Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:3][OH:4].B#B.[BH4-].[Na+].[OH-:17].[Na+].O.OO.[Cl-].[Na+]>C1COCC1.O.COCCOCCOC>[F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:17])[CH2:3][OH:4]
Reactant: C=CCCCCCCC(F)CO
Reactant: [OH-]
Agent: B#B
Agent: OO
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOCCOC
Product: OCCCCCCCCC(F)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In 6 ml of dried THF, 585 mg (3.36 mmol) of the substrate (-)-2-fluoro-9-decen-1-ol was dissolved, and the solution was kept ice-cooled. Into the resulting solution, diborane prepared by dropwise adding 0.78 g (5.5 mmol) of a boron trifluoride ether complex to a 6 ml dried diglyme solution of 189 mg (5 mmol) of sodium borohydride was blown (for about 10 minutes). With further stirring at room temperature, the reaction mixture turned into a gel with progress of the reaction. After it was left to stand for 30 minutes, 0.5 ml of distilled water was dropwise added, followed by addition of 3 ml of an aqueous 3N sodium hydroxide solution and 3 ml of 30% hydrogen peroxide water. The reaction mixture was stirred for 30 minutes, sodium chloride was added, and the organic layer was taken out. Extraction from the aqueous layer was carried out twice using 2 ml of ethyl ether, and the extract was dried with anhydrous magnesium sulfate together with the organic layer previously taken out, followed by micro-distillation to give 493 mg (2.56 mmol) of 2-fluoro-1,10-decanediol. (0.7 torr, 170° to 190° C., 76% yield)
Reaction SMILES: [CH:1]1[C:6](Br)=[CH:5][C:4]2[O:8][C:9]([F:12])([F:11])[O:10][C:3]=2[CH:2]=1.[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C(OCC)C>[F:11][C:9]1([F:12])[O:10][C:3]2[CH:2]=[CH:1][C:6]([B:24]([OH:29])[OH:25])=[CH:5][C:4]=2[O:8]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-2,2-difluorobenzodioxole (1.18 g, 4.97 mmol) in anhydrous diethyl ether (8 mL) at −78° C. was treated with 2.5M n-BuLi in hexane (2.4 mL, 5.97 mmol), stirred for 1 hour, and treated with triisopropyl borate (1.5 mL, 6.46 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The reaction was quenched with saturated NH4Cl/10% HCl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was used directly without further purification. 1H NMR (CD3OD) δ 7.26-7.11 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:27][O:26][C:8]1[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:28])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:17]=[C:32]([CH2:31][O:30][CH3:29])[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (for a preparation see Intermediate 63, 500 mg) was dissolved in DCM (20 ml) and the reaction mixture was cooled to 0° C. 2-Methoxyacetyl chloride (1.1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 30 min. The mixture was hydrolysed using a solution of sodium hydrogen carbonate and extracted with DCM. The organic was dried over Na2SO4, filtered and concentrated to dryness. The obtained residue was dissolved in acetic acid (5 ml) and the reaction mixture was heated to 130° C. for 16 h. The reaction mixture was treated with sodium hydroxide (1M) and extracted with DCM. The organic was dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, eluting with DCM/methanol (95:5). The resulting compound was recrystallised from acetonitrile and dried under vacuum to give 4-(8-methoxy-2-(methoxymethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (50 mg) as a cream-coloured powder.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[C:29]([C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-cyanopyridin-3-yl)boronic acid to afford a light green solid. UPLC-MS (condition 1) tR=2.46 min, m/z=484.1 [M+H]+, m/z=482.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.65 (m, 1H) 1.78-1.93 (m, 1H) 2.17-2.29 (m, 1H) 2.96 (dd, J=10.64, 6.97 Hz, 1H) 3.11-3.23 (m, 2H) 3.24-3.40 (m, 3H in HDO) 4.62 (br. s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=8.56 Hz, 2H) 8.02-8.17 (m, 3H) 8.79 (d, J=1.22 Hz, 1H) 8.84 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.C([O:13][CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:6][N:7]([CH3:10])[CH:8]=[C:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:14]=[O:13]
