCC1.CCCCCC.ClCCl.O>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:24][CH2:25][C:26]([OH:29])([CH2:1][S:2][CH2:3][S:4]([CH3:6])=[O:5])[CH2:27][CH2:28]2)=[O:22])=[CH:30][CH:31]=1)([O-:14])=[O:13]
Reactant: O=C1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CSCS(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)CSCC1(O)CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To methyl methylthiomethyl sulfoxide (2.23 g) in dry tetrahydrofuran (10 ml) was added dropwise n-butyl lithium (1.15 g) in dry hexane (11.6 ml) at -60° to -70° C. under nitrogen atmosphere and the mixture was stirred for 20 minutes at the same temperature. Subsequently, 1-p-nitrobenzyloxycarbonyl-4-piperidone (5.0 g) in dry tetrahydrofuran (30 ml) was added dropwise thereto at -55° to -70° C. under nitrogen atmosphere. The reaction mixture was diluted with dichloromethane (200 ml) and water (215 ml), warmed slowly to room temperature, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 1-p-nitrobenzyloxycarbonyl-4-hydroxy-4-methylsulfinylmethylthiomethylpiperidine.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12]Br)(=O)C.[CH:15]([NH2:17])=[S:16].C(N)=O>CC(C)=O>[S:16]1[CH:12]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[N:17]=[CH:15]1
Reactant: NC=S
Reactant: CC(=O)Oc1ccccc1C(=O)CBr
Solvent: CC(C)=O
Solvent: NC=O
Product: Oc1ccccc1-c1cscn1
Temperature: 10 °C

Procedure:
o-(Bromoacetyl)phenyl acetate (5.0 g, 19.5 mmol) was treated with crude thioformamide (filtrate concentrated in vacuo from reaction of P2S5 (1.1 eq.) and (25 mmol) formamide in THF (30-40° C., 5 hours)) in refluxing acetone (60 mL). After 16 hours the reaction mixture was cooled to about 10° C. and the precipitated HBr salt of 2-(thiazol-4-yl)phenol was recovered. 31%, 1.50 g, LSIMS m/z=178 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH2:9]([NH:16][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: NCc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NCc2ccccc2)nn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred solution of 3-chloro-6-methylpyridazine (215 mg, 1.66 mmol) and benzylamine (267 mg, 2.5 mmol) in toluene (20 mL) was added sodium tert-butoxide (480 mg, 5.0 mmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (20 mg). The reaction mixture was stirred at 140° C. under microwave irradiation for 2 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane) to give the title compound (302 mg, 91%) as an off-white solid. δH (CDCl3) 7.25-7.41 (5H, m), 7.02 (1H, d, J 9.0 Hz), 6.55 (1H, d, J 9.0 Hz), 4.91 (1H, s), 4.60 (2H, d, J 5.8 Hz), 2.53 (3H, s). LCMS (ES+) 200 (M+H)+, RT 2.50 minutes (Method 2).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1OC
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1OC

Procedure:
The product from Example 1d (277 mg, 1.56 mmol) was reacted with the product from Example 51b (430 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (628 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3H) 2.76 (s, 3H) 3.56 (s, 3H) 3.68 (s, 3H) 6.24 (d, J=6.99 Hz, 1H) 6.82 (m, 3H) 7.29 (m, 3H) 7.79 (d, J=8.46 Hz, 1H) 8.38 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.46 Hz, 1H) 10.97 (s, 1H) 14.35 (s, 1H); MS (ESI+) m/z 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[C:19]([CH3:22])[O:20][N:21]=[C:11]3[C@H:10]([CH2:23][C:24](OC(C)(C)C)=[O:25])[N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:38]([NH2:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[C:19]([CH3:22])[O:20][N:21]=[C:11]3[C@H:10]([CH2:23][C:24]([NH:40][CH2:38][CH3:39])=[O:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN
Reactant: Cc1onc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)OC(C)(C)C
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: ClCCl
