Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([S:5]([O-:8])(=[O:7])=[O:6])[CH2:3][OH:4].[C:10]1([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:36]12([C:47](Cl)=[O:48])[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([C:39]3=[O:46])[CH2:37]1)[CH2:43]2.Cl>C(#N)C.CCOCC.C(C(C)=O)C(C)C>[C:36]12([C:47]([O:4][CH2:3][C:2]([F:9])([F:1])[S:5]([O-:8])(=[O:7])=[O:6])=[O:48])[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([C:39]3=[O:46])[CH2:37]1)[CH2:43]2.[C:23]1([S+:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1C2CC3CC1CC(C(=O)Cl)(C3)C2
Reactant: O=S(=O)([O-])C(F)(F)CO
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: O=C1C2CC3CC1CC(C(=O)OCC(F)(F)S(=O)(=O)[O-])(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 g of acetonitrile, 5.4 g (0.01 mole) of the intermediate, triphenylsulfonium 1,1-difluoro-2-hydroxy-ethanesulfonate (purity 78%), 1.0 g (0.01 mole) of triethylamine and 0.24 g (0.002 mole) of N,N-dimethylaminopyridine were dissolved and ice cooled. 2.6 g (0.012 mole) of 4-adamantanone-1-carbonyl chloride, prepared above, was added dropwise to the solution at a temperature below 5° C. It was stirred at room temperature for 1 hour. Dilute hydrochloric acid (1 g of 12N hydrochloric acid in 10 g of water) was added to the solution. The acetonitrile was distilled off in vacuum, after which 50 g of dichloromethane, 50 g of methyl isobutyl ketone, and 20 g of water were added to the residue. The organic layer was separated and washed with 20 g of water. The solvent was distilled off in vacuum. Ether was added to the residue for crystallization. The crystals were filtered and dried, obtaining the target compound. 4.8 g (yield 80%). On 1H-NMR analysis, methyl isobutyl ketone and ether were observed as a trace amount of residual solvent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)c1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C4,2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[F:15][C:16]1[C:17]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3CCCN3)c21
Reaction time: 2.5 h

Procedure:
Using Method C above, (S)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 87B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.2 mL of H2O and stirred for 2.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitatiion out of THF with excess of hexanes. (Yield 8 mg, 18%).
Reaction SMILES: [Cl:1][Si:2]([CH3:10])([CH3:9])[CH:3]=[CH:4][Si:5]([Cl:8])([CH3:7])[CH3:6]>[Pd]>[Cl:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][Si:5]([Cl:8])([CH3:7])[CH3:6]
Reactant: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Agent: [Pd]
Product: C[Si](C)(Cl)CC[Si](C)(C)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
H2 gas was forced into 300.0 g (1.41 mol) of 1,2-bis (chlorodimethylsilyl)ethene and 1.5 g(0.7 mmol of pure Pd) of Pd/active carbon while stirring at a temperature of 50° C., until a pressure of 5.0 bar was reached. As a result of the reaction, the pressure gradually decreased again to about 2.0 to 2.5 bar (progressing hydrogenation reaction). Further H2 gas was forced in until a pressure of 5.0 bar was reached. Once again the pressure decreased to 2.0 to 2.5 bar, as a result of the hydrogenation reaction. This process was repeated about 15 to 20 times until the pressure remained constant at 5 bar when further H2 gas was forced in, i.e. no more H2 gas was absorbed by the system. Stirring was then continued for 2 h at a pressure of 5 bar and a temperature of 50° C. After venting, filtration was effected over a pressure drop. The results are summarized in Table 1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Yield: 90.6 %