Reactant: CN(C)C=O
Reactant: CCOC(COc1ccc(OC)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(OC(C=O)=CN(C)C)cc1
Temperature: 50 °C
Yield: 43.7 %

Procedure:
Phosphorus oxychloride (18.4 g, 120 mmol) was added to dimethylformamide (8.8 g, 120 mmol), maintaining the temperature below 25° C. by an external ice-bath. Upon completion of the addition the reaction mixture was heated to 50° C. for 45 minutes and then cooled to room temperature. Chloroform (35 ml) was added and the resulting solution was brought to reflux. 4-Methoxyphenoxyacetaldehyde diethylacetal (9.61 g, 40.0 mmol) was added in portions. After heating for 3 hours at reflux the solution was cooled to room temperature and poured carefully onto a solution of potassium carbonate (115 g) in water (100 ml). The mixture was cooled in an ice-bath to around room temperature and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding a brown oil. The residue was heated with ethyl acetate:heptane and decanted, leaving a brown oil. The solvent was removed in vacuo to give a brown oil, which was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (3.87 g, 44% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][CH:6]([C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH:6]([C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reaction time: 0.75 h
Yield: 52.3 %

Procedure:
0.19 g (0.560 mmol) of methyl 4-[α-(2-dimethylaminoethoxy)benzyl]cinnamate was dissolved in 4 ml of methanol and 13 mg (0.056 mmol) of nickel chloride hexahydrate was then added. Forty-two mg (1.12 mmol) of sodium boronhydride was further added thereto under ice-cooling in divided portions for 1 hour and stirred for further 45 minutes. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in chloroform and washed with water and brine. After the organic phase was dried (MgSO4), the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 (v/v)) to obtain 0.10 g (0.293 mmol) of methyl 3-{4-[α-(2-dimethylaminoethoxy)benzyl]phenyl}propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]1)[CH2:7][CH2:6]2>CO.CCO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)N(CCn1cc([N+](=O)[O-])cn1)CC2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: COc1cc2c(cc1OC)N(CCn1cc(N)cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,6-dimethoxy-1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline (1.53 g, 4.81 mmol) in MeOH (50 mL), PtO2 (200 mg, 0.88 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 1 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with MeOH. The filtrate was concentrated under reduced pressure to obtain 1-(2-(5,6-dimethoxyindolin-1-yl)ethyl)-1H-pyrazol-4-amine as a brown oil, which was used in the next step without further purification. LC-MS conditions B: tR=0.38 min, [M+H]+=289.18.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[C:22]([OH:23])=[CH:21][C:20]([N:24]2[C:29](=[O:30])[C:28]([F:31])=[C:27]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[N:26]=[C:25]2[O:39][CH3:40])=[C:19]([F:41])[CH:18]=1.[C:42](O)(=[O:47])[CH2:43][CH2:44][C:45]#[CH:46].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[C:42]([O:23][C:22]1[CH:21]=[C:20]([N:24]2[C:29](=[O:30])[C:28]([F:31])=[C:27]([C:32]([F:37])([F:38])[C:33]([F:34])([F:36])[F:35])[N:26]=[C:25]2[O:39][CH3:40])[C:19]([F:41])=[CH:18][C:17]=1[Cl:16])(=[O:47])[CH2:43][CH2:44][C:45]#[CH:46]
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C#CCCC(=O)Oc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.74 g of N,N'-dicyclohexylcarbodiimide is added while stirring at room temperature to a solution of 1.60 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 0.30 g of 4-pentynoic acid and 0.05 g of 4-pyrrolidino-pyridine in 50 ml of methylene chloride and the mixture is stirred at room temperature for 5 hours. Insoluble constituents are subsequently filtered off under suction and the filtrate is evaporated to dryness. The residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent. The product is recrystallized from n-hexane/diethyl ether. There is obtained 2-chloro-4-fluoro-5-[5-fluoro-2 -methoxy-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-phenyl 4-pentynoate, m.p. 107°-109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH3:23])=[C:13](Cl)[N:12]=2)=[CH:6][N:5]=1)[CH3:2].[CH2:25]([O:27]C1C=CC(NC2N=C3C(N(CCCC)C=N3)=C(Cl)N=2)=CN=1)C.C[O-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([O:27][CH3:25])[N:12]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCCCn1cnc2c(Cl)nc(Nc3ccc(OCC)nc3)nc21
