Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39]([O:46][C:47](=[O:50])[CH2:48]Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:48][C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:50])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3cc(C)c(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3cc(C)c(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 250 mg 4-{2-[(4-Hydroxy-6,7-dimethyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 1.5 ml of DMF, 202 mg of cesium carbonate and 142 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 290 mg.
Reaction SMILES: [O:1]=[C:2]([CH3:25])[CH:3](C(OCC)=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(O)(=O)C.Cl.O>C(Cl)Cl.[OH-].[Na+]>[O:1]=[C:2]([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]
Reactant: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)CCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 350 g of crude N-[7-oxo(6-carboethoxy)octyl]phthalimide and 1000 ml of acetic acid, concentrated hydrochloric acid, and water was refluxed for three hours. The reaction mixture was stripped, the residue dissolved in methylene chloride and basified with 2 N NaOH solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and stripped to an orange oil, 73% pure by gc (SE-30, 90-280°@16°/min). This material was used without further purification in Preparation 3.
Reaction SMILES: C(Cl)(F)C(F)(F)C(Cl)(F)F.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>O>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)F
Agent: FC(Cl)C(F)(F)C(F)(F)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1

Procedure:
Until HCFC-225cb becomes available in commercial quantities, HCFC-225cb may be prepared by a standard and well-known organic synthesis technique. For example, to prepare 1,3-dichloro-1,1,2,2,3-pentafluoropropane, 2,2,3,3-tetrafluoropropanol, tosyl chloride, and water are reacted together to form 2,2,3,3-tetrafluoropropyl p-toluenesulfonate. Then, N-methylpyrrolidone, potassium fluoride, and the 2,2,3,3-tetrafluoropropyl p-toluenesulfonate are reacted together to form 1,1,2,2,3-pentafluoropropane. Then, chlorine and the 1,1,2,2,3-pentafluoropropane are reacted to form 1,1,3-trichloro-1,2,2,3,2-pentafluoropropane. Finally, isopropanol and the 1,1,3-trichloro-1,2,2,3,2-pentafluoropropane are reacted to form 1,3-dichloro-1,1,2,2,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])[C:8]=2[CH:7]=1)[CH3:4].[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][CH3:37])[CH:27]=1)=[O:25]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][C:28]=3[O:36][CH3:37])(=[O:34])=[O:33])[C:11](=[O:19])[N:12]([C:13]([CH3:17])([CH3:18])[CH2:14][O:15][CH3:16])[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(C(C)(C)COC)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C(C)(C)COC)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
0.12 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 1 g of 5- ethoxy-1,3-dihydro-3-(2-methoxy-1,1-dimethylethyl)-2H-benzimidazol-2-one and 30 ml of THF and the mixture is stirred for 30 minutes at RT. 1.2 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride are then added and the mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give 1.7 g of the expected product, which is used as such in the next step.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[Na].Cl.[OH-].[K+].[CH3:12][CH2:13][CH2:14]O>>[O:7]=[C:1]1[CH2:2][CH2:3][CH:4]([O:6][CH2:12][CH2:13][CH3:14])[NH:5]1
Reactant: O=C1CCC(=O)N1
Reactant: CCCO
Agent: Cl
Agent: [K+]
Agent: [Na]
Product: CCCOC1CCC(=O)N1
Reaction time: 4 h

Procedure:
To a mixture of 28.64 g of succinimide and of 1200 cm3 of N-propanol, cooled to -7° C., 7 g of sodium bobohydride is added. This is agitated for 4 hours at -7° to 0° C., while adding every 15 minutes 15 drops of a 2N solution of hydrochloric acid in N-propanol. The mixture is then taken to a pH of about 2 by adding a 2N solution of hydrochloric acid in N-propanol, agitated for 1 hour at about 0° C., then returned to pH 7 by the addition of a saturated solution of potassium hydroxide in N-propanol. After allowing a return to ambient temperature, the solvent is evaporated off under reduced pressure. The residue is extracted with 550 cm3 of chloroform, filtered, the organic solution is washed with water, dried and the solvent is evaporated under reduced pressure. 27.5 g of the expected product is obtained. m.p. 52°-54° C.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[N:19]O)=[N:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:5]([C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: ON=Cc1ccc(Oc2ccccc2)cn1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Oc2ccccc2)cn1

