Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[C:7]=1[NH2:8].[C:31](O)(=[O:35])[C@@H:32]([CH3:34])[OH:33].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:8][C:7]1[N:6]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[C:5]2[N:4]=[C:3]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:35])[C@H:32]([OH:33])[CH3:34])[CH2:27][CH2:26]2)[C:2]=1[Br:1]
Reactant: C[C@@H](O)C(=O)O
Reactant: Nc1c(Br)c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude 6-bromo-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-7-amine, D-(−)-lactic acid (18.5 mg, 0.20 mmoL), EDC (78.7 mg, 0.41 mmoL), HOBt (27.7 mg, 0.20 mmoL) and DIEA (238 uL, 1.37 mmoL) in DMF (4 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-1-(4-(7-amino-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidin-1-yl)-2-hydroxypropan-1-one, LCMS tR=4.39 Min (10 min run, UV254nm). Mass calculated for, M+ 513.0, observed LC/MS m/z 514.43 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:4]2[C:5]([O:7][C:8](=O)[NH:9][C:3]=12)=[O:6].[Cl:17][C:18]1[C:19]([N:24]2[C:28](C(Cl)=O)=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[Cl:17][C:18]1[C:19]([N:24]2[C:28]([C:8]3[O:7][C:5](=[O:6])[C:4]4[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:2]([CH3:1])[C:3]=4[N:9]=3)=[CH:27][C:26]([C:32]([F:35])([F:33])[F:34])=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 100 °C

Procedure:
A mixture of 505 mg (1.63 mmol) of the title material from Step A, 344 mg (1.55 mmoles) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (which can be prepared according to Example 7) and 2 mL of pyridine was heated at 100° C. for 3 hours. The resulting mixture was cooled to 25° C. and partitioned between ethyl acetate and dilute aqueous HCl. The organic layer was washed three times with dilute aqueous HCl, dried over anhydrous magnesium sulfate and concentrated to give a brown solid that was used in the next step without further purification. 1H NMR (CDCl3): δ 8.86 (d, 1H), 8.60 (dd, 1H), 8.38 (d, 1H), 8.03 (dd, 1H), 7.59 (s, 1H), 1.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32].C[O-].[Na+:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O-:33])=[O:32].[Na+:36]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy) chroman-4-carboxylic acid (49.4 mg, 0.0975 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (195 μL, 0.0975 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate (51.5 mg, 0.0974 mmol, 99.9% yield) as a solid. MS (apci) m/z=507.6 (M+2H—Na).
Reaction SMILES: [C:1](=[O:19])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[NH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21]1.O>ClCCl.CO>[OH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:20]([C:1]([O:2][CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)=[O:19])[CH2:21]1
Reactant: OCC1CCNC1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1cscn1)N1CCC(CO)C1
Reaction time: 15 h
Yield: 21.6 %

Procedure:
A solution of 3.00 g (10.70 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate in 20 ml of dichloromethane is added at ambient temperature, via a dropping funnel, to a solution of 1.13 g (11.24 mmol) of pyrrolidin-3-ylmethanol (commercial) in 20 ml of methanol. The solution is stirred for 15 hours. Water is subsequently added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed with a 1M aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution. After having dried the organic phases over sodium sulphate, the mixture is filtered and the filtrate is evaporated to dryness. 0.56 g of the desired product is thus obtained in the form of an oil after purification on a column of silica gel, elution being carried out with a dichloromethane/methanol (97/3 to 95/5) mixture.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.O1CCCC1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH2:27][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(CN3CCOCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 17 mg (0.19 mmol) morpholine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (1 ml), and methylene chloride (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 43 mg (59%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-morpholin-4-ylmethyl-thiazol-2-yl)-amine as a yellow oil. MS ISP (m/e): 386.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.65 (s, 1H), 7.27 (s, 1H), 7.19 (d, 1H), 7.11 (s, 1H), 6.97 (d, 1H), 6.87 (s, 1H), 3.86 (s, 3H), 3.71 (t, 4H), 3.61 (s, 2H), 2.49 (t, 4H), 2.30 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35](I)[C:28]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[CH:16][CH:15]=3)[C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc(Nc3noc4ccccc34)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Nc4noc5ccccc45)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C

Procedure:
