Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH2:1]([CH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)O)ccc12
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC1CNc2cc(C(=O)O)ccc21
Yield: 48.8 %

Procedure:
3-(n-Dodecyl)indole-6-carboxylic acid (16.1 g) in suspension in glacial acetic acid (200 ml), containing perchloric acid (12.2 ml; of strength (70% w/v) was hydrogenated over palladium on charcoal (1.8 g of 5% w/w) at atmospheric pressure and at a temperature of 80°-90° C. The mixture was then hot filtered through diatomaceous earth and was poured into water (1500 ml) to give an off-white solid. The solid was collected, washed with water (2×100 ml) and was dissolved in ethyl acetate (1000 ml). The ethyl acetate solution was washed with an aqueous solution of sodium carbonate (of strength 2N, 150 ml) and the organic layer was separated and was dried over magnesium sulphate. The organic solvent was removed in vacuo to give (RS)-3-(n-dodecyl)indoline-6-carboxylic acid (7.9 g), in the form of a white solid (m.p. 100°-102° C.).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.[NH:13]([C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([O:25][CH3:26])[N:18]=[C:17]([CH3:27])[N:16]=1)[NH2:14]>C(O)(=O)C>[CH3:26][O:25][C:19]1[N:18]=[C:17]([CH3:27])[N:16]=[C:15]([N:13]=[N:14][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:12])[C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: COc1nc(C)nc(NN)c1C(F)(F)F
Solvent: CC(=O)O
Product: COc1nc(C)nc(N=Nc2ccc3ccccc3c2O)c1C(F)(F)F
Temperature: 110 °C

Procedure:
Then, a flask was loaded with acetic acid (50 ml) and 1,2-naphthoquinone (2.9 g), and the temperature was raised up to 110° C. with stirring to dissolve 1,2-naphthoquinone. To this mixture, 4-hydrazino-6-methoxy-2-methyl-5-(trifluoromethyl)pyrimidine (4 g) was added in 30 minutes. After stirring at 110° C. for 3 hours, the heating was stopped and left to cool. The reaction mixture was filtrated. The filtrated crystals were recrystallized with dioxane to give crystals, which were then filtrated and dried to give intended crystals (2.3 g).
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([O:28]C(C)(C)C)=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O>>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate (48 mg, 0.094 mmol) dicloromethane (1 mL) and TFA (726 μL) were added and stirred at room temperature for four hours. The dicloromethane and TFA were evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by reverse phase preparative HPLC to yield 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoic acid. ESI-MS m/z calc. 453.11. Found 454.3 (M+1)+. Retention time 1.63 minutes.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:14][N:13]([O:15]CC3C=CC=CC=3)[C:12]2=[O:23])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[OH:15][N:13]1[CH2:14][C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:23]
Reactant: O=C(Cc1ccccc1)N[C@H]1CN(OCc2ccccc2)C1=O
Agent: [Pd]
Product: O=C(Cc1ccccc1)N[C@H]1CN(O)C1=O
Reaction time: 1 h