Procedure:
A solution of sodium amide is prepared using 5 g of sodium metal in 500 ml liquid ammonia and 0.1 g ferric nitrate catalyst. A solution of 19 g of 2-methyl-5-phenoxypyridine in 20 ml of anhydrous diethylether is added dropwise, followed by a solution of 11 g of n-butylnitrite in 20 ml of anhydrous diethylether. The ammonia is allowed to evaporate and the resulting mixture of solids is treated with 27 g of ammonium sulfate, 100 ml of diethylether and 100 ml of water. The mixture is extracted with 500 ml of dichloromethane. The organic solution is dried, concentrated and the mixture of oximes can be used directly. One isomer is isolated by crystallization from anhydrous diethylether, 5-phenoxy-2-pyridinecarboxaldehyde oxime, m.p. 130°-131° C. To 59 g of reagent thionylchloride is added 5 g of 5-phenoxy-2-pyridinecarboxaldehyde oxime in portions. After the initial exothermic reaction subsides, the solution is refluxed 30 minutes. The solution is concentrated at reduced pressure, is dissolved in 200 ml dichloromethane and is washed until neutral with dilute ammonium hydroxide. The organic solution is dried, concentrated and distilled to yield 5-phenoxy-2-pyridinecarbonitrile, m.p. 84°-85° C., identical by mixed melting point, infrared and proton magnetic resonance spectrum to that prepared by Process I.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 3-pyridylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22](=[N:28]O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[O:12][N:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(Cc2ccc(C(F)(F)F)cc2)n1
Yield: 30.4 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(4-(trifluoromethyl)phenyl)acetic acid (0.773 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL), and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.345 g (34%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([CH2:20][CH:21]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:25][O:26][C:27](=[O:40])[C@H:28]([NH2:39])[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:25][O:26][C:27](=[O:40])[C@H:28]([NH:39][CH2:21][CH2:20][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](N)CCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)[C@@H](CCOCc1ccccc1)NCCN(CCC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1E, 3-[(2-oxo-ethyl)-(3-trifluoromethyl-phenyl)-amino]-propionic acid tert-butyl ester (example 5A) and (R)-2-amino-4-benzyloxy-butyric acid methyl ester hydrochloride (intermediate 7) gave the title compound as yellow oil. MS: 539.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([NH2:26])[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCO2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([NH2:26])[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Reactant: Nc1nc(CCl)cs1
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(N)n2)c(C#N)c1C1CCCCO1

Procedure:
50 mg (0.14 mmol) of the compound from Example 31A, 39 mg (0.21 mmol) of 4-(chloromethyl)-1,3-thiazol-2-amine and 48 mg (0.58 mmol) of sodium bicarbonate in 2.0 ml of dry DMF are reacted analogously to the preparation of the compound of Example 14.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]([Cl:14])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].CCCCCCC.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1>O.C(#N)C.N12CCN(CC1)CC2>[Cl:3][C:4]([Cl:14])=[CH:5][CH:6]1[CH:8]([C:9]([O:11][CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)=[O:10])[C:7]1([CH3:12])[CH3:13]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCCCC
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Potassium hydroxide (2.0 g, 0.032 mole) was dissolved in 7 ml of water. To this solution was added 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (6.6 g, 0.032 mole), which may be prepared according to the method of Farkas, et al., loc. cit. After dissolution, 100 ml of heptane was added, and the mixture was heated under reflux using a DeanStarke trap to remove the water from the mixture. The dry mixture was then cooled to 60°, and a solution of 3-bromomethylbiphenyl (7.5 g, 0.032 mole) and 0.1 g of 1,4-diazabicyclo[2.2.2]octane in 60 ml of acetonitrile was added. 3-Bromomethylbiphenyl may be prepared according to the method of M. Gomberg and J. C. Pernert, J. Am. Chem. Soc., 48, 1372 (1926) and H. O. Huisman, et al., Rec. Trav. Chim., 71, 899 (1951). The mixture was then heated under reflux for 5.5 hours. After cooling to room temperature, the reaction mixture was contacted with 100 g of ice in a separatory funnel, and when the ice had melted the phases were separated. The aqueous phase was saturated with sodium chloride before being extracted twice with 100 ml portions of heptane. The heptane extracts and the organic phase were combined, and the combined organic phase was washed with one 200 ml portion of a saturated sodium chloride solution. The solvent was removed from the organic phase using a rotary evaporator, leaving an oily, straw-colored residue weighing 9.9 g. The oil was distilled in a short path, air-bath heated Kugelrohr distillation apparatus at a pressure of 0.25 mm. After removing low boilers from the oil at a temperature below 145°, [1,1'-biphenyl]-3-ylmethyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (6.5 g, 54.4% yield) was obtained at a temperature of 165°-175°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:34]([CH3:38])[C:35](O)=[O:36])[CH2:29][CH2:28][CH2:27]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:34]([CH3:38])[C:35]([N:4]1[CH2:3][CH2:2][N:1]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][N:18]=4)(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:6][CH2:5]1)=[O:36])[CH2:29][CH2:28][CH2:27]2
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(N2CCNCC2)cc1
Reactant: CC(C(=O)O)N1CCCc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CC1)N1CCCc2cc(Cl)ccc21

