Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:42][CH2:43][C:44](SC1C=CC(F)=CC=1)=[O:45])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:44](=[O:45])[CH2:43][CH2:42][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(F)cc1)C(=O)OCc1ccccc1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
A solution of benzyl 2-aminoacetate hydrochloride (17.6 mg, 0.0871 mmol) and DIPEA (0.0152 ml, 0.0871 mmol) in DMF (0.0871 ml) was added to a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-((4-fluorophenyl)thio)-5-oxopentanoate (Compound 5e-2) (30.0 mg, 0.0670 mmol) in DMF (0.463 ml) and water (0.220 ml), and the mixture was stirred at 50° C. for six hours. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 5-((2-(benzyloxy)-2-oxoethyl)amino)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (Compound 5d-2) (29.4 mg, 91%).
Reaction SMILES: [Br:1]C1CC2C(=CC=CC=2F)C1=O.[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]2[C:17]([CH2:18][CH2:19][C:20]2=[O:24])=[CH:16][CH:15]=1>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:19]1[CH2:18][C:17]2[C:21](=[C:22]([Cl:23])[C:14]([Cl:13])=[CH:15][CH:16]=2)[C:20]1=[O:24]
Reactant: O=C1c2cccc(F)c2CC1Br
Reactant: O=C1CCc2ccc(Cl)c(Cl)c21
Agent: Br[Cu]Br
Solvent: C1COCCO1
Product: O=C1c2c(ccc(Cl)c2Cl)CC1Br

Procedure:
The 2-bromo-6,7-dichloro-1-indanone is prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 7.42 g of 6,7-dichloro-1-indanone, 21.8 g of copper bromide and 240 ml of dioxane. After purification by silica column chromatography with an ethyl acetate-cyclohexane mixture (10-90 by volume) as eluent, 6.79 g of 2-bromo-6,7-dichloro-1-indanone are obtained which melt at 103° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[O:15].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:24])([F:25])[F:26])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccccc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (1 g) was dissolved in dry dichloromethane (20 ml) and cooled in an ice-bath. A 1M solution of BBr3 in dichloromethane (4 ml) was added drop-wise, and the solution stirred at room temperature for 30 minutes. Water was added, and after vigorous stirring, the mixture was extracted with dichloromethane. Drying (MgSO4), filtration, concentration in vacuo and flash chromatography provided a product which was slurried with petrol, filtered, washed with petrol and dried to afford 1-(2-Hydroxy-5-trifluoromethyl-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (340 mg). Mp.=158-159° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].C1C=CC=CC=1.[CH3:20][OH:21].N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:21][CH3:20])=[O:11]
Reactant: CO
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCC1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A mixture of 30 g of (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 50 ml of benzene was added to a solution of 15 g of methanol, 15 g of pyridine and 200 ml of benzene and the mixture was stirred at 20° C. for 8 hours and was then poured into iced water. The decanted organic phase was washed with water, with a sodium bicarbonate solution, with water, with dilute hydrochloric acid and finally with water. The organic phase was dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with an 8-2 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to recover the fraction with an Rf=0.5. The solvent was distilled off under reduced pressure at 45° C. and the residue was rectified under reduced pressure to obtain 23 g of methyl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 63°-64° C. at 0.1 mm Hg and a specific rotation of [α]D20 =+119° (c=1.5% in chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:8]=4[C:9]([OH:17])=[CH:10][C:11]=3[C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].Cl>O.C(COC)OC>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:8]2[C:9]([OH:17])=[CH:10][C:11]3[C:12]([CH3:15])([CH3:16])[C:13]4[CH:14]=[C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])[CH:3]=[CH:4][C:5]=4[C:6]=3[C:7]=2[CH:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc2c(O)cc3c(c2c1)-c1ccc(Br)cc1C3(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The product of Step 3 of Example 5, (9-bromo-2-methoxy-7,7-dimethyl-7H-benzo[c]fluoren-5-ol (6 g)) and 2-methoxyphenyl boronic acid (2.8 g) were added to a solution of dimethoxyethane (40 mL) and water (20 mL) in a 250 mL round bottom 3-necked flask, followed by addition of Na2CO3 (3.5 g). The resulting solution was bubbled with nitrogen for 10 minutes and then the Palladium catalyst, Pd[PPh3]4, 0.5 g, was added to the reaction mixture. Then the reaction mixture heat to reflux temperatures under a nitrogen atmosphere. The reaction was monitored by TLC analysis. By the end of reaction, the reaction was cooled to room temperature and quenched by adding water (30 mL). The pH of reaction mixture was adjusted to 5-6 by adding hydrochloric acid (37%, 7.5 g) slowly. The product was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to yield the product, 2-methoxy-9-(2-methoxyphenyl)-7,7-dimethyl-7H-benzo[c]fluoren-5-ol (5.7 g) which was used for next reaction as is.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.O.[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>[Re].C(O)CCC>[C:5]1(=[O:7])[O:1][CH2:2][CH2:3][CH2:4]1.[O:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: C1CCOC1
Reactant: C1=CCOC1
Agent: [Re]
Solvent: O
Solvent: CCCCO
Product: O=C1CCCO1
Product: c1ccoc1

