Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH2:12])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N:15]#[C:16]Br>CO>[NH2:15][C:16]1[S:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][N:12]=1
Reactant: N#CBr
Reactant: NNC(=S)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(OCc2ccccc2)s1
Temperature: 0 °C
Yield: 58.5 %

Procedure:
In a 250 ml round-bottom flask equipped with a mechanical stirrer were mixed (benzyloxythiocarbonyl)hydrazine and 2N sodium hydroxide (90 ml). This mixture was stirred vigorously and cooled to 0° C. A solution of cyanogen bromide (14.5 g, 0.137 mol) in methanol (60 ml) was added dropwise at a rate that kept the reaction temperature between about 0°-5° C. A precipitate formed. When the addition was complete, the reaction mixture was filtered and the residue was rinsed well with water and dried in vacuo. The product was recrystallized from methanol/water to give a white solid of 16.6 g, 58.5% yield with a m.p. of 173°-175° C.
Reaction SMILES: [Br-].[Br-].[Br-].[Al+3].[F:5][CH:6]([F:33])[C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(OC)C=CC=CC=1>[N+](C)([O-])=O.ClCCl>[F:33][CH:6]([F:5])[C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([OH:16])=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C(=O)OCc1ccccc1)N1COC(C(F)F)=C(c2ccccc2)C1=O
Agent: [Al+3]
Agent: [Br-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)(C(=O)O)N1COC(C(F)F)=C(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A solution of aluminium tribromide (3.85 g) in nitromethane was added in portions to a stirred solution of benzyl 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.93 g) and anisole (3.1 g) in dichloromethane at 0° C. under an inert atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 2 hours and diluted with dichloromethane. The dichloromethane solution was washed in turn with 2 M hydrochloric acid and with water. The organic solution was extracted with 1 M sodium bicarbonate, the aqueous extract was then washed with diethyl ether and acidified to pH 1 with 2 M hydrochloric acid. The acidic solution was extracted with ethyl acetate, the extract was dried (magnesium sulphate) and evaporated under reduced pressure to give 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1, 3-oxazin-3-yl)-2-methylpropanoic acid (0.70 g) as a pink solid, m.p. 149-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.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]>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:22]=[N:23][CH:24]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1=NC2(CCOc3ccc(-c4cncc(Cl)c4)cc32)N=C1N
Temperature: 130 °C
Yield: 64.3 %

Procedure:
6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (60 mg, 0.20 mmol, Intermediate 4), 5-chloropyridin-3-ylboronic acid (62 mg, 0.40 mmol) and 2M K2CO3 (aq, 0.20 mL, 0.41 mmol) were mixed in dioxane (5 mL) and degassed by passing nitrogen through for 5 min. Then (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (8 mg, 10 μmol) was added and the mixture was heated in a microwave oven at 130° C. for 1 h. Purification by preparative chromatography HPLC gave the title compound (42 mg, 63% yield): 1H NMR (400 MHz, CDCl3) δ ppm 2.17 (m, 2 H), 2.37 (s, 3 H), 4.59 (m, 2 H), 5.04 (br s, 2 H), 6.73 (d, 1 H), 7.01 (d, 1 H), 7.34 (dd, 1 H), 7.70 (m, 1 H), 8.45 (m, 1 H), 8.55 (m, 1 H); MS (ES+) m/z 327 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Br:28])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:29].[CH3:30][S:31]([CH2:34][C:35](O)=[O:36])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl>[Br:28][C:20]1[CH:19]=[C:18]([C:12]2([C:14]([F:15])([F:16])[F:17])[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[C:4]([Cl:29])[CH:5]=3)[CH2:13]2)[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1
Reactant: NCc1ccc(C2=NOC(c3cc(Br)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)CC(=O)NCc1ccc(C2=NOC(c3cc(Br)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl

Procedure:
To a solution of 0.15 g of 3-(4-aminomethyl-3-chlorophenyl)-5-[3-bromo-5-(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole and 0.083 g of (methylsulfonyl)acetic acid in 3 mL of dichloromethane, 0.11 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the resultant mixture was stirred at room temperature for 15 hours. After the completion of the reaction, the reaction mixture was diluted with 3 mL of chloroform, and then 3 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the diluted reaction mixture, followed by separating off the organic phase. The separated organic phase was dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order. From the resultant organic phase, the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate to obtain 0.14 g of the objective substance as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH2:27][C:28]([O:30]C)=[O:29])[O:5][CH2:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]2([CH3:23])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][C@@H:8]2[CH2:10][C@@H:9]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]3([CH3:23])[CH2:21][CH2:22]3)=[O:18])[CH2:15][CH2:16]2)[CH:24]=[CH:25][C:26]=1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methylcyclopropyl 4-[(1R,2S)-2-{2-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenoxy]ethyl}cyclopropyl]piperidine-1-carboxylate (0.450 g, 1.04 mmol) in 14 ml anhydrous tetrahydrofuran was added by 7 ml methanol and 7 ml water. Lithium hydroxide (0.393 g, 16.39 mmol) was added into the reaction mixture, and the reaction was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under vacuum, and the remaining aqueous layer was extracted with dichloromethane (3×50 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 420.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[C:35]([CH2:34][CH2:33][N:28]5[CH2:29][CH2:30][CH2:31][CH2:32]5)[CH:36]=4)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Reactant: Nc1cccc(CCN2CCCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccc(CCN5CCCC5)c4)c3)C(C)(C)C2=O)cc1
Temperature: 90 °C
Yield: 4 %