Reactant: CCCCn1cnc2nc(Nc3ccc(OCC)nc3)nc(Cl)c21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1cnc2c(OC)nc(Nc3ccc(OCC)nc3)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of a 4:1 mixture of 2-[(2-Ethoxypyrid-5-yl)amino]-6-chloro-9-butyl-9H-purine and 2-[(2-Ethoxypyrid-5-yl)amino]-6-chloro-7-butyl-7H-purine (214 mg; 0.62 mmol) in methanol (15 mL) is treated with sodium methoxide (4 mL of a 25% wt. solution in methanol) and the mixture is stirred at room temperature for three days. The reaction mixture is concentrated in vacuo , the residue is treated with water (30 mL), neutralized with acetic acid, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water (2×30 mL) and brine (1×30 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residue is purified by preparative thin layer chromatography on silica gel by elution with ethyl acetate-hexane (3:1) to afford 2-[(2-Ethoxypyrid-5-yl)amino]-6-methoxy-9-butyl-9H-purine (94 mg), m.p. 174-176° C. (compound 1).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]1([C:7]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH2:9][Cl:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)c1cccc(C(=CCO)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(=CCCl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a three-necked flask with thermometer and presion-compensated addition funnel, a solution of 14.0 g of methyl 2-[3-(1-phenyl-3-hydroxy-1-propenyl)phenyl]propionate in 20 mL dry methylene chloride was placed and cooled to 0° C. A solution of 3.77 mL of thionyl chloride and 5 mL methylene chloride was added along 30 min, keeping the temperature at 5-10° C. After standing for 1 hour, solvents were removed under vacuum. The resulting residue (13,8 g) was identified as the title compound and it was used in subsequent reaction without any further purification. IR Spectrum (film), cm-1 : 3080-2910, 1740, 1430, 1240, 1200, 1160, 1065, 690.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20](I)=[CH:19][C:18]=3[Cl:25])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:14][CH3:15])[N:11]=[CH:10][CH:9]=3.[NH:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.C1COCC1.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].C(Cl)Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:30]4[NH:29][N:28]=[CH:32][CH:31]=4)=[CH:19][C:18]=3[Cl:25])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:14][CH3:15])[N:11]=[CH:10][CH:9]=3
Reactant: OB(O)c1ccn[nH]1
Reactant: COc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccc(Br)cc3c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-N-(2,6-dichloro-4-iodophenyl)-1-methoxybenzo[c]-2,6-naphthyridin-5-amine (500 mg, 0.87 mmol) in DMF (20 mL), was added 1H-pyrazol-5-ylboronic acid (107 mg, 0.96 mmol), PdCl2(dppf)-CH2Cl2 adduct (142 mg, 0.17 mmol) and sodium carbonate (0.87 mL, 1.74 mmol, 2M in water). The solution was heated to 100° C. in the microwave in a sealed tube for 45 min. The reaction was diluted with ethyl acetate:THF (2:1) and extracted with water followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with THF in hexanes(10-50%) to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=2[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:27]1([C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=[C:31]2[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=23)=[O:39])[CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=3[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (125 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 mg, 0.67 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (257 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].[Na+].O.O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:13][C:12]2[CH:14]=[C:15]([C:17]3[S:21][CH:20]=[N:19][CH:18]=3)[CH:16]=[C:10]([CH3:9])[CH:11]=2)=[N:7][CH:6]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(Nc2ncc(Cl)cn2)cc(-c2cncs2)c1