Procedure:
In a manner similar to that described in Example 5 14 mL/h of 2,5-dihydrofuran and 24 mL/h of water were passed over the rhenium-on-activated charcoal catalyst at 220° C. At quantitative conversion, γ-butyrolactone was formed with a selectivity of 87% (furan: 2.5%; tetrahydrofuran: 9%; n-butanol: 1%; remainder: various non-analyzed low-boiling fractions).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4](O)=O.B#B.[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].C(Cl)[Cl:27]>C1COCC1.C1COCC1.O>[Cl:27][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][C:9]=1[NH2:11])[CH2:4][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]
Reactant: ClCCl
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with diethyl 3-chloro-4-aminobenzylphosphonate to generate the title compound. The diethyl 3-chloro-4-aminobenzylphosphonate was prepared from commercial 2-chloro-4-nitrobenzoic acid upon sequential treatment with 1) diborane in THF; 2) φ3P,CBr4 in CH2Cl2 ; 3) P(OEt)3 at 125° C.; and 4) reduction with Na2S2 O4 in THF/H2O at 100° C.
Reaction SMILES: C1([Se]Cl)C=CC=CC=1.N1C=CC=CC=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:27])[CH2:17]1>ClCCl>[CH3:15][CH:16]1[CH2:17][C:18](=[O:27])[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH2:21]1
Reactant: CCOC(=O)C1CCC(C)CC1=O
Agent: Cl[Se]c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=CCC(C)CC1=O
Temperature: 0 °C
Yield: 105.2 %

Procedure:
A suspension of phenylselenium chloride (27.29 g) in dichloromethane (250 mL) was stirred at 0° C. and treated dropwise with pyridine (11.81 g). The resulting mixture was stirred for 30 min, and then treated with a solution of racemic ethyl 4-methyl-2-oxocyclohexanecarboxylate (25 g) in dichloromethane (20 mL) in one portion. The color changed from brown to yellow, and the mixture was stirred at 0° C. for 15 min. After this time, the mixture was washed twice with 1 M aqueous HCl. The organic layer was cooled to 0° C. and then treated with 30% aqueous hydrogen peroxide (10.5 mL). After stirring for 10 min, an additional 30% aqueous hydrogen peroxide (10.5 mL) was added, followed by another an additional 30% aqueous hydrogen peroxide (10.5 mL) after 20 min. The resulting solution was stirred for 15 min and then treated with water (100 mL). The aqueous and organic layers were separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated under vacuum to provide racemic ethyl 4-methyl-6-oxocyclohex-1-enecarboxylate (26 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O.Cl.[H][H]>C(O)(=O)C.[Pt](=O)=O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:2]1
Reactant: [H][H]
Reactant: CO
Reactant: O=C(O)Cc1ccccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CC1CCCCN1
Yield: 75.9 %

Procedure:
Pyridylacetic acid hydrochloride (10.00 g, 57.6 mmol) and platinum(IV) oxide (1.00 g, 4.4 mmol) were shaken in a mixture of 75 ml acetic acid, 75 ml methanol, and 10 ml conc. HCl on Parr under 60 psi hydrogen at room temperature overnight. The mixture was then filtered through Celite, and the filtrate evaporated under reduced pressure to yield 8.42 g (75.9%) of the title compound as an off-white solid. MS (NH3 -CI/DDIP): m/e 158 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 1.50-1.96 (m, 6H); 2.80 (m, 2H); 3.20-3.60 (m, 3H); 3.76 (s, 3H). 13C NMR (60 MHz, d6 -DMSO): δ 21.94; 28.05; 37.46; 40.49; 44.12; 57.33; 52.74; 170.39.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:67](O)(=[O:71])[C@@H:68]([CH3:70])[OH:69]>C1COCC1>[OH:69][C@H:68]([CH3:70])[C:67]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:71]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@@H](C)O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added diisopropylethylamine (0.22 mL, 1.26 mmol), HATU (175 mg, 0.46 mmol) and D-(−)-lactic acid (41 mg, 0.46 mmol). The reaction mixture was stirred at RT for 18 hours and then concentrated in vacuo. The resultant residue was partitioned between DCM and an aqueous saturated sodium bicarbonate solution and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give a cream solid that was freeze-dried from methanol and water to give 318 as a white solid (59 mg, 32%). LCMS: RT=4.44 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.18 (1 H, ddd, J=8.24, 4.14, 1.84 Hz), 7.01 (1 H, s), 5.82-5.72 (1 H, m), 5.04 (1 H, s), 4.65-4.55 (1 H, m), 4.35-4.29 (2 H, m), 4.28-4.17 (2 H, m), 4.11 (1 H, dd, J=13.38, 6.69 Hz), 3.86-3.75 (2 H, m), 3.42-3.36 (2 H, m), 1.50 (6 H, d, J=6.59 Hz), 1.16 (3H, d, J=6.70 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCOCC1.C(OCC)(=O)C>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 71.3 %

