Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:13]([CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)#[N:14]
Reactant: N#CCCl
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCN1CCCc2ccccc21

Procedure:
162 parts of 1,2,3,4-tetrahydroquinoline, 126 parts of chloroacetonitrile and 66 parts of sodium carbonate are stirred for 6 hours at a temperature of 105°-115° C. After cooling, the thick brown suspension is diluted with methylene chloride and filtered. After washing thoroughly with methylene chloride, the filtrate is concentrated as far as possible in a water jet vacuum and the residue is subsequently distilled. The main fraction boils at 148°-150° C. at a pressure of 1 torr.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)[C:3]([NH2:5])=[NH:4].[SH:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1.[O-]CC.[Na+]>C(O)C>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:13][CH2:14][CH2:15][NH:16][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: Cc1ccc(Cc2cnc(NCCS)[nH]c2=O)cn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
2-Guanidino-4-chloromethylthiazole hydrochloride is reacted with 2-(2-mercaptoethylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone and sodium ethoxide in ethanol to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11]Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CCl)NCc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CN1CCOCC1)NCc1ccccc1
Yield: 98 %

Procedure:
The mixture of the above obtained methyl[(4Z)-4-[1-(benzylamino)-2-chloroethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (XIII), 0.32 g), morpholine (1 eq.) and DIPEA (1 eq.) was stirred at room temperature in toluene (3 mL) under nitrogen for 0.5 h at 90° C. Additional 0.5 eq. of morpholine wad added to push reaction to completion. The solvent was removed in vacuo. The resulting brown residue was proved to be the pure methyl[(4Z)-4-[1-(benzylamino)-2-morpholin-4-ylethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (0.37 g). Yield 98%. MS (ESI+): 483.9; MS (ESI−): 481.8.
Reaction SMILES: [CH3:1]C1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.C=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][S:31][S:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:33]([S:32][S:31][CH2:30][C@H:26]1[C:27](=[O:29])[O:28][CH2:1][N:25]1[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH3:34]
Reactant: CCSSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C=O
Solvent: Cc1ccccc1
Product: CCSSC[C@H]1C(=O)OCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
((1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1.07 g, 4.62 mmol) and paraformaldehyde (847 mg, 2.89 mmol) were added to a solution of dicyclohexylamine (R)-2-((tert-butoxycarbonyl)amino)-3-(ethyldisulfanyl)propanoate (Compound 2d-f) (2.00 g, 4.32 mmol) in toluene (8 ml), and the mixture was stirred at 100° C. overnight. The reaction solution was then returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→87/13) to afford (R)-tert-butyl 4-((ethyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (2e-F) (847 mg, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:29])=[O:28])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32]
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Reactant: CC(C)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)ccc1Cl

Procedure:
Prepared from 25 mg (0.092 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 81 mg (0.32 mmol) of 4-chloro-3-iso-propyl-benzenesulfonyl chloride in 0.2 mL pyridine using procedure x. After the sulfonylation was complete, 3 mL methanol, 0.5 mL water and 44 mg sodium hydroxide were used. Yield: 18 mg of a yellow solid. LC-MSD, m/z for C22H18Cl2N4O3S [M+H]+=489.0, 491.0
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[N:3]=1.[ClH:18]>ClCCl.O1CCOCC1>[ClH:18].[NH:9]1[CH2:10][CH:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH2:8]1
Reactant: Cc1nc(C2CN(C(=O)OC(C)(C)C)C2)no1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(C2CNC2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)azetidine-1-carboxylate (97 mg, 0.41 mmol; which may be prepared as described in Step 4) in dichloromethane was added dropwise HCl 4N in dioxane (2.0 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (101 mg, quantitative) as a white solid. The product was used in the next step without further analysis.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:16])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CO
Reactant: CCc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)OC)cc1
Reaction time: 3 h

Procedure:
A mixture of 4-ethylbenzoic acid (5.12 g), thionyl chloride (3.0 ml) and methanol (150 ml) was heated and refluxed. After 3 hours, the mixture was concentrated under reduced pressure to give methyl 4-ethylbenzoate (5.59 g). This product was used in the subsequent step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: N[n+]1ccccc1
Reactant: CC(C)C(=O)C#Cc1ccc(Cl)cc1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C(=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Yield: 43.4 %