Procedure:
To an ethanolic (100 ml) solution of (S)-3-[(phenylacetyl)amino]-1-[(phenylmethyl)oxy]-2-azetidinone (0.8 g, contaminated with triphenylphosphine) is added 10% palladium on charcoal catalyst (0.4 g) and the mixture is hydrogenated under ca. 1 atom pressure for one hour. The reaction mixture is filtered through prewashed Celite and concentrated under reduced pressure to an oily residue. The product is partitioned between 50% sodium bicarbonate solution and ethyl acetate. The aqueous layer is acidified with potassium bisulfate and extracted with ethyl acetate (three 50 ml portions). The combined extracts are dried over sodium sulfate and concentrated to a crystalline solid (ca. 200 mg). Recrystallization from methanol/chloroform affords an analytical sample, melting point 145°-146° C. dec.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH3:31])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[C:35]2[NH:39][N:40]=[CH:41][C:34]=12.C(N(CC)CC)C>ClCCl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[NH:19][CH:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:33]4[N:38]=[CH:37][N:36]=[C:35]5[NH:39][N:40]=[CH:41][C:34]=45)[CH2:14][CH2:13]3)[N:16]([CH3:31])[CH:17]=2)=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C=C(c2ccc(F)c(C(F)(F)F)c2)NC1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Add hydrogen chloride (4.00 equiv; 81.41 mmoles; 20.35 mL) to a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g; 1.00 equiv; 20.35 mmoles) in dichloromethane (101.77 mL), at RT. Stir the solution at RT for 1 hour. Remove the solvent under reduced pressure, and dissolve the crude in isopropyl alcohol (101.77 mL). Add 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.65 equiv; 33.58 mmoles; 5.19 g) and triethylamine (10 equiv; 203.54 mmoles; 28.37 mL). Stir the mixture at reflux for 1 hour. Remove the solvent under reduced pressure and triturate the crude in water overnight. Filter the solid and triturate in hot acetonitrile, filter and dry in vacuo. 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (8.42 g; 18.86 mmoles; 92.66% yield) is obtained as a light yellow solid.
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[N:7]1)C)C.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:31]([C:33]3[C:34]([O:48][CH3:49])=[C:35]([CH:41]4[CH2:44][N:43]([CH2:45][C:46]#[N:47])[CH2:42]4)[C:36]([CH3:40])=[C:37]([Cl:39])[CH:38]=3)[CH3:32])[N:28]=[C:29](Br)[C:22]=12.C(=O)([O-])[O-].[Na+].[Na+].O.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O.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>[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:31]([C:33]3[C:34]([O:48][CH3:49])=[C:35]([CH:41]4[CH2:44][N:43]([CH2:45][C:46]#[N:47])[CH2:42]4)[C:36]([CH3:40])=[C:37]([Cl:39])[CH:38]=3)[CH3:32])[N:28]=[C:29]([C:9]3[CH:10]=[N:6][NH:7][CH:8]=3)[C:22]=12
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC#N)C1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(-c3cn[nH]c3)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC#N)C1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
Into a microwave vial was weighed 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16 mg, 0.058 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.4 mg, 0.0029 mmol). A solution of (3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile (14 mg, 0.029 mmol, racemic intermediate from Example 125, Step 3) in N,N-dimethylformamide (0.25 mL) was added followed by 2.0 M sodium carbonate in water (73 μL, 0.14 mmol). The resulting mixture was stirred at 120° C. for 5 h. The mixture was filtered and concentrated. To a mixture of the crude coupling product in tetrahydrofuran (0.3 mL) was added 3.0 M hydrochloric acid solution in water (100 μL, 0.3 mmol) and stirred for 2 h at room temperature. The mixture was neutralized with sat. NaHCO3 and extracted with dichloromethane. The organic was dried (MgSO4), filtered, and concentrated. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 1.0 mg (7.2% for 2 steps) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN9O (M+H)+: m/z=478.2; Found: 478.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:28])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Li+]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:28])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(Cl)cc2)cc1

Procedure:
This ester was reacted with excess methanolic lithium hydroxide at room temperature, followed by evaporation of the methanol. The residue was dissolved in water and acidified with 2N hydrochloric acid to give 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)acetic acid as colorless crystals, mp 170-172° C., Electrospray Mass Spec 406.4 (M−H)−
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: OCC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(OCC3CCC(O)CC3)c2c1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (79 mg (1.5 eq.) was added at 0° C. to a solution of 4-hydroxymethyl-cyclohexanol (3 g, 12 mmol, synthesised analogously to J. Org. Chem. 1994 59 p. 2748–2761) in DMF (30 ml). After 20 minutes, a solution of 4-chloro-6-methoxy-quinazoline (1.94 g, 10 mmol) in DMF (10 ml) was added and the reaction mixture was heated to 40° C. After a further 2 hours, the reaction mixture was concentrated to dryness. The residue was diluted with water (100 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexane 1/2).
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C@@H:11]([NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1>[Pd]>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][C@@H:11]([CH2:12][N:13]([CH3:15])[CH3:14])[CH2:10][C:9]([OH:36])=[O:8])=[O:35]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: [Pd]
Product: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A solution of (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (125 mg, 0.25 mmol) was hydrogenated under atmospheric pressure in the presence of palladium (10% on activated charcoal, 30 mg). After 30 min, the catalyst was filtered off and the filtrate concentrated and dried to afford (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid (96 mg, 89%). Light yellow oil, m/e=413.2 ([M−H]−).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:17])[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])([CH3:3])[CH3:2].[Br:18]Br>O1CCOCC1.O.CCOC(C)=O>[Br:18][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:17])[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: Cc1c(C(C)C)c(=O)n(-c2ccccc2)n1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-isopropyl-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.8 g) in a round bottom flask under argon in dioxane (15 mL) was added bromine (0.55 g). The reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-bromomethyl-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 309.3 ([M+H]+).
Reaction SMILES: [CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=O)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:20])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 55.7 %