A mixture of N-benzo[d]isoxazol-3-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.087 g, 0.000258 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.088 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate (0.053 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(benzo[d]isoxazol-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. It was dissolved in ethyl acetate (5 mL) and treated with a 4N aqueous solution of hydrochloric acid (1 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield N3-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}benzo[d]isoxazol-3-amine acetate (0.009 g, 0,0000185 mol) as a white solid.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.[CH2:19]([N:21]([CH:30]([O:35][CH3:36])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20].CN(CCN(C)C)C.[CH3:45][Si:46](Cl)([CH3:48])[CH3:47]>C1COCC1>[CH2:19]([N:21]([CH:30]([O:35][CH3:36])[C:31]([CH3:32])([CH3:34])[CH3:33])[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=1[Si:46]([CH3:48])([CH3:47])[CH3:45])[CH3:20]
Reactant: CCN(C(=O)c1ccccc1)C(OC)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCN(C(=O)c1ccccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (140.6 mL, 182.8 mmol) was added dropwise to a dry-ice/acetone cooled solution of N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)benzamide (35 g, 140.6 mmol) and TMEDA (25.44 mL, 168.6 mmol) in THF (280 mL), maintaining the internal reaction temperature ≤-60° C. The yellow solution was stirred at -78° C. for 1 h, then was cannulated into a dry-ice/acetone cooled solution of TMSCl (26.72 mL, 210.6 mmol) in THF (140 mL) at a rate which maintained the internal reaction temperature ≤-55° C. The resulting mixture was warmed to 0° C. and partitioned between ether and sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum to give 44.8 g of the title compound as a pale yellow solid, a 99% yield. m.p. 76°-78° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.O>[OH:11][C:9]1[C:4]2[CH:5]=[N:6][N:7]([CH3:8])[C:3]=2[NH:2][C:14](=[O:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of sodium metal (12.7 g, 0.55 mol) in ethanol is treated at room temperature with ethyl 5-amino-1-methyl-4-pyrazolecarboxylate (25 g, 0.148 mol), stirred for 0.5 h, treated dropwise with a solution of diethyl malonate (80 mL, 0.52 mol in ethanol over a 0.5 h period, heated at reflux temperature for 56 h, cooled to room temperature, diluted with water, washed with ethyl acetate, acidified to pH 2 with HCl and filtered. The filtercake is washed sequentially with water, ethanol, ethyl acetate and toluene and dried in vacuo at 40° C. for 16 h to afford the title product as a white solid, 28.7 g (82% yield), identified by HNMR analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of p-Tolylamine (626 mg, 5.89 mmol), and Hunig's base (2.054 ml, 11.8 mmol) in tetrahydrofuran (20 mL) was added the product from Example 86A (1.20 g, 5.89 mmol) in tetrahydrofuran (10 mL) dropwise over 10 minutes. The solution was stirred at room temperature for 1 hour, the reaction mixture diluted with water and the title compound was collected by filtration (1.77 g, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O[C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[S:44]([C:47]1[N:51]2[C@:52]([CH3:77])([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([C:71]4[CH:72]=[N:73][CH:74]=[N:75][CH:76]=4)=[CH:67][CH:66]=3)[C:53](=[O:63])[N:54]([C:55]3[CH:60]=[C:59]([Cl:61])[CH:58]=[C:57]([Cl:62])[CH:56]=3)[C:50]2=[N:49][CH:48]=1)(=[O:46])=[O:45])=[O:38])(C)(C)C.[CH3:78][O:79][CH2:80][CH2:81][NH2:82].Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH3:78][O:79][CH2:80][CH2:81][NH:82][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[S:44]([C:47]1[N:51]2[C@:52]([CH3:77])([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([C:71]4[CH:76]=[N:75][CH:74]=[N:73][CH:72]=4)=[CH:67][CH:66]=3)[C:53](=[O:63])[N:54]([C:55]3[CH:56]=[C:57]([Cl:62])[CH:58]=[C:59]([Cl:61])[CH:60]=3)[C:50]2=[N:49][CH:48]=1)(=[O:45])=[O:46])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
TBTU (0.077 g), DIPEA (0.090 mL) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.10 g) were combined in 5% DMF-CH2Cl2 (4.2 mL) at room temperature. 2-Methoxyethylamine (0.036 g) was then added and the reaction solution was stirred overnight. The reaction was diluted with CH2Cl2, poured into 1N HCl, and extracted with CH2Cl2. The organic layers were subsequently extracted with CH2Cl2 from saturated aqueous NaHCO3 followed by brine. The combined organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography to afford 0.045 g of the title compound (684.2, M+1) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][Mg]Br.Cl>C(OCC)C>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])([OH:5])[CH3:18]
Reactant: C[Mg]Br
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CCOCC
