Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCC1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3.0 M solution of phenylmagnesium bromide in ether (49.7 mL, 149 mmol) was added THF (300 mL). To this solution cooled to 0° C. cyclopentanone (13.23 mL, 149 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, then at reflux for 2 h. Ice (20 g) was added, followed by 6 N HCl, until the precipitate dissolved. The product was extracted with ether. The combined etherial layers were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give cyclopentenylbenzene (21.49 g, 149 mmol, 100% yield) as a colorless oil. LC-MS (M+H)+=145.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.48 (2H, d, J=7.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H, t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[F:7][C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][C:12]([O:18][CH3:19])=[N:11][C:10]=2[C:9]=1[CH:20]=O.[NH4+].[Cl-].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]1[C:9]([CH:20]=[CH2:1])=[C:10]2[C:15]([N:14]=[CH:13][C:12]([O:18][CH3:19])=[N:11]2)=[CH:16][CH:17]=1
Reactant: COc1cnc2ccc(F)c(C=O)c2n1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(F)ccc2ncc(OC)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl triphenyl phosphonium bromide (154 g, 430 mmol) was suspended in THF (1 L) and cooled to 0° C. KOtBu (44.4 g, 400 mmol) was added in one portion and the yellow suspension was stirred at 0° C. for 15 min before a solution of 6-fluoro-3-methoxyquinoxaline-5-carbaldehyde (71 g, 340 mmol) in THF (550 mL) was added dropwise over 70 min. The mixture was stirred at 0° C. for 60 min. Sat. NH4Cl solution (250 mL) and water (250 mL) were added and the phases were separated. The org. layer was dried over MgSO4, filtered and concentrated to dryness. The residue was purified by two filtrations over a plug of silica gel (2×250 g) using an Hept/EA (2:1) mixture as eluent to afford the title alkene as an orange solid (62.7 g, 89% yield).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50]>C(OCC)(=O)C>[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50].[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1/[CH:1]=[CH:2]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ncccn1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C(=C/c1nc2ccccc2n1-c1ncccn1)\c1ccccc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]2[O:18][CH2:9]2)[O:3][CH2:2]1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1cc2c(cc1CC1CO1)OCO2

Procedure:
Safrole oxide was prepared by stirring a solution of safrole (1.48 mL, 10 mmol) and m-chloroperoxybenzoic acid (2.70 g, 11 mmol) in methylene dichloride (25 mL) overnight. The reaction was quenched by pouring into water (50 mL). The aqueous was extracted with ether (3×25 mL). The organic layers were combined and washed with 10% aqueous sodium sulfate (2×25 mL), saturated aqueous sodium bicarbonate (3×25 mL), and brine (25 mL). The organic phase was dried over magnesium sulfate and the solvents were removed in vacuo. The resulting yellow oil was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3](C(O)=O)=[CH:2]1.C(=O)=O.C>C(O)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: O=C=O
Solvent: CCO
Product: O=c1cc[nH]c2ccccc12

Procedure:
The 4(1H)-quinolone-3-carboxylic acid (65.5 g) was stirred and heated in a flask set in a fluidised sand bath at 270° C., under nitrogen, until no more CO2 was evolved (about twenty minutes). The fused mass was allowed to cool and then dissolved in boiling ethanol (400 ml). The solution was treated with charcoal, and filtered. The filtrates were evaporated to dryness, the residue dissolved in boiling n-butanol (80 ml), the solution cooled, and an equal volume of diethyl ether then added. The cream solid was collected and dried to give 4(1H)-quinolone, m.p. 205° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([F:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[F:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: NCCc1ccccc1
Reactant: CC(F)c1ncnc(Cl)c1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(F)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-fluoro-ethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>C(O)C>[CH3:13][C:4]1[O:3][C:2]([NH:17][CH2:14][CH2:15][CH3:16])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1oc(Cl)nc1-c1ccccc1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1nc(-c2ccccc2)c(C)o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 2-chloro-5-methyl-4-phenyl-1,3-oxazole (1.46 g, 7.56 mmol) in ethanol (15 mL) was added propylamine (5 mL), and the mixture was stirred in a sealed tube at 110° C. for 8 hr. The reaction mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to give the title compound (850 mg, yield 52%) as a yellow powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5][N:6]=[N+:7]=[N-:8].[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23]>>[CH:18]1[C:13]([C:12]([C:11]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:5][N:6]3[N:7]=[N:8][C:24]([C:25]([NH2:27])=[O:26])=[C:22]3[NH2:23])=[CH:9][C:10]=2[Cl:21])=[O:20])=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=1
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: N#CCC(N)=O
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N

Procedure:
After protection of the alcohol group in 3,5-dichlorobenzyl alcohol, as the TBDMS ether step (step 1), the ether is reacted with 4 chlorobenzoyl chloride to form the substituted benzophene (step 2). The benzophene is treated with thionyl chloride (step 3) and then with sodium azide (step 4) to form 3,5-dichloro-4-(4-chlorobenzoyl)benzyl azide. Reaction of this azide with cyanoacetamide produces L651582 (step 5). Reaction of L651582 with orotic acid forms the L651582 orotate (2:1) (step 6).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=O)C.[BH4-].[Na+]>CO.C1COCC1>[CH2:18]([O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:6]3[C:4](=[O:3])[NH:24][CH2:23][C:20]([CH3:22])([CH3:21])[N:7]3[C:8]=2[CH:9]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)(C)C#N)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Temperature: 0 °C
Yield: 31.3 %

Procedure:
1-(Cyano-dimethyl-methyl)-1H-indole-2,6-dicarboxylic acid diethyl ester (238, 0.725 mmol) was suspended in 3 mL of MeOH and 2 mL of THF, and 188 mg (1.45 mmol) of CoCl2 was added. While the mixture was stirred in a 0° C. bath, 274 mg (7.25 mmol) of NaBH4 was carefully added in small portions. The cold bath was removed and the mixture was stirred for 30 min. The vessel was sealed and heated to 60° C. with stirring for 4 h. The mixture was cooled and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was then washed with 1 M NaHSO4 and brine, dried with Na2SO4, filtered, and concentrated. The residue was chromatographed (1-5% MeOH in CH2Cl2) to provided 65 mg of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester. ESI-MS m/z 287 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8](F)[N:7]=1)=[O:4].[NH3:20].O>CC(O)C>[NH2:20][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: N
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1N
Temperature: 70 °C
Yield: 55 %

Procedure:
To a stirred solution of ethyl 6-[(2,2-dimethylpropanoyl)amino]-2-fluoronicotinate (M. C. Coldwell et al., Bioorg. Med. Chem. Lett., 1995, 39, 5, 1.5 g, 5.59 mmol) in 2-propanol (16 mL) was added 25% aqueous ammonia (4 mL) and the mixture was heated in a sealed tube at 70° C. for 4.5 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/pentane (1:6 to 1:2) to give 810 mg (55%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:11][CH:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:18]CC1.[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:11][CH:10]1[CH2:12][CH2:13][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=CC1CC1NC(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CC1CCO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
N-tert-Butoxycarbonyl-2-ethenylcyclopropylamine (3.96 g, 21.6 mmol) from Step C was dissolved in 21 mL of tetrahydrofuran (THF). A 1M solution of borane THF.complex in THF (43.27 mL, 2 equivalents) was added at 0° C. under a nitrogen atmosphere. After the reaction mixture was stirred at 0° C. for 2.5 h, TLC analysis (on silica gel plates eluted with 25% ethyl acetate in hexane) showed the presence of starting material. A second aliquot (2 mL) of the borane-THF solution was added. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 0.5 h then cooled to 0° C. again. A 6N aqueous solution of sodium hydroxide (25.1 mL, 3.5 equivalents) was added to the reaction mixture followed by 30% aqueous hydrogen peroxide solution (7.6 mL, 1.5 equivalents) and the resultant solution was stirred at 0° C. for 10 minutes. The reaction mixture was again allowed to warm to ambient temperature and stirred at ambient temperature for 1.5 h. Anhydrous potassium carbonate was added as a solid. The reaction mixture was then diluted with 100 mL of ethyl acetate, washed with 100 mL of 1N aqueous phosphoric acid solution, 100 mL of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel with solvent gradient elution of from 1% methanol in chloroform, initially, to a final concentration of 2% methanol in chloroform yielded 4.37 g (100% yield) of N-tert-butoxycarbonyl-2-(2'-hydroxyethyl)cyclopropylamine. CDI NH3MS, M/Z: 202 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2C=CC(O)=CC=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1>O>[C:10]([C:7]1[CH:6]=[CH:5][C:4]([OH:3])=[CH:9][CH:8]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(O)cc1
Yield: 2.8 %

Procedure:
1784 g of water, 385 g of NaOH, and 232 g of bisphenol A (BPA) were added to a polymerization reactor and were then dissolved while mixing under a N2 atmosphere. 4.3 g of p-tert butylphenol (PTBP) and 13.1 g of the siloxane compound obtained according to each of Examples 1 and 2, and Comparative Examples 1 and 2, which was dissolved in methylene chloride (MC), were added thereto. Subsequently, 128 g of triphosgene (TPG) was dissolved in MC, and then a dissolved TPG solution was added thereto and reacted therewith for 1 hour while maintaining pH of the TPG solution at 11 or more. After 10 minutes, 46 g of triethylamine (TEA) was added thereto and thereby a coupling reaction occurred.
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[OH:15][C@H:13]1[CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C@@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Iodomethane (4.17 ml) was added to (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (15.00 g) in DMF (100 ml) at 0° C. Caesium carbonate (25.4 g) was added in one portion and the resulting mixture stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (2×150 ml). The combined organics were washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) as a yellow oil. 1 NMR Spectrum: (DMSOd6) 1.32 (9H, s); 1.77-1.85 (1H, m); 2.24-2.38 (1H, m); 3.07-3.15 (1H, m); 3.47 (1H, q); 3.63 (3H, t); 4.16-4.23 (2H, m); 4.92-4.98 (1H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].S(Cl)([Cl:12])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)/C=C/C(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)/C=C/C(=O)Cl

Procedure:
To a solution of (E)-4,4-dimethyl-2-pentenoic acid (Gream, G. E.; Serelis, A. K. Aust. J. Chem. 1978, 31, 863) (200 mg, 1.6 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-4,4-dimethyl-2-pentenoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (150 mg, 0.81 mmol) and (E)-4,4-dimethyl-2-pentenoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate yielded the titled compound. MW: 313.83; mp: 171.0-172.3° C.; 1H-NMR (CDCl3) δ: 8.86-8.82 (1H, m), 8.27 (1H, d, J=16.3 Hz), 8.21-8.13 (2H, m), 7.72-7.65 (1H, m), 7.62-7.43 (4H, m), 6.31 (1H, d, J=16.3 Hz), 1.17 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:20][C:21]#[CH:22])[C:8](=[O:19])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:5][N:4]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:20][C:21]#[CH:22])[C:8](=[O:19])[CH2:9][NH:10][CH3:11])=[CH:5][N:4]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: C#CCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCN(C(=O)CNC)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl (2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(prop-2-yn-1-yl)amino)-2-oxoethyl)(methyl)carbamate (0.47 g, 1.16 mmol) in DCM (1.16 ml) was added 2,2,2-trifluoroacetic acid (1.16 ml) and the reaction mixture was stirred at ambient temperature for 1 h. To the mixture was added toluene and then the reaction was concentrated to dryness. The oil was redissolved in DCM and saturated NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with DCM. The organic layers were combined, the solvent evaporated, and the residue purified using silica gel chromatography (0-15% MeOH/DCM) to afford the title compound as yellow oil (0.258 g, 0.849 mmol, 73%): IR (thin film) 1696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.19 (s, 1H), 8.06 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.47 (dd, J=8.3, 4.7 Hz, 1H), 4.48 (s, 2H), 3.49 (s, 2H), 2.49 (s, 3H), 2.28 (t, J=2.5 Hz, 1H); ESIMS m/z 304 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: Fc1ncccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(2-Fluoro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-fluoro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (93 mg, 81%). m.p.=215-221° C.; LCMS (m/e) 391 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.94-8.85 (m, 1H), 8.75 (s, 1H), 8.24-8.17 (m, 1H), 7.49 (d, 2H, J=7.6 Hz), 7.36-7.27 (m, 1H), 7.19-7.12 (m, 1H), 6.90 (m, 2H, J=7.6 Hz), 6.85 (m, 1H, J=4.2 Hz), 6.70 (s, 1H), 3.92-3.85 (m, 4H), 3.17-3.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:19][C@@H:20]1[C:28](=[O:29])[N:27]2[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]3[C:32]4[CH:39]=[CH:38][N:37]([S:40]([C:43]5[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=5)(=[O:42])=[O:41])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:26]2)[CH2:21]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C@@H:20]2[C:28](=[O:29])[N:27]3[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]4[C:32]5[CH:39]=[CH:38][N:37]([S:40]([C:43]6[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=6)(=[O:42])=[O:41])[C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:26]3)[CH2:21]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](N)C(=O)N5C4)ncnc32)cc1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](Nc6cc(F)cc(Cl)c6)C(=O)N5C4)ncnc32)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
A mixture of 3-chloro-5-fluorophenylboronic acid (44 mg, 0.25 mmole) 127.b, powdered 4 Å molecular sieves (0.3 g), cupric acetate (83 mg, 0.45 mmole), triethylamine (69 μL (0.68 mmole), and anhydrous THF (3 mL) was stirred under a N2 atmosphere for 5 min. A solution of (2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one (0.1 g) 127.5 in anhydrous THF (1.5 mL) was added and the reaction mixture was stirred at room temperature for 24 hr and then heated at 60° C. for 48 hr. The mixture was diluted with EtOAc and filtered through a celite plug. The filtrate was concentrated in vacuo, absorbing onto 3 g silica gel. Purification by flash column chromatography (ISCO 24 g SiO2, 40% EtOAc/hex then gradient to 100% EtOAc) afforded 19.4 mg of (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one 127.6 as a white solid. LCMS (ESI) m/z: 569.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]([CH3:36])[CH:31]=[CH:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1.Cl>CN1C(=O)CCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:38]=[CH:37][C:29]4[N:30]([CH3:36])[CH2:31][CH2:32][S:33](=[O:35])(=[O:34])[C:28]=4[CH:27]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CN1C=CS(=O)(=O)c2cc(N)ccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CN1CCS(=O)(=O)c2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3c(F)cccc3Br)C4)ccc21
Temperature: 120 °C
Yield: 31.1 %

Procedure:
83 mg 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 85 mg 7-Amino-4-methyl-4H-benzo[1,4]thiazin-1,1-dioxide (starting material n)) in 0.8 ml NMP were treated with 0.2 ml 2M HCl in ether and heated to 120° C. for 6 hrs. The mixture was purified by preparative HPLC-MS to yield 34 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: [OH-]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 31 °C

Procedure:
The residue obtained (Formula IV) was suspended in 4.5 liter methanol. A solution of potassium hydroxide (225 gm) in water (1550 ml) was added drop-wise under heating over a period of one hour. The reaction mass was then refluxed for 2 hours and cooled to 30-32° C. and filtered. The filtrate was neutralized with 50% aqueous hydrochloric acid to precipitate atovaquone in a cis/trans-isomeric mixture (116 gm).