Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1
Reactant: OCCNCc1ccccn1
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Product: Cc1cccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C@H:3]1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.N>>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][C@H:7]1[CH2:6][O:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1
Reactant: Oc1cccnc1
Reactant: CN1C=CC=C[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1CCC[C@H]1COc1cccnc1
Yield: 31 %

Procedure:
(S)-1-Methyl-2-pyridinemethanol was reacted with triphenylphosphine, DEAD and 3-hydroxypyridine according to the procedure outlined in Example 1a The crude product was purified by flash chromatography (2×) using (10% MeOH/CHCl3) to remove the diethyl hydrazine dicarboxylate impurity and give a yellow oil in 31% yield. MS (DCI/NH3) m/e 193 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (t, J=1.5 Hz, 1H), 8.22 (t, J=3 Hz, 1H), 7.24-7.2 (m, 2H), 4.14-4.05 (dd, J=9, 6 Hz, 1H), 4.00-3.93 (dd, J=9, 6 Hz, 1H), 3.243.14 (m, 1H, 2.81-2.7 (m, 1H), 2.54 (s, 3H), 2.44-2.31 (m, 1H, 2.14-2.00 (m, 1H, 1.96-1.71 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:5]=[C:4]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[N:3]=1.ClC1N=C(OCCCCCCCCCCCC)N=C(OCCCCCCCCCCCC)N=1.[C:79]1([C:85]2[CH:91]=[C:90]([OH:92])[CH:89]=[C:88]([C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)[C:86]=2[OH:87])[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[OH:87][C:86]1[C:85]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:91][C:90]([O:92][C:2]2[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:5]=[C:4]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[N:3]=2)=[CH:89][C:88]=1[C:93]1[CH:94]=[CH:95][CH:96]=[CH:97][CH:98]=1
Reactant: Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CCCCCCCCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCCCCCCCC)n1
Agent: CCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCC)n1
Product: CCCCCCCCCCCCCCCCCCOc1nc(OCCCCCCCCCCCCCCCCCC)nc(Oc2cc(-c3ccccc3)c(O)c(-c3ccccc3)c2)n1

Procedure:
The preparation of the 2-chloro-4,6-distearoxy-s-triazine was carried out in the manner indicated for the 2-chlor-4,6-dilauroxy-s-triazine in Example I. Also the addition reaction with 2,6-diphenyl hydroquinone was also performed in the same manner as Examples I and II. The resulting reaction product had a melting point of 33° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:26]=[CH:25][C:18]3[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)#[N:36].O>O1CCOCC1.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(O)=O>[Cl:28][C:4]1[CH:3]=[C:2]([C:41]2[CH:42]=[CH:43][C:38]([CH2:37][C:35]#[N:36])=[CH:39][CH:40]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([C:15]1[CH:26]=[CH:25][C:18]2[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=2[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=CO
Solvent: C1COCCO1
Solvent: O
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F