Procedure:
To a solution of 1.15 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 50 mL of dioxane are successively added, under argon, 567 mg of 3-(2-pyrrolidin-1-ylethyl)aniline obtained in stage c) below, 3.4 g of caesium carbonate, 207 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 67 mg of palladium diacetate. The reaction mixture is heated at 90° C. for 3 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 65 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-{[3-(2-pyrrolidin-1-ylethyl)phenyl]amino}pyridin-4-yl)methyl]imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.O=S(Cl)[Cl:12]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccs1
Solvent: ClCCl
Product: O=C(Cl)Cc1cccs1
Temperature: 50 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 mmol) in DCM (50 mL) was added dropwise SOCl2 (0.5 mL), the mixture was heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure to give compound 2-(thiophen-2-yl)acetyl chloride, which was used directly in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9].C(N(CC)CC)C.O=C1CCC(=O)N1[C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:42]([O-])=[O:43])=[C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])[CH:31]=2)[N:26]([CH2:45][CH:46]([CH3:48])[CH3:47])[N:25]=1>ClCCl.C(OCC)(=O)C>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[C:42]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])=[O:43])[N:26]([CH2:45][CH:46]([CH3:48])[CH3:47])[N:25]=[CH:24]2
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: CN1CC[C@H](N)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 120.2 %

Procedure:
(S)-3-Amino-1-methylpyrrolidin-2-one hydrochloride (211 mg, 1.40 mmol) was dissolved in triethylamine (0.195 mL, 1.40 mmol) and dichloromethane (7 mL). To this, 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 651 mg, 0.677 mmol) was added, and the reaction was allowed to stir at ambient temperature for 16 hours. The crude reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 25% acetone/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Id) (360 mg, 58%). Mass spec: 443 (M+1). 1H NMR (CDCl3) δ 8.36 (s, 1H), 8.29 (br, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.92 (m, 1H), 4.56 (ddd, 1H), 4.22 (d, 2H), 3.42 (m, 2H), 2.93 (s, 3H), 2.82 (m, 1H), 2.37 (m, 1H), 1.99 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:15](=[O:17])[CH3:16])[O:8][C:7]=2[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(CNC(C)=O)=CO2
Temperature: 0 °C

Procedure:
The crude amine obtained in Step C is dissolved in 10 ml of anhydrous pyridine; the mixture is then cooled to 0° C. 0.41 g (4 mmol) of acetic anhydride is added to that solution; stirring is then maintained for 30 minutes. The solvent is then evaporated in vacuo; the residue is then taken up in dichloromethane. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the title amide is obtained pure in the form of a white solid after passage over a silica column (eluant:MeOH/CH2Cl2: 10/90).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1.CS(C)=O.C(CN)O>O>[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:20][CH2:19]1
Reactant: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCC(F)(F)CC1
Solvent: NCCO
Solvent: CS(C)=O
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
N-(4-Fluoro-3-nitrophenyl)ethanesulfonamide (26 g, 0.107 mol), [(4,4-difluorocyclohexyl)methyl]amine (approx. 15 g), DIPFA (20 mL) and DMSO (100 mL) were mixed together and heated to 65° C. overnight. Ethanolamine (5 g) was added and the reaction mixture was stirred until complete disappearance of N-(4-fluoro-3-nitrophenyl)ethanesulfonamide (approx. 4-5 hrs.). The room temperature cooled down reaction mixture was poured in cold water (900 mL). The product was extracted with DCM (5×200 mL). The combined organic phases were washed with HCl 2N (3×200 mL) and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (this material can be re-crystallized using a mixture of EtOAc and hexane) to provide the title product (24.2 g) as orange solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].NCCCCN.C([Li])CCC.[I:25]I.[NH4+].[Cl-]>C(OCC)C>[I:25][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: II
Agent: NCCCCN
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -13 °C
Yield: 23.3 %