Product: CC(O)(c1cc(Cl)ccc1N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 g of 2-amino-2′,5-dichlorobenzophenone dissolved in 100 ml of diethyl ether, at −30° C., are added 12.5 ml of 3M methylmagnesium bromide solution, and the mixture is maintained at room temperature for 18 hours. 6 ml of 3M methylmagnesium bromide solution are added and the mixture is left at room temperature for 1 hour. The resulting mixture is hydrolysed with 2M hydrochloric acid solution and washed with water. The organic phase is dried over anhydrous sodium sulfate to give 4.3 g of the expected product.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C1COCC1>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[S:15][C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[N:13][C:12]=2[C:27]([NH2:29])=[O:28])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A solution of 2-cyclopentylacetyl chloride (0.35 mL, 2.64 mmol) in THF (2 mL) was added dropwise to a mixture of 5-amino-2-(naphthalen-2-ylamino) thiazole-4-carboxamide (0.15 g, 0.53 mmol) and pyridine (2 mL) in THF (10 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed successively with ether and EtOAc to give 0.12 g (58% yield) of the titled compound.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([O:26]CC)=O)=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:30]([CH3:29])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)=[O:26])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CCCC2)cc1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCCC4)cc3)o2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using Ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), N-methyl-1-[4-(pyrrolidin-1-ylmethyl)phenyl]methanamine (30 mg, 0.15 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). The crude product was purified twice using FCC, eluting with 95:4.5:0.5, then 98:1:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [Na].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[C:13](#[N:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:22][C:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc(NN)cc1
Reactant: N#CC=Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(N2N=C(N)CC2c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A 4.42 g. amount of sodium metal is dissolved in 300 ml. of absolute ethanol, then 27.8 g. of p-methoxyphenylhydrazine hydrochloride is added followed in 5 minutes by 20.64 g. of cinnamonitrile. The reaction mixture is refluxed for 7 hours, then is evaporated to dryness in vacuo. Water is added to the residue to give a sludge. The mixture is filtered and the residue is evaporated to dryness. The solid is dissolved in dichloromethane and crystallized as described in Example 16 to give 4.75 g. of the desired product as colorless needles, m.p. 163.5°-166° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=1
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1cc(Cl)cs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2nc(Cl)ccc21

Procedure:
The title compound was prepared from 5-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole (Example 27) according to the procedure of Example 2C, using 5-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole (0.75 g, 2.39 mmol), N-chlorosulfonyl isocyanate (0.31 mL, 3.56 mmol), and acetonitrile (12 mL). Hydrolysis of the N-chlorosulfonyl carboxamide was achieved by stirring in DMSO (8 mL) for 4 hours at room temperature in a flask open to the air. The product was obtained by dilution of the mixture with water followed by filtration and recrystallized from acetic acid. Yield: 352 mg (41%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH4-].[Na+].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCOCC1.C(O)(=O)C.O>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:35]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:41])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: O=C1CCC(=O)O1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Artemisinin (500 mg) and polyhydroxy compound (dextrose, 2.5 g) are stirred in 1,4-dioxan (15 ml) at room temperature for 5 minutes. Sodium borohydride (2.5 g) is added slowly for 10 minutes and the reaction mixture is stirred for about 2 hours at room temperature (20-30° C.). After completion of the reaction (Checked by TLC), succinic anhydride (250 mg) and anion exchange (basic) resin (1.5 g) are added at room temperature and the reaction mixture is stirred further for 2 hours at room temperature. Cold water (50 ml) is added to the reaction mixture and pH is adjusted between 6-7 with dilute acetic acid and extracted with 40% ethyl acetate in hexane (3×25 ml). The combined extract is washed with water (50 ml). The ethyl acetate n-hexane extract is dried over anhydrous sodium sulphate and evaporation of the solvent yield 655 mg of crude artesunic acid which upon purification over silica gel (1:5 ratio) with 20-30% ethyl acetate in hexane, furnish pure artesunic acid in 93% w/w (465 mg) yield (according to CO-TLC). After drying the pure α-artesunic acid, mp 140-142° C. is chareterised by spectral analysis.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[CH3:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: CNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-methylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 278°-280° C.) and piperazine in dioxane at 80° C.