Procedure:
A mixture of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 73 step 6, 40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (10 mg), Cs2CO3 (84 mg) and (4-cyanomethylphenyl)boronic acid (CAS Reg. No. 91983-26-5, 27 mg) in dioxane (1 ml) and water (0.1 ml) was heated at 80° C. for 20 min in a sealed tube. The mixture was acidified with HCOOH and then purified by prep. HPLC (C18-column, solvent gradient 30-98%) to give the title compound (27 mg). MS (m/e)=514.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].O1[CH2:18][CH:17]1[CH2:19][N:20]1C(=O)C2C(=CC=CC=2)C1=O.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]1[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:17]([CH2:19][NH2:20])[CH2:18]1
Reactant: CC(C)(CO)NCc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)COC(CN)CN1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
A mixture of Intermediate 2 (0.260 g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.205 g) was heated at 80° C. under nitrogen for 3 h. The mixture was treated with concentrated sulphuric acid (0.3 ml) then stirred at 150° C. for 18 h. The mixture was treated with water (25 ml) then washed with ethyl acetate (2×25 ml). The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound as a brown oil (0.225 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]=[O:11]
Reactant: OCc1c(Cl)ccc(F)c1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of (2,6-dichloro-3-fluorophenyl)methanol (9.0 g, 46 mmol) in dichloromethane (200 mL) was added molecular sieves (4A, powder, 40g) and pyridinium dichromate (PDC: 45g, 120 mmol). The mixture was stirred at room temperature for 2 h and diluted with Et2O (200 mL). The mixture was filtered through Celite and the solvent was removed in vacuum. The residue was washed with a small amount of dichloromethane to give a white solid (4.6 g, yield 52%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Li+].[CH3:21][Si:22]([CH3:46])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:23]1[CH2:28][CH:27]2[C:25]([CH2:29][OH:30])([O:26]2)[CH:24]1[CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]2[C:25]([OH:26])([CH2:29][OH:30])[CH:24]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:23]([Si:22]([CH3:46])([CH3:21])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28]2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Reactant: C[Si](C)(c1ccccc1)C1CC2OC2(CO)C1COCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(c1ccccc1)C1CC(n2cnc3c(OCc4ccccc4)nc(N)nc32)C(O)(CO)C1COCc1ccccc1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
To a 1-L 3-necked round bottomed flask equipped with a mechanical stirrer and a thermometer, was charged 2-amino-6-benzyloxypurine (24 g, 0.1 moles), lithium hydride (0.48 g, 0.06 moles) and DMF (40 mL). The mixture was heated at 60° C. for about 1 hour under an atmosphere of argon. 77 (60 g, 0.1 moles) in 20 mL DMF was added. The reaction temperature was heated at 105° C. for 5 hours, cooled to room temperature and diluted with EtOAc (600 mL). The organic layer was washed with brine (300 mL), 1 M citric acid (150 mL), and NaHCO3 solution (100 mL). The organic layer was concentrated in vacuo to furnish crude title product (60 g) as an oil. It was crystallized from EtOAc and hexane to give 23 g of the title compound as a crystalline solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)=O>C1COCC1>[C:7](/[CH:9]=[CH:18]/[C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)#[N:8]
Reactant: N#CC1(C=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0° C. was added slowly dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to ambient temperature. The solution was then re-cooled to 0° C. and a solution of 1-formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at ambient temperature. The mixture was then diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[OH:11])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Yield: 86.4 %

Procedure:
To a solution of 17 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 11.8 g of ethyl bromoacetate in 50 ml 2-butanone and the mixture is heated at 95°. To the mixture is added 12 g of potassium carbonate and 5.3 ml of dimethylformamide and the reaction mixture is refluxed at 100° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The aqueous phase is extracted two times with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from acetone and hexane gives 19.5 g of ethyl[ (6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate, mp 101°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH:36]([CH3:38])[CH3:37])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 2-bromopropane (103 μL). The reaction mixture is stirred at room temperature for 4 h. Additional 2-bromopropane (103 μL) is added and the mixture is heated to 60° C. for 20 h. The reaction mixture is allowed to cool to room temperature, is poured into water (25 mL), and then extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 173 mg (38%) of the title compound as a white solid.
Reaction SMILES: [Al].[CH2:2]=[CH2:3].[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:4]=[CH2:5].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: c1ccccc1
Agent: C=C
Agent: [Al]
Product: CCc1ccccc1
Reaction time: 0 h

Procedure:
In a glass tube reactor was placed aluminium-exchanged bentonite particles (20 ml) prepared as described in B above through which was passed a mixture of benzene and ethylene in a molar ratio of 8:1. The residence time was 10 seconds, the temperature of the reactor was 386° C. and the pressure was atmospheric. An ethylene conversion to ethyl benzene of 6.1% was obtained. The weight ratio of ethyl benzene to diethyl benzenes was about 32:1 The selectivity of both benzene and ethylene to ethyl benzene was approximately 95%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S-:14].[K+]>>[CH3:13][S:14][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: COC(=O)Cc1cccc(N)c1
Agent: [K+]
Product: CSc1cccc(CC(=O)O)c1
Yield: 17.2 %

Procedure:
Prepared in an essentially similar fashion from methyl 3-aminophenylacetate (111 g, 0.67 mole) and potassium methanethiolate (2.68 mole) to give 3-methylthiophenylacetic acid (21.0 g). Mp=76°-77° C., 1H NMR (DMSO-d6, 200 MHz) δ: 2.44 (s, 3H, SCH3), 3.53 (s, 2H, ARCH2), 7.02-7.28 (m, 4H, Ar), 12.30 (br s, 1H, CO2H). Mass spectrum (CI--CH4): 183 (M+1, 100%). (Lit. ref.: Plant Physiol 42(11) 2596-1600 (1967).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24]>CCOCC>[ClH:24].[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CCOCC
Product: O=c1[nH]c2ncccc2n1C1CCNCC1

Procedure:
A solution of tert-butyl 4-(2,3-dihydro-2-oxoimidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (3.39 g, 10.7 mmol) in 2N HCl in Et2O (20 ml) was stirred from 0° C. to