Procedure:
From 4.0 g (0.0133 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 24), 100 ml of phosphorus oxychloride and 100 ml of chloroform and refluxing on a steam bath for four hours, following the procedure of Example 27, there is obtained 2.1 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 216°-217° C. after recrystallization from pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])(O)=O.[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1COCC1.O>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)CCl
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a stirred solution of methyl 2-aminobenzoate (906 mg, 6.0 mmol) and NaHCO3 (554.4 mg, 6.6 mmol) in THF (12 mL) and water (12 mL) at 0° C. was added 2-chloroacetyl chloride (806 mg, 7.2 mmol) dropwise. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by flash chromatography to give methyl 2-(2-chloroacetamido)benzoate (1.31 g, 96%). LC-MS (ES-API); rt 8.65 min; m/z calculated for C10H10ClNO3 [M+Na]+ 250.0, found 250.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:8]=1[Br:9].C(O)(=O)C.O[CH2:29][NH:30][C:31](=[O:33])[CH3:32]>O1CCCC1>[Br:3][C:4]1[N:5]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:8]=1[Br:9]
Reactant: CC(=O)NCO
Reactant: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(Br)c1Br)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)NCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
A mixture of sodium hydride (0.5 g, 60%, 0.0125 mol) and tetrahydrofuran is treated with 2,3-dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (4.67 g, 0.01 mol), stirred for 15 minutes and treated with a solution of N-(hydroxymethyl)acetamide acetate (ester) (1.64 g, 0.0125 mol) in tetrahydrofuran. The reaction mixture is heated at reflux for 18 hours, concentrated in vacuo and poured into a water/ether mixture. The organic phase is separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a white solid (4.56 g).
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([N:16]2[C:36](=[O:37])[C:29]3[C@@H:30]4[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]4)[C:28]=3[N:15]2[CH3:13])[CH:23]=[CH:22][CH:21]=1
Reactant: CN(NC(=O)OC(C)(C)C)c1cccc(Cl)c1F
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cccc(Cl)c1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 6.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(3-chloro-2-fluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (434 mg, 1.6 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.7 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified on an ISCO system, eluting with 30-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated with methanol. The residue was triturated with ether/hexane and the solvent was removed with a pipet. The solid was drie under high vacuum at 90° C. to give (4S,7R)-2-(3-chloro-2-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (37 mg, 7%) as a white solid. ES(+)-MS (M+H) 335.
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:13]([C:15]([OH:17])=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CO.Cl[Ni]Cl>[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]([OH:17])=[O:16])[CH3:14])[CH2:4][CH2:3]1
Reactant: C=C(C(=O)O)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C(=O)O

Procedure:
One embodiment of the invention provides a process for the conversion of artemisinic acid into artemisinin employing steps such as reduction and photo oxidation and the reduction is carried out by the following steps comprising (i) dissolving artemisinic acid and NiCl2.6h2O in dry methanol; (ii) adding sodium borohydride to the resultant solution at 0° C. over a 2 hr. period; (iii) neutralising the solution obtained in step (ii) with 5% aqueous HCl solution and (iv) isolating and crystallizing the dihydro artemisinic acid in ethyl acetate to obtain pure dihydro artemisinic acid. However, the step of photo oxidation is carried out by comprising (i) dissolving the dihydroartemisinic acid in the solvent dichloromethane-ethyl acetate; (ii) oxidising the solution obtained in the step (i) in the presence of fluorescent light (40W) daily for two hours upto 8 days; (iii) concentrating the solution obtained in step (ii) and recrystallizing the residue in hexane to isolate artemisinin.
Reaction SMILES: OO.[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:5])[CH3:4].S([O-])([O-])=[O:16].[Na+].[Na+]>C(O)(=O)C>[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:16])(=[O:5])[CH3:4]
Reactant: CC(=O)NCCc1ccccn1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NCCc1cccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
30 wt % Hydrogen peroxide (80.3 ml) was added dropwise to a solution of 2-(2-acetylaminoethyl)pyridine (64.5 g) in acetic acid (65 ml) at 70°-75° C. and the mixture was stirred at the same temperature for 8 hours. After the mixture was ice-cooled and the mixture was added to a mixture of sodium sulfite (56.9 g) in ice water (200 ml). The solvent was removed by concentration in vacuo and the residue was extracted with a tetrahydrofuran. The extract solution was dried over magnesium sulfate and evaporated to give 2-(2-acetylaminoethyl)pyridine N-oxide (70.82 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:1][C:2]1[C:6]([S:7]([NH:12][C@H:13]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1noc(C)c1S(=O)(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3,5-dimethyl-4-isoxazolesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.3–7.1 (m, 5H) 7.05 (t, 2H, J=6.5 Hz), 6.81 (d, 1H, J=7.1 Hz), 4.65 (dd, 1H, J=6.3, 2.2 Hz), 3.11 (t, 2H, J=7.2 Hz), 2.4 (m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0–1.8 (m, 7H), 1.21 (d, 6H, J=7.1 Hz); ESMS m/e: 539.5 (M+H)+.