Temperature: 110 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
A flask containing 2,5-dichloropyrimidine (2 g, 13.42 mmol), 3-methyl-5-(1,3-thiazol-5-yl)aniline (2.55 g, 13.42 mmol), PdOAc2 (0.603 g, 2.68 mmol), Xantphos (2.330 g, 4.03 mmol), and cesium carbonate (8.75 g, 26.8 mmol) was degassed for 5 min. Dioxane (89 ml) was added and argon was bubbled through the mixture for 15 min. The temperature was increased to 110° C. and the reaction was stirred 14 h at that temperature. The cooled reaction was diluted with brine and water and extracted three times with CH2Cl2. The organic layer was concentrated under reduced pressure and purified by flash chromatography (0-70% EtOAc:Hexanes) to give 5-chloro-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (2.95 g, 73%) as a white solid. MS ESI: [M+H]+ m/z 303. 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.37 (s, 2H), 8.08 (s, 1H), 7.71 (s, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 2.40 (s, 3H). rhSYK activity=++.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[H-].[Na+]>CN(C=O)C>[CH:14]1([CH2:13][N:6]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (15.0 g, 98.0 mmol), (bromo-methyl)cyclohexane (17.6 g, 100 mmol) and K2CO3 (41.4 g, 300 mmol) in dry DMF (150 mL) was stirred at 50° C. overnight, then cooled to rt and filtered. To the filtrate was added NaH (12.0 g, 60%, 300 mmol) slowly. Then the mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with EA twice. The combined organic phases were washed with water (3×) and brine (2×), dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE=1/20) to give compound 1a (19.9 g, 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: COc1ccc(COC[C@H](C)NC(C)C)cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(OC)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-2-(4-methoxy-benzyloxy)-1-methyl-ethyl]-amine as described for example 1.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].OCC(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C)=O>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Reactant: CCCCCCOC(=O)CO
Product: CCCCCCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with HO—CH2COOnHex.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[CH:3]=[C:2]([NH:15][CH2:14][CH2:13][NH2:16])[N:7]2[N:8]=1
Reactant: Cc1cc(Cl)n2nc(C)cc2n1
Reactant: NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NCCN)n2nc(C)cc2n1
Yield: 94.5 %

Procedure:
To a stirred solution of 7-chloro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (3.0 g, 16.5 mmol) in ethanol (60 mL) was added ethylene diamine (4 mL, 60 mmol). After refluxing 18 hours the reaction was cooled, poured into saturated aqueous sodium bicarbonate, and then washed with ethyl acetate. The aqueous layer was then extracted with 3:7 isopropyl alcohol/chloroform, the combined extracts were dried (Na2SO4) and then concentrated under reduced pressure to give the title compound as an amorphous brown solid (3.2 g, 94%): +APcI MS (M+1)+ 206; 1H NMR (methanol-d4) δ: 6.05 (s, 1H), 6.00 (s, 1H), 3.45 (m, 2H), 2.91 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:21]([O:22]C(=O)C3C=CC=CC=3)[C@H:11]2[O:12]C(=O)C2C=CC=CC=2)[N:6]=1)=O.[NH3:43]>CO>[C:35]([O:34][CH2:33][C@H:31]1[O:32][C@@H:10]([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:43])=[O:2])=[N:6]2)[C@H:11]([OH:12])[C@@H:21]1[OH:22])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: N
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Solvent: CO
Product: NC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O)[C@H]2O)n1
Reaction time: 4 h

Procedure:
A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester and methanol saturated at 0° with anhydrous ammonia was stirred at 0° for 4 hr. The resulting solution was evaporated to dryness under reduced pressure and the product was crystallized from aqueous ethanol to give 1-(5-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with mp 182°-184°.