Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:37].[N:38]12[CH2:45][CH2:44][CH:41]([CH2:42][CH2:43]1)[C@@H:40]([NH:46][C:47]([C:49]1[S:50][C:51]3[C:57](Br)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:37].[N:38]12[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45]1)[C@@H:40]([NH:46][C:47]([C:49]1[S:50][C:51]3[C:57]([C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:12][CH2:11][CH2:10][C:9]5=[O:13])=[CH:4][CH:3]=4)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: O=C1CCCN1c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCCC4=O)cc3)c2s1

Procedure:
116.5 mg (0.49 mmol) of 1-(4-bromophenyl)-2-pyrrolidinone, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 71 mg (39% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][C@H:3]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26]1>C1COCC1>[Si:5]([O:4][C@@H:3]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:2][N:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CBr)c1ccc(C#N)cc1
Reactant: CCOC(=O)C[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Yield: 62.1 %

Procedure:
To a mixture of (S)-4-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)benzonitrile (7 g, 20.57 mmol) and sodium bicarbonate (2.073 g, 24.68 mmol) in THF (100 mL) was added (R)-ethyl 2-(piperidin-3-yl)acetate (3.52 g, 20.57 mmol). The reaction was heated at reflux for 5 days and then cooled, filtered, and concentrated in vacuo. The crude product was purified on a silica gel cartridge eluting with methanol/dichloromethane gradient (0% for 5 minutes then 0-100% over 20 minutes) to afford 5.5 g of ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate. MS (M+1)=431; HPLC RT=1.90 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.76 (1H, m), 4.12 (2H, q), 2.75 (1H, m), 2.69 (1H, m), 2.52 (1H, dd), 2.33 (1H, dd), 2.18 (2H, m), 2.10 (1H, dt), 2.00 (1H, m), 1.88 (1H, tt), 1.72 (1H, m), 1.59 (2H, m), 1.25 (3H, t), 1.0 (1H, m), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][N:4]1[C:12]2[N:11]=[C:10]([CH2:13][CH3:14])[NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:16].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][N:4]1[C:12]2[N:11]=[C:10]([CH2:13][CH3:14])[NH:9][C:8]=2[C:7](=[S:20])[NH:6][C:5]1=[O:16]
Reactant: CCc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)CC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)c(=S)[nH]c(=O)n2CC(C)CC
Temperature: 10 °C
Reaction time: 4.5 h

Procedure:
3-(2-Methylbutyl)-8-ethylxanthine (13.33 gm) and phosphorus pentasulphide (14.23 gm) were refluxed in pyridine (190 ml) at a bath temperature of 140° C. After 4.5 hr, the brown solution was cooled to 10° C. and 2N sodium hydroxide (70 ml) was added. The pyridine was removed in vacuo from the suspension.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(Cl)Cl.[CH3:38][O:39][C:40]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:43][CH2:42][C:41]5[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:40]=5[O:39][CH3:38])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNCc2ccn3nc(C)c(-c4nc(Cc5ccc(Cl)cc5)c(-c5nnc[nH]5)s4)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a suspension of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0.300 g, 0.690 mmol) in acetic acid (0.20 mL, 3.5 mmol) and dry methylene chloride (10 mL, 200 mmol) was added 2,4-dimethoxybenzylamine (0.207 mL, 1.38 mmol), followed by additional of sodium triacetoxyborohydride (0.363 g, 1.71 mmol). The mixture was stirred at rt. for 16 hours. The mixture was basified with NaHCO3 solution to =pH 8 then extracted with DCM. The DCM solution was washed with water. The crude product was purified by column chromatography (SiO2, elution with 0-100% MeOH in DCM) to afford a solid product (0.252 g, yield 62%). LCMS: (FA) ES+ 586, 588; ES− 584, 586. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.28-7.30 (d, J=8.53 Hz, 2H), 7.09-7.11 (d, J=8.53 Hz, 2H), 7.01-7.03 (d, J=8.28 Hz, 1H), 6.78-6.80 (d, J=7.03 Hz, 1H), 6.33-6.37 (m, 2H), 4.53 (s, 2H), 3.65 (s, 2H), 3.64 (s, 6H), 3.61 (s, 2H), 2.61 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=1[C:23]1[N:27]2[CH:28]=[C:29]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(-c3c(Cl)cccc3Cl)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Intermediate 1d (404 mg, 2.48 mmol) was added to a stirred solution of sodium hydride (60% in mineral oil, 298 mg, 7.44 mmol) in anhydrous DMF (15 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 15 min, then Intermediate 26c (0.70 g, 2.48 mmol) was added, and stirring at 60° C. was continued for 1 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and water (1:1) and extracted with EtOAc (×3). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 followed by brine, dried and concentrated in vacuo. The resultant residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM to afford the title compound (345 mg, 33%) as a brown residue. LCMS (Method 3): Rt 2.34 min, m/z 425, 427. [MH+].
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=1)=O.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])(=[O:25])[CH3:24]>CN1C(=O)CCC1>[C:23]([NH:26][C:27]1[CH:28]=[C:29]([NH:30][C:4]2[N:9]=[C:8]([NH:10][C:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NC3(c4ccccc4)CC3)n2)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To a solution of 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in NMP (1 mL) was added 3-acetamidoaniline (27 mg, 0.18 mmol) and pTsO.RH2O (30 mg, 0.16 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (38 mg). MS found for C22H22N6O2 as (M+H)| 403.5. λ=251.1.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=1[C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of methyl 2-bromo-3-methylbenzoate (22.33 g, 97.5 mmol), potassium phosphate (82.8 g, 390 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium (II), complex with dichloromethane (1:1) (3.98 g, 4.87 mmol), and p-trifluoromethylphenylboronic acid (22.2 g, 117 mmol) in 500 mL of DME is degassed and refluxed under an atmosphere of argon overnight. The mixture is concentrated, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by silica gel chromatography eluting with ethyl acetate/toluene (1:9) to give methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:45][CH2:46]C>CN(C=O)C.O>[CH2:1]([O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)[CH2:45][CH3:46]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
Ethyl ((1S)-5-{3-[2-hydroxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-phenoxy]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 165, 90 mg, 0.177 mmol) was dissolved in DMF (3 mL) after which Cs2CO3 (69.3 mg, 0.213 mmol) and water (3 drops) were added. Iodopropane (0.02 mL, 0.213 mmol) was added to the flask, and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the filtrate purified by preparative HPLC giving the desired ester as a white solid (88.7 mg, 91%). 1H NMR (400 MHz, CD2Cl2): δ 7.47 (s, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 6.79 (s, 1H), 6.71 (dd, 1H), 4.23 (t, 2H), 4.19-4.13 (m, 4H), 4.03 (t, 2H), 3.50 (m, 1H), 2.94-2.78 (m, 6H), 2.70 (dd, 1H), 2.44-2.25 (m, 4H), 1.92-1.70 (m, 7H), 1.28 (t, 3H), 1.07 (t, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[Br:14])[CH:2]=C.[O:15]=[O+][O-].CSC>CO.CCOC(C)=O>[Br:14][C:5]1[C:6]2[CH2:10][O:9][C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[O:15]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1Br)COC2=O
Solvent: CO
Solvent: CSC
Solvent: CCOC(C)=O
Product: O=CCc1ccc2c(c1Br)COC2=O
Temperature: 25 °C

Procedure:
To a solution of 5-allyl-4-bromo-2-benzofuran-1(3H)-one (120 mg, 0.47 mmol) in methanol (20 mL) was bubbled ozone at −78° C. until the solution turned light blue. Excess ozone was removed by bubbling nitrogen through, which was followed by addition of dimethyl sulfide (0.35 mL, 4.7 mmol). The reaction was allowed to warm to RT, diluted with EtOAc, washed with brine, adsorbed onto silica gel, and purified by MPLC. Removal of solvent gave rise to (4-bromo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[C:10]([O:23][CH3:24])[CH:9]=2)=[O:4].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:21][CH3:22])=[C:10]([O:23][CH3:24])[CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1[nH]c(=O)c2cc(OC)c(OC)cc2c1-c1ccncc1
Product: COC(=O)c1nc(Cl)c2cc(OC)c(OC)cc2c1-c1ccncc1
Reaction time: 0.33 h

Procedure:
To phosphorus oxychloride (100 ml) is added 3-methoxycarbonyl-4-(4-pyridyl)-6,7-dimethoxyisoquinolin-1(2H)-one (6 g), and the mixture is heated under reflux for 2.5 hours. The reaction mixture is concentrated, and thereto is added chloroform. To the mixture is further added gradually a saturated aqueous sodium hydrogen carbonate solution, and the mixture is stirred for 20 minutes. The organic layer is collected, dried, and concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:ethyl acetate=5:1) to give 1-chloro-3-methoxycarbonyl-4-(4-pyridyl)-6,7-dimethoxyisoquinoline (5.17 g).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(Br)ccn1N
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 89.6 %

Procedure:
The title compound was prepared from methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (9.05 g, 25.6 mmol) and (S)-2-(benzyloxycarbonylamino)propanoic acid (5.72 g, 25.6 mmol) following the experimental procedure described in Preparation 73a. 9.73 g (84% yield) of the desired compound were obtained.
Reaction SMILES: [OH-].[Na+].[Br:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH:5]1Br>CO>[Br:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(Br)C(Br)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccccc2cc(Br)c2ccccc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
Sodium hydroxide (51.5 g, 1.29 mmol) was added to a stirring slurry of 10,11-dibromo-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one (2) (157.0 g, 428.9 mmol) in 1.8 L of methanol and the resulting mixture was heated to 70° C. under nitrogen. LC/MS analysis after six hours revealed consumption of the starting material. The slurry was allowed to cool to room temperature and the solid was collected by vacuum filtration, washed with a small amount of methanol, and dried under vacuum to afford 113 g (92%) of 10-bromo-dibenzo[a,d]cyclohepten-5-one (3). ESI MS m/z 286.5, 288.5 (M+H)+. 1H NMR (d6-DMSO, 250 MHz): 8.05 (1H, d), 7.89-7.63 (6H, m), 7.42 (1H, m), 6.67 (1H, s).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: ClCc1cccc(Cl)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(N)c2nc(CN3CCN(Cc4cccc(Cl)c4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.2 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-chlorobenzyl chloride (0.015 mL; 0.12 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 9 mg of yellow colored 3-[4-(3-Chloro-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: C(=O)C1C=CC=CC=1.[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[NH:27]1[C:23]([C:22]2[CH:25]=[CH:26][C:19]([N:16]3[CH2:17][CH2:18][C:13]4([O:12][CH2:11][CH2:10][O:9]4)[CH2:14][CH2:15]3)=[CH:20][CH:21]=2)=[N:24][N:29]=[N:28]1
Reactant: N#Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(N2CCC3(CC2)OCCO3)ccc1-c1nnn[nH]1
Temperature: 95 °C
Yield: 80.1 %

Procedure:
A mixture of 4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzonitrile benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (10 mmol, 2.44 g), sodium azide (30 mmol, 1.95 g) and triethylamine hydrochloride (30 mmol, 4.13 g) in toluene was heated to ˜95° C. over night (Koguro, K., Oga, T., Missui, S. and Orita, R. Synthesis, 1998, 910). After cooling the mixture was poured into water and the solid which was formed was collected. To the aqueous layer 36% hydrochloric acid was added dropwise to salt out more solid. The combined solids were dried to yield the title compound as an off-white solid (2.30 g, 80%); 1H NMR (300 MHz, DMSO-d6) δ 1.70 (t, J=5.7 Hz, 4 H), 3.44 (t, J=5.7 Hz, 4 H), 3.92(s, 4 H), 7.12(d, J=9.0 Hz, 2 H), 7.85(d, J=9.0 Hz, 2 H); MS (ES) m/z: 288.4 (MH+); HRMS Calcd. for C14H17N5O(M+): 287.1382. Found: 287.1375.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][CH2:11][C:12]3=[O:17])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1>>[O:17]=[C:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]4[N:26]=[C:27]5[C:22]([CH2:21][CH2:20][C:19](=[O:18])[NH:28]5)=[CH:23][CH:24]=4)[CH2:5][CH2:6]3)=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=C1CCCc2c1cccc2N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4CCCC5=O)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 169–170° C. MS: APCI: M+1: 449.2 (Exact Mass: 448.25).
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.[BH4-].[Na+].CC(O)=O.CO>CO>[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]([OH:8])[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
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Artemisinin (compound 3) (0.5 g, 1.8 mmole) in 40 mL of MeOH was cooled in an ice-bath to 0°-5° C. To the solution was added in small portions 0.25 g (6.6 mmole) of NaBH4 over a period of 30 minutes. The solution was stirred at 0°-5° C. for 2 hours after the addition of NaBH4 was complete. The solution was neutralized with 30% AcOH/MeOH and evaporated to dryness under reduced pressure. The white residue was extracted 3 times with 50 mL of EtOAc. The EtOAc extracts were combined, filtered, and evaporated to dryness to give 0.38 g (75%) of white needles mp 152°-154° C. (dec). Recrystallization from EtOAc-hexane raised the melting point to 153°-155° C. (lit. mp 153°-154° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:68]=[CH:67][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]([CH2:18][C@H:19]2[N:22]([C:23]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=P(OC(C)C)(OC(C)C)OC(C)C)[C:21](=[O:50])[C@@H:20]2[C@H:51]([O:53][C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=2)=[O:55])[CH3:52])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C=CC(O)=CC=1)O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:68]=[CH:67][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]2[CH2:18][C@@H:19]3[C@@H:20]([C@H:51]([O:53][C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=4)=[O:55])[CH3:52])[C:21](=[O:50])[N:22]3[C:23]=2[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=2)=[O:38])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)OP(OC(C)C)(OC(C)C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 120 °C
Yield: 51.2 %

Procedure:
A mixture of 48 mg of (3S, 4R)-4-([2-(p-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-1-[1-(p-nitrobenzyloxycarbonyl)-1-triisopropoxyphosphoranylidenemethyl]-2-azetidinone and 30 mg of hydroquinone in 5 ml of xylene was heated at 120° C. under a stream of a nitrogen gas for 13 hours. The xylene was then distilled off and the residue was subjected to chromatography using a Lobar column A eluted with a 2:1 by volume mixture of chloroform and ethyl acetate, to give crude crystals, which were recrystallized from a mixture of benzene and ethyl acetate, affording 19 mg (yield 51%) of colourless prisms, melting at 148°-150° C.