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c1noc2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a round bottomed flask was added tert-butyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate (0.059 g, 0.140 mmol), CH2Cl2 (2 mL), and TFA (0.400 mL, 5.19 mmol). The reaction was stirred at room temperature for 2 h before concentrating. The crude residue was dried for 30 min before addition of DMF (2 mL), ethylamine (0.098 mL, 0.195 mmol, 2M in THF), HATU (0.080 g, 0.209 mmol), and Hunig's Base (0.073 mL, 0.419 mmol). The reaction was stirred at room temperature for 1 h before diluting with water and extracting with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)-N-ethylacetamide (0.022 g, 0.056 mmol). 1H NMR (500 MHz, Acetone-d6) δ 7.76-7.72 (m, 1H), 7.71-7.66 (m, 1H), 7.49-7.42 (m, 3H), 7.41-7.36 (m, 3H), 7.32 (br. s, 1H), 4.62 (dd, J=5.4, 8.3 Hz, 1H), 3.35-3.21 (m, 2H), 3.20-3.09 (m, 2H), 2.67 (s, 3H), 1.14 (t, J=7.3 Hz, 3H); LC/MS m/z 394.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(I)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a solution of methyl 5-iodo-2-((methylsulfonyl)amino)benzoate (Preparation 49, 0.50 g) and K2CO3 (0.41 g) in DMF (10 mL) is added iodomethane (0.10 mL) at ambient temperature. After 24 hrs, the solvent is removed in vacuo and the residue is partitioned between Et2O (20 mL) and water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude yellow liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 0.48 g (92%) of the title compound as a white solid. Physical characteristics: m.p. 105-106° C.; 1H NMR (300 MHz, CDCl3) δ 8.22, 7.86, 7.18, 3.91, 3.27, 2.96; IR (diffuse reflectance) 1718, 1443, 1330, 1289, 1258, 1150, 1056, 970, 964, 957, 888, 839, 772, 732, 712 cm−1; MS (ESI+) m/z 370 (MH+). Anal. Found: C, 32.74; H, 3.30; N, 3.81.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.CS(C)=O.[NH2:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](F)[C:19]([Br:26])=[C:18]([CH3:27])[C:15]=1[C:16]#[N:17].C(N(CC)CC)C>O>[NH2:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)[C:19]([Br:26])=[C:18]([CH3:27])[C:15]=1[C:16]#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(Br)c(F)c([N+](=O)[O-])c(N)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])c(N)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (140 μl, 1.10 mmol) was added to a dimethyl sulfoxide (2 ml) solution of 2-amino-5-bromo-4-fluoro-6-methyl-3-nitrobenzonitrile (I-266) (274 mg, 1.00 mmol) and triethylamine (209 μl, 1.50 mmol), followed by stirring at room temperature for 30 minutes. The reaction liquid was poured into water, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the entitled compound (359 mg, 97%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:17][NH:13][C:14]([N:1]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([NH:13][CH3:17])=[O:15])=[O:15]
Reactant: Nc1cnc2ccccc2c1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CNC(=O)N(C(=O)NC)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.0 g of 3-aminoquinoline are added in portions to a solution of 1.65 ml of N,N-dimethylcarbamoyl chloride in 3.9 ml of pyridine and the reaction mixture is stirred at room temperature for 24 h. The reaction mixture is then poured onto 50 ml of ice-water. Customary working up and purification of the crude product by chromatography over 100 g of silica gel (mobile phase L) gives 3-(N,N-dimethylaminocarbonylamino)quinoline: Rf (L)=0.23; MS:M+=215.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:26]=[CH:25][C:16]2[C@H:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:18][O:19][C:15]=2[CH:14]=1.Br[C:28]1[C:41]([CH3:42])=[CH:40][C:31]([C:32]([NH:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[O:33])=[CH:30][C:29]=1[CH3:43]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C@H:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C@H:6]3[C:7]4[C:3](=[C:2]([C:28]5[C:41]([CH3:42])=[CH:40][C:31]([C:32](=[O:33])[NH:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][C:29]=5[CH3:43])[CH:10]=[CH:9][C:8]=4[F:11])[CH2:4][CH2:5]3)=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: Cc1cc(C(=O)NCC(C)(C)O)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)NCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared following a procedure analogous to that described in Step 5 in the preparation of Intermediate 1, starting from 4-bromo-N-(2-hydroxy-2-methyl-propyl)-3,5-dimethyl-benzamide.