Procedure:
Equip a 250 mL 3-neck round bottom flask with: a magnetic stirrer, a thermocouple, a dry ice/acetone bath, a nitrogen atmosphere, and an addition funnel. Charge 2,2-dimethyl-N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethyl ether (67 mL), tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to −78° C. Add slowly via glass syringe n-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Allow the reaction to warm to −13° C. over 2 hours. Cool the reaction to −78° C. Add an iodine solution (8.5 g, 33.6 mmol in 20 mL THF) to the reaction via the addition funnel and mix 2.5 hours at −68° C. Quench the reaction by the addition of saturated aqueous NH4Cl solution (40 mL). Extract with ethyl acetate (100 mL) and discard the aqueous phase. Wash the organic layer with a saturated aqueous sodium thiosulfate solution (100 mL) and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and filter. Concentrate in vacuo to give brown oil. Chromatograph on silica (80 g) eluting with a gradient of 100% dichloromethane to 70% ethyl acetate/30% dichloromethane to afford the title compound (1.19 g, 23%). MS (ES) m/z 305 [M+1]+
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].O.[NH:11]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][C:18]3[C:23]([CH:12]12)=[CH:22][CH:21]=[CH:20][CH:19]=3>[N+](C)([O-])=O>[N+:6]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH:13]3[CH2:14][C:15](=[O:16])[NH:11][CH:12]32)=[CH:19][CH:20]=1)([O-:9])=[O:7]
Reactant: O=C1CC2Cc3ccccc3C2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C1CC2Cc3ccc([N+](=O)[O-])cc3C2N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Sulphuric acid (72 mL) was added to a cooled mixture of nitric acid (63.5 mmol, 4.4 mL) and water (11.3 mL), and the mixture was added dropwise to a cold (2-8° C.) suspension of 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (10 g, 57.7 mmol) in nitromethane (100 mL). The mixture was stirred 1.5 h at 2-8° C. after end of addition, and poured onto a mixture of ice and water (1 L). The white suspension was stirred for one hour, filtered and washed with water. The white solid was suspended in 1 L of ethyl acetate, dried and concentrated under vacuum. 7-nitro-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (9.2 g, 73%) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.16-8.08 (2H, m), 7.39 (1H, d), 6.89 (1H, brs), 5.09 (1H, d), 3.49-3.37 (2H, m), 2.93 (1H, d), 2.78 (1H, dd), 2.26 (1H, dd) ppm.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:17][O:16][CH3:15])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCCl
Reactant: Oc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCOc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution was prepared by combining 10 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 5 g of 2-chloroethyl methyl ether, 7.4 g of potassium carbonate, and 20 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 20 g of water was added to quench the reaction. To the solution, 40 g of toluene was added for extraction. The organic layer was separated and washed with sodium hydroxide aqueous solution and water in sequence. The organic layer was concentrated in vacuum, obtaining 13 g of the target compound, 4-(2-methoxyethoxy)phenyl phenyl sulfide as oily matter. Yield 93%.
Reaction SMILES: Cl[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:15]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=1.[CH:60]1(B(O)O)[CH2:62][CH2:61]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:60]1([C:2]2[C:10]3[O:9][CH2:8][CH2:7][C:6]=3[C:5]([CH:11]3[C@H:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:15]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:14]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[O:12]3)=[CH:4][C:3]=2[CH2:50][C:51]2[CH:52]=[CH:53][C:54]([O:57][CH2:58][CH3:59])=[CH:55][CH:56]=2)[CH2:62][CH2:61]1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2C2CC2)OCC3)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (235 mg, 0.290 mmole) in toluene (10 mL) were added cyclopropylboronic acid (49.8 mg, 0.580 mmole), Pd(OAc)2 (19.5 mg, 0.0290 mmole), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23.8 mg, 0.0580 mmole), and K3PO4 (246 mg, 1.16 mmole). The resulting solution was stirred at 110° C. overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (102 mg, 43%) as a yellow gum.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:33][O:34][C:35](=[O:42])[CH2:36][NH:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][S:38]([NH:37][CH2:36][C:35]([O:34][CH3:33])=[O:42])(=[O:40])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)CNS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CNS(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 1.08 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0° C. under a nitrogen atmosphere and treated with 0.8 ml of pyridine and a solution of 1.5 g of N-(chlorosulphonyl)-glycine methyl ester in 5 ml of dichloromethane. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was then diluted with ethyl acetate and washed with 2M aqueous hydrogen chloride and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (3:2) for the elution to give 0.831 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetate in the form of a solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
92.8 g of 4-hydroxybenzaldehyde are dissolved in 820 ml of dimethylformamide. After the addition of 228 g of 4-(2-chloroethyl)morpholine and 415 g of finely powdered potassium carbonate the reaction mixture is heated to 100° overnight under argon and while stirring vigorously. The cooled solution is poured into 3 1 of ice-water, extracted with ethyl acetate, washed with water, dried and evaporated. The residual dark oil is distilled in a high vacuum and gives 132 g of 4-(2-morpholinoethoxy)benzaldehyde as a yellowish oil, boiling point 145°-150° /33 pa.