Procedure:
Synthesized according to general procedure 5, method A. The reaction was set up with 0.11 mmol 4-(piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.17 mmol 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid, 0.17 mmol BOP reagent, 0.17 mmol triethylamine and 300 μL DMF. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=541.1; tR=3.11 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl-].C([O:29][C:30](=O)[C:31](O)=[O:32])C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=2)[NH:18][C:30](=[O:29])[C:31]1=[O:32])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(=O)O
Reactant: CCOP(=O)(CNc1cc(F)ccc1N)OCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
660 mg of N(-2-amino-5-fluorophenyl)-aminomethanephosphonic acid diethyl ester is introduced in 70 ml of absolute tetrahydrofuran with 509 mg of triethylamine. A solution of 685 mg of oxalic acid ethyl ester chloride in 30 ml of tetrahydrofuran is slowly instilled into this solution. The batch is stirred for 4 hours at room temperature. After suctioning-off of the precipitated salts, the filtrate is concentrated by evaporation, boiled in a mixture of 23 ml of ethanol and 23 ml of 1N hydrochloric acid for 2 hours at 110° C. bath temperature. It is evaporated to dryness and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 561 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CC(C)=[O:31].S(=O)(=O)(O)N.Cl([O-])=O.[Na+]>O>[CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]([OH:31])=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CC(C)=O
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: COc1ccc2c(Oc3ccc(C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (0.565 g, 1.53 mmol) was added a 2:1 acetone:H2O solution (21 mL). The turbid solution was cooled in an ice-water bath and sulfamic acid (0.158 g, 1.63 mmol, 1.06 eq) was added portionwise over several minutes. The reaction mixture was stirred for 5 min and sodium chlorite (80% tech. Grade) (0.185 g, 1.64 mmol, 1.07 eq) was added portionwise. The reaction mixture was stirred for 30 min. The acetone was removed in vacuo and the reaction mixture was partitioned between H2O and CH2Cl2. The organic phase was separated and the aqueous phase was extracted with CH2Cl2. The organic extracts were combined, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.47 g (80%) of the compound 16 as a gold-yellow amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 2.17 (s, 3H), 3.86 (s, 3H), 6.64 (d, J=8.7 Hz, 2H), 7.07 (dd, J=2.6 Hz, 9.2 Hz, 1H), 7.16 (m, 2H), 7.21-7.30 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.70 (m, 3H), 12.63 (br s, 1H). AP LRMS m/z 385 (M+H)+.
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].NC1N=C2C(N=CN2[CH:28]2[C:30]([C:35]([O:37][CH3:38])=[O:36])([C:31]([O:33][CH3:34])=[O:32])[C:29]2([Cl:40])[Cl:39])=C(Cl)N=1>CN(C)C=O>[Cl:11][C:29]([Cl:39])([Cl:40])[CH:28]=[C:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]([O:37][CH3:38])=[O:36]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: COC(=O)C1(C(=O)OC)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
In a 0.3-liter four-necked flask, 7.06 g (41.6 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 12.4 g (89.7 mmol) of potassium carbonate were added to 188 ml of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. Next, 16.0 g (61.2 mmol) of dimethyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for four hours at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were collected by filtration, washed with 100 ml of water, and then dried under reduced pressure, to give 12.14 g (34.7 mmol) of white crystals of 2-amino-6-chloro-9-(3,3-dicarbomethoxy-2,2-dichlorocyclopropyl)purine. The yield was 83.4%.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[BH4-].[Li+].C(O)(=O)C>O1CCCC1>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH2:3][OH:2])([O-:14])=[O:13]
Reactant: COC(=O)C(c1ccccc1Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(CO)c1ccccc1Cl
Yield: 45.6 %

Procedure:
A mixture solution of α-(5-chloro-2-nitrophenyl)-2-chlorophenyl acetic acid methyl ester (26.3 g) and lithium borohydride (2 g) in tetrahydrofuran (200 ml) was stirred for 4 hours at room temperature. This mixture solution was added to a 20% aqueous solution of acetic acid (50 ml), which was extracted with acetic acid ethyl ester. The extract solution was washed with water, dried over anhydrous sodium sulfate and, then, the solvent was distilled off. The residual oily compound was purified by means of a silica-gel column chromatography to give 11.0 g of an oily compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[C:25]3[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[C:35](OCC)=[O:36])[N:29]=2)[CH:19]=1)([CH3:17])[CH3:16]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:35]([C@@H:31]2[CH2:32][CH2:33][CH2:34][N:30]2[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[C:18]([CH:15]([CH3:16])[CH3:17])[NH:22][N:21]=3)[C:25]3[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1
Reactant: CNc1ccc(F)nc1
Reactant: CCOC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)N(C)c3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a solution of 6-fluoro-N-methyl-pyridin-3-amine (1.05 g, 8.34 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2M in THF) (4.15 mL, 8.34 mmol) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 30 min. followed by the dropwise addition of solution of ethyl (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate (0.8 g, 2.083 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with saturated solution of ammonium chloride (30 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with water (40 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to afford (2S)—N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-methylpyrrolidine-2-carboxamide (190 mg) as solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.19-1.30 (m, 6H), 1.80-2.30 (m, 6H), 2.58-2.68 (m, 2H), 2.70-2.88 (m, 2H), 2.91-3.00 (m, 1H), 3.28 (s, 3H), 3.61-3.78 (m, 1H), 3.79-3.90 (m, 1H), 4.40 (brs, 1H), 6.18 (s, 1H), 6.66 (s, 1H), 7.00 (brs, 1H), 8.01 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained by using the chiral (R) starting material.