Procedure:
To a solution of Ethyl-4,6-dichloroquinoline-3-carboxylate (1.0 g, 3.7 mmol) in 1,4-dioxane (10 mL) was added a solution of 4-benzylbenzenamine (733 mg, 4.0 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirred at 85° C. 1 hour, the reaction mixture was then cooled down to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 NNaOH solutions to reach the pH about 9. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (1.1 g, 65% yield) as a yellow solid.
Reaction SMILES: [N:1]([C@H:4]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:5][S:6][CH2:7][C@@H:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:9][C:10](=[O:26])[O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N+]=[N-].[C:52](Cl)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63].CCN(C(C)C)C(C)C>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:52]([NH:1][C@H:4]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:5][S:6][CH2:7][C@@H:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:9][C:10](=[O:26])[O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)N=[N+]=[N-]
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (5R,9R)-tert-butyl 9-azido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate (1.0 eq), Pd(OH)2 (0.5 eq), dodecanoyl chloride (2.4 eq), and DIEA (4.8 eq) in EtOAc (0.01 M) was stirred under H2 (1 atm) at 25° C. overnight. The reaction was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate as a colorless oil.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCCC2C)ncn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 2-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. and 3 hours at 120° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 66 mg of 4-(2-butynyloxy)-6-(2-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (20)).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[O:33][CH3:34])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CC1CCCC1)C(=O)c1ccc2c(ccn2C)c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)N(C)CC4CCCC4)cc23)c(OC)c1
Yield: 13.2 %

Procedure:
Silver(I) oxide (0.30 g) was added to a solution of 5-[N-(cyclopentylmethyl)-N-methylcarbamoyl]-1-methylindole (G) (0.35 g) in dioxane (2 ml). The mixture was protected from light, stirred, and heated to reflux under an atmosphere of nitrogen for 2 hours. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (0.33 g) in dioxane (1 ml) was added and the mixture was heated to reflux for an additional 18 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was evaporated to give an amber gum which was purified by flash chromatography on silica gel (223 ml), eluting with chloroform to give the title compound (75.2 mg, 13%) as a white foam; partial nmr (80 MHz, CDCl3): 3.01(s, 3H, CONCH3), 3.51(br d, 2H, NCH2), 3.74(s, 3H, NCH3), 3.89(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.10(s, 2H, ArCH2), 6.81(s, 1H, H2 -indole).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][OH:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1.N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-hydroxyethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g )in pyridine (10 ml) is added with stirring methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dissolved in dichloromethane. The mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.59 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=O)[O:24]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.[H-].[NH2:33][NH2:34].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([NH:33][NH2:34])=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3F)CC2)cc1
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3F)CC2)cc1
Yield: 79.5 %

Procedure:
To a solution containing 5 (0.3 g, 0.7 mmol) and hydrazine monohydride (0.19 mL, 3.7 mmol) in 1,4-dioxane. The reaction mixture was stirred and heated to reflux for 4 h. After cooling to room temperature water was added and the mixture was stirred for 30 min. The precipitated solid was filtered and the solid was washed with acetonitrile and then dried under vacuum to obtain the hydrazinecarboxamide intermediate 6 (0.2 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:5][NH2:6]
Reactant: CS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The purified intermediate 2-(3-fluoro-4-methylsulfonyl-benzyl)-isoindole-1,3-dione (5.50 g, 15.6 mmol) is dissolved in a mixture of methanol (250 mL) and dichloromethane (250 mL). Hydrazine hydrate (4.6 g, 78.4 mmol) is added, and the mixture is stirred at 60° C. for 3 h. The mixture is filtered, and the filtrate is treated with water. The mixture is extracted with ethyl acetate, and the organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed-phase HPLC (Luna C18 250*50 mm, gradient of acetonitrile in water, 0.1% TFA). Yield: 3.1 g (81% of theory); ESI mass spectrum: [M+H]+=204; Retention time HPLC: 0.17 min (X012_S01).