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:16]=[C:17]([Si:21]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Br:40])[CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:40][C:36]1[CH:35]=[C:34]([Si:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][CH:18]=2)[C:22]2[CH:23]=[C:24]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:25]=[CH:26][CH:27]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A suspension of 9H-carbazole (3.60 g, 21.53 mmol), bis(3-bromophenyl)diphenylsilane (21.28 g, 43.1 mmol), Pd2(dba)3 (0.394 g, 0.431 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (dppf, 0.394 g, 0.431 mmol) and sodium tert-butoxide (4.14 g, 43.1 mmol) in xylene (150 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic solution was isolated by filtration. Upon evaporation of the solvent, the crude product was purified by column chromatography on silica gel with hexane:EtOAc (9:1, v/v) as eluent to yield 9-(3-((3-bromophenyl)diphenylsilyl)phenyl)-9H-carbazole (6.1 g, 49%) as white solid
Reaction SMILES: [CH2:1](O)[CH2:2]CCO.C(O[Si](C)(C)C)(C)C.[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][S:24]([CH:27]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]([O:40][CH3:41])([O:38][CH3:39])[CH2:29][CH2:28]1)(=[O:26])=[O:25].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][S:24]([CH:27]1[CH2:28][CH2:29][C:30]2([O:38][CH2:39][CH2:2][CH2:1][CH2:41][O:40]2)[CH:31]=[C:32]1[C:33]([O:35][CH2:36][CH3:37])=[O:34])(=[O:25])=[O:26]
Reactant: OCCCCO
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: CC(C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCCCO2
Yield: 2.9 %

Procedure:
34 mg (0.61 mmol) of 1,4-butanediol was dissolved in 5 ml of dichloromethane, 0.32 ml (1.83 mmol) of isopropoxytrimethylsilane, and 200 mg (0.47 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 4 μl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1), and the resulting solid was further washed with hexane to give 6 mg of the title compound as a white powder (yield: 3%).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[C:17]([OH:19])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:2][O:3][N:4]([CH3:5])[C:17](=[O:19])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:8])=[O:9])=[CH:15][CH:14]=1)[CH2:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (1.22 g) in acetonitrile (40 mL) was added triethylamine (4.35 mL) for neutralization, and 2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-3-yl)propanoic acid (3.12 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.40 g) and 1-hydroxybenzotriazole (191 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.96 g, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[OH-].CC(O)C.[NH:23]1[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CN(C=O)C>[NH2:28][C:27]1[CH:29]=[CH:30][N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24](=[O:25])[N:26]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A 0.1 M solution of tetra-N-butylammonium hydroxide in a mixture of MeOH and 2-propanol (90 mL, 9.0 mmol) was added dropwise to a stirred suspension of cytosine (1 g, 9.0 mmol) in DMF (70 mL). The solution became clear and benzyl bromide (2.14 mL, 18 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-amino-1-benzyl-1H-pyrimidin-2-one (1 g, 57% yield) as a white solid.
Reaction SMILES: [N:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:3]1([NH2:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=NN1CCCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 14.7 mmol) in THF (40 mL) was added dropwise under N2 to a suspension of LAH (0.56 g, 14.7 mmol) in THF (10 mL) cooled with an ice-bath such that the temperature did not rise above 150° C. The mixture was stirred at room temperature for 1 h, quenched with saturated Rochelle's salt solution (15 mL) and extracted with ether (3×20 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:4) gave 2,3,4,5-tetrahydro-1H-1-benzazepin-amine (1.63 g, 68%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ1.50-1.72 (m, 2H), 1.78-1.92 (m, 2H), 2.70-2.82 (m, 2H), 3.180-3.22 (m, 2H), 3.78 (br, 2H), 6.91 (td, J=7.3, 1.5 Hz, 1H), 7.10 (dd, J=1.1, 7.4 Hz, 1H), 7.21 (td, J=8.0, 1.4 Hz, 1H), 7.28 (dd, J=1.4, 8.0 Hz, 1H) ppm.