Procedure:
Starting with 4.9 g (35.8 mmol) of 4-chloroethynylbenzene, 3.76 ml of isobutyryl chloride and 4.88 g ZnCl2, the corresponding 1-(4-chlorophenyl)-4-methylpent-1-yn-3-one was prepared using the same procedure as in Example 5(a) to obtain 9.21 g of crude oil intermediate. Starting with 9.21 g (35.8 mmol) of 1-(4-chlorophenyl)-4-methylpent-1-yn-3-one, 9.90 g (44 mmol) of 1-aminopyridinium iodide and 11 g DBU, the desired product was obtained—4.64 g (43%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one as in Example 5(b). Compound 1024.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13]O>>[S:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CO
Reactant: O=C(O)c1ccc2sccc2n1
Product: COC(=O)c1ccc2sccc2n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a cold solution of HCI (10%) in MeOH (10 mL) was added thieno[3,2-b]pyridine-5-carboxylic acid (1.0 g, 5.6 mmol, and the mixture heated to reflux for 2 hr. After cooling to r.t., half the solvent was removed by evaporation and the remainder was partitioned between EtOAc and H2O. Solid NaHCO3 was added until the system remained basic. Separation, drying and evaporation of the organic layer afforded 0.75 g (70%) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C@H:13]([C:15](O)=[O:16])[CH3:14])[CH2:4][CH2:3]1.[N+](=C)=[N-]>C(OCC)C>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C@H:13]([CH:15]=[O:16])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C=O
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Dihydroartemisinic aldehyde was synthesized from the isolated dihydroartemisinic acid. The acid was converted to methyl dihydroartemisinate with excess diazomethane in diethyl ether at 0° C. for 5 minutes. The ether and diazomethane were removed under a stream of nitrogen and the methyl ester was reduced to (11R)-dihydroartemisinic alcohol with excess 1.5 M diisobutyl aluminum hydride in toluene at room temperature for 10 min under nitrogen. With subsequent extraction, oxidation to the aldehyde with pyridinium chlorochromate (Corey & Suggs 1975) and purification by HPLC the (11R)-dihydroartemisinic aldehyde was produced at an overall yield of 48% with >99% purity according to GC analysis.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:36]([NH2:38])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)=[O:22])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:36]([NH2:38])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:33])[CH3:34])[CH:27]=1)=[O:22])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(N)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)[C@@H](N)Cc2ccccc2)C(N)=O)c1

Procedure:
To a solution of 188 mg (0.287 mmol) of Z-Phe-Cha-Phe(3-tBu)-NH2 in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent, chloroform:methanol=10:1) to yield Phe-Cha-Phe(3-tBu)-NH2 in the amount of 69.0 mg (46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH3:13].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[C:16]([F:21])[CH:17]=2)=[O:8])[CH:10]=1
Reactant: CCOc1ccccc1F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
5-bromo-2-chloro-benzoyl chloride 2a (12.4 g, 48.8 mmol) and 1-ethoxy-2-fluoro-benzene 4b (6.84 g, 48.8 mmol) were dissolved in 100 mL dichloromethane and cooled to 0° C., followed by addition of aluminum trichloride (5.86 g, 44 mmol) in batch. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was partitioned after 20 mL 2 M hydrochloric acid was dropwise added in an ice bath. The aqueous phase was extracted with 30 mL dichloromethane and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (12.7 g, yellow solid), yield: 72.6%.
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])=O)=[N:10]1>O>[CH3:6][O:7][N:8]=[C:14]([C:11]1[CH:12]=[CH:13][O:9][N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31]
Reactant: CON
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccon2)c1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CON=C(c1ccon1)c1ccccc1COc1cc(C)ccc1C

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.50 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone (0.64 g, 2 mmol), and the mixture was stirred under reflux for 17 hours. After completion of the reaction, water (100 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (benzene/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone O-methyloxime (a mixture of isomers A/B) (0.55 g, 81.8%) as colorless crystals. mp. 104-108° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(-c2ccccc2)cc1
Yield: 55.7 %

Procedure:
A solution of benzoic acid N′-[3-(4-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (100 mg, 0.26 mmol) in DME (5 ml)/2M Na2CO3 (450 μL, 0.90 mmol) was treated with phenylboronic acid (47 mg, 0.39 mmol) and Pd[PPh3]4 (30 mg, 0.026 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (56 mg, 56%). LC-MS m/e 387.17 (M+H+)
Reaction SMILES: O[CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@H:4]([CH2:13][O:14][CH2:15]OC)[CH:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CS(Cl)(=O)=O.C(N(CC)CC)C.Cl.C1CCN2C(=NCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][O:14][CH2:13][C@@H:4]1[C:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:2][CH2:6][N:5]1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)[C@H]1COCOC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)[C@H]1COC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 72.6 %