Procedure:
A solution of lithium aluminum hydride (1.40 g, 36.9 mmol) in tetrahydrofuran (15.0 mL) and a solution of 3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.40 g, 3.82 mmol) in tetrahydrofuran (30.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 20-30% EtOAc/heptane) afforded 1.22 g (90%) of the title compound as a white solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 7.74, 7.63-7.61, 7.48, 7.45-7.40, 7.36, 3.84, 3.00-2.92; 13C NMR (100 MHz, CDCl3) δ 142.5, 139.3, 136.9, 135.2, 134.5, 128.9, 128.6, 128.5, 128.3, 127.3, 127.0, 126.4, 119.1, 117.8, 112.8, 108.8, 60.7, 55.7, 53.8, 28.6, 23.9; IR (drift) 3385, 3371, 1467, 1344, 1328, 1120, 1027, 870, 820, 765, 756, 750, 735, 728, 698 cm−1; MS (EI) m/z 352 (M+); Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.24; H, 6.89; N, 8.05.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[N:29]([C@H:30]2[C@H:35]([OH:36])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[C:28](=[O:44])[CH2:27][S:26]1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:27]4/[C:28](=[O:44])[N:29]([C@H:30]5[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32][CH2:31]5)[C:25](=[O:24])[S:26]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 5) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxy-piperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH:12]([C:14]([O:16]C(C)(C)C)=[O:15])[N:11]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:10]1=[O:26]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:8][N:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[N:11]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:10]1=[O:26]
Reactant: CN1CC(C(=O)OC(C)(C)C)N(CC(F)(F)F)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(C(=O)O)N(CC(F)(F)F)C1=O
Yield: 100.3 %

Procedure:
A solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (180 mg, 0.9 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml), under argon at −35° C., was treated with sodium hydride (60% dispersion in oil) (36.0 mg, 0.900 mmol). The mixture was stirred at −35° C. for 15 minutes and then 2,2,2-trifluoroethyl trichloromethanesulfonate (507 mg, 1.800 mmol) was added and the reaction mixture was stirred at −35° C. for 2 hours (the temperature increased slowly to −15° C.). The reaction was quenched with water (5 ml) and allowed to warm to room temperature and the reaction mixture was extracted with ethyl acetate (2×20 ml). The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (10 ml), water (2×10 ml) and brine (20 ml) and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 42%). LC/MS [M+H]+=283. (ii) A solution of 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 0.379 mmol) in TFA/DCM (1:2, 3 ml) was stirred at room temperature for 4 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylic acid (assume ˜0.38 mmol) which was used in the next reaction. LC/MS [M+H]+=227.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@H:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([NH3+:30])[CH3:29])=[N:26][CH:27]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]([CH3:12])[C:9]([NH:30][C@@H:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][N:26]=2)[CH3:29])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: COc1ccc([C@@H](C)[NH3+])nc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](C)c2ccc(-c3ccccc3)c(F)c2)nc1
Reaction time: 2 h

Procedure:
To a solution of 0.70 g (2.87 mmol) (S)-(+)-2-fluoro-alpha-methyl-4-biphenylacetic acid in 6.00 ml DMF was added 0.60 g (3.15 mmol) (1R)-1-(5-methoxypyridin-2-yl)ethanaminium chloride, 0.51 g (3.73 mmol) HOAT, 0.71 g (3.73 mmol) EDC, and 1.50 mL (8.60 mmol) DIEA. After 2.00 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 30-65% EtOAc:hexane) afforded (2S)-2-(2-fluoro-1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]propanamide. 1H NMR (CDCl3, 400 MHz) δ 8.19 (m, 1H); 7.56-7.54 (m, 2H); 7.46-7.34 (m, 4H); 7.20-7.14 (m, 4H); 6.78 (br d, 1H, J=7.33 Hz); 5.09 (m, 1H); 3.85 (s, 1H); 3.60 (q, 1H, J=7.15 Hz, 14.29 Hz); 1.53 (d, 3H, J=7.14); 1.37 (d, 3H, J=6.77 Hz). HRMS (ES) exact mass calcd for C23H23FN2O2: 379.1817, Found: 379.1817.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClC1C=CC=CC=1>[CH3:11][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Clc1ccccc1
Product: COc1ccc(NC(C)=O)cc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
A 2.5 liter flask is charged with 800 g of chlorobenzene. With stirring, 123.2 g of 100% p-anisidine (preferably as melt) are then added. Then 102 g of acetic anhydride are added dropwise in the course of about 15 minutes, whereupon the temperature rises to 65° C. After stirring for 15 minutes at 65° C., the mixture is cooled to about 30° C. within about 10 minutes using a cooling bath, whereupon beige-coloured crystals of the acetanisidide begin to precipitate in the temperature range from about 45° C. The resultant suspension is slightly viscous, but readily stirrable. The addition of 800 g of 92% sulfuric acid is then commenced, with care being taken that the temperature does not much exceed 30°-40° C. The addition takes about 10 minutes. With further cooling, the addition of 101.2 g of 62.3% HNO3 is commenced immediately at a maximum temperature of 25° C. During the addition, the temperature can be allowed to rise to 20°-25° C. With the first few drops of HNO3 the emulsion starts becoming fluid immediately and the original blue colour changes to brown. The addition is complete after about 10 minutes and the batch is stirred for 20 minutes at 20° to 25° C. until the reaction is complete. Volume of the solution: about 1450 ml. The reaction mixture is then charged into a 2 liter separating funnel, whereupon a lower, dark-brown layer separates immediately. The upper, chlorobenzene layer is largely colourless or only a pale yellow colour. The lower layer is then passed slowly into a glass beaker, into which a mixture of 300 g of ice and water is stirred. The temperature is kept at around +5° C. by the constant addition of altogether about 1500 g of ice (duration c. 30 minutes). A thick yellow suspension is finally obtained. The suspension is stirred and then filtered. The filter cake is washed with 350 ml of ice-water, well pressed and, if desired, dried. Mother liquor and wash water are combined. The amount of chlorobenzene remaining in the separating funnel is about 760 g and, after replenishment to the original amount, can be re-used in the next batch. Yield: about 193 to 195 g of 4-acetamido-2-nitro-anisole in 99% purity. Melting point: about 150°-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.830 g, 6.3 mmol) and the mixture was stirred at 0° C. To the reaction mixture, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for an hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and was washed with water (150 mL). The reaction mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 15-20% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1)[NH2:12]
Reactant: COC1=NCCCCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC1=NCCCCC1

Procedure:
A 22.5 g portion 7-methoxy-3,4,5,6-tetrahydro-2H-azepine was reacted with 11.3 g of hydrazine hydrate in 200 ml of ethanol by the procedure of Example 9, giving the desired intermediate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:12]2[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 4-fluorobenzenesulfonyl chloride (292 mg), the title compound was obtained as a colorless oil (yield 436 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 97.7 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.335 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 19, 0.255 g) in DCM (4 mL) and pyridine (2 mL) and the resultant mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl cis-(3aRS,9bRS)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.486 g) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[CH2:48][C:44]3[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(CNc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazole carboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml). The solution was added with sodium cyanoborohydride (54.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After the reaction, the solvent was distilled off. A 1 mol/l sodium hydroxide aqueous solution was added to the residue, and chloroform extraction was then carried out. The extract was washed with saturated saline solution and then dried with magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (212 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-fluoro-4-methyl-benzoic acid (Aldrich, 3.08 g, 20 mmol) in diethyl ether (30 mL), oxalyl chloride (2.85 mL, 30 mmol) was added slowly followed by a drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure to give 3-fluoro-4-methyl-benzoyl chloride that was used directly for the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>O1CCOCC1>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:15]2[C:14]([C:9]3[O:10][C:11](=[O:13])[C:12]4[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=4[N:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:33]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of compound S (37.60 g, 125 mmol) and triethylamine (42 mL, 301 mmol) in anhydrous 1,4-dioxane (800 mL) was added dropwise (S)-(−)-3-(dimethylamino)-pyrrolidine (17.1 g, 150 mmol) at room temperature under Ar. The resulting mixture was stirred for 8 hours. The solution was concentrated, and diluted with water (200 mL) and EtOAc (50 mL). The resulting solution was basified to pH 9 with saturated sodium bicarbonate and then extracted with ethyl acetate (3×300 mL). The organic layers were combined and washed with water, brine, and dried over anhydrous Na2SO4 followed by the removal of EtOAc in vacuo. The crude product was purified by column chromatography (Chromatrex NH-DM2035, Fuji Sislysia Chemical Co. Ltd.) using a gradient of 20-25% ethyl acetate/hexanes to yield compound 132 (37.03 g, 73%) as a yellow amorphous solid.