Procedure:
To a solution of 1-allyl 3-tert-butyl (2S)-4-hydroxy-2-[(methoxymethoxy)methyl]-1,3-pyrrolidinedicarboxylate (1.47 g, 4.26 mmol) in dichloromethane (20 ml) were added at −30° C. methanesulfonyl chloride (0.50 ml, 6.5 mmol), triethylamine (1.2 ml, 8.6 mmol) and 4-dimethylaminopyridine (52 mg, 0.43 mmol) and the mixture was stirred at 0° C. for 75 minutes. The reaction mixture was poured into diluted hydrochloric acid and the mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was dissolved in dicholomethane (10 ml) and the solution was cooled to 0° C. and thereto was added DBU (0.95 ml, 6.4 mmol). The mixture was raised to room temperature and stirred just for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and the solution was extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified with silica gel (30 g) chromatography (hexane/ethyl acetate=4/1→2/1) to give 1-allyl 3-tert-butyl (2S)-2-[(methoxy)methyl]-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (0.92 g, 66%).
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:16].C(O)(=O)C.[Br:21]Br.[OH-].[Na+]>ClCCl.O>[Br:16][C:15]1[C:9]2[C:10](=[N:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[C:12]([Br:21])=[CH:13][CH:14]=1
Reactant: BrBr
Reactant: c1ccc(-n2nc3ccccc3n2)cc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(Br)c2nn(-c3ccccc3)nc12
Temperature: 150 °C
Yield: 78 %

Procedure:
2-phenyl-2H-benzotriazole (1.10 g, 5.1 mmol) was placed in a 1-neck 250-mL round bottomed flask. HBr/acetic acid (45% w/v, 20 mL) and bromine (0.79 mL, 15.3 mmol) were added. The flask was connected to a condenser and a scrubber. The mixture was heated in an oil bath at 150° C. for 0.5 hr. The solution was cooled to room temperature. Bromine (0.79 mL, 15.3 mmol) was again added to the reaction mixture and it was again heated to 150° C. for 1 hr. This step was repeated three more times. Water (200 mL) and dichloromethane (200 mL) were added to the reaction mixture followed by aqueous sodium hydroxide (1.5 M) solution to neutralize the acid. The organic layer was separated and dried with MgSO4. The solution was filtered and the solvent concentrated using a rotary evaporator. The solid was further dried under high vacuum at 60° C. for 2 hr. Yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])=[O:16]>O1CCCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:11][N:10]=[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:25]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1ccccc1NC(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1-c1cc(-c2c(Cl)cccc2Cl)no1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.25 g, 5.6 mmol) and 2,2-dichloro-N-(2-ethynylphenyl)acetamide (1.93 g, 8.5 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(2-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a light brown solid, 1.24 g.
Reaction SMILES: C([C@@:3]1([CH:10]=[CH2:11])[CH2:5][C@@:4]1([C:7]([O-:9])=[O:8])[NH2:6])C.[C:12]([O:16][C:17]([N:19]1[CH:28]([C:29]([OH:31])=O)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH:25]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=N[C:50]2C=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:49]([O:9][C:7]([C@@:4]1([NH:6][C:29]([CH:28]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[CH:25]=3)[CH2:20][N:19]2[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[O:31])[CH2:5][C@H:3]1[CH:10]=[CH2:11])=[O:8])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Oc3cccc(Cl)c3)cc2CC1C(=O)O
Reactant: C=C[C@]1(CC)C[C@]1(N)C(=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C

Procedure:
To a flask charged with ethyl-(1R,2S)-1-amino-2-vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), 2-(tert-butoxycarbonyl)-6-(3-chlorophenoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.31 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were added 30 mL DMF to make a solution. It was cooled to 0° C. in an ice-water bath, followed by slow addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while stirring. The reaction was allowed to warm up to rt and stirred overnight.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1.CO>C(OCC)(=O)C>[O:10]=[C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Temperature: 80 °C
Yield: 80.8 %

Procedure:
A mixture of 1-(2-hydroxyphenyl)ethanone (50 g, 0.37 mol), benzyl 4-oxopiperidine-1-carboxylate (94 g, 0.40 mol), pyrrolidine (61 mL, 0.73 mol) and methanol (24 mL) was heated at 80° C. for 20 hours. After cooling to 25° C., the reaction mixture was diluted with ethyl acetate (1000 mL) and partitioned with 1M aqueous HCl (500 mL). The organic phase was washed with 1M aqueous HCl (2×500 mL), water (500 mL), saturated sodium chloride solution (500 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate in hexane) afforded benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (105 g, 81% yield) as a yellow oil. ESI-MS m/z calc. 351.2. found 352.2 (M+1)+; Retention time: 2.30 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=7.8 Hz, 1H), 7.54-7.47 (m, 1H), 7.44-7.29 (m, 5H), 7.02 (dd, J=14.8, 7.8 Hz, 2H), 5.16 (s, 2H), 4.10-3.90 (m, 2H), 3.36-3.24 (m, 2H), 2.73 (s, 2H), 2.12-2.00 (m, 2H), 1.71-1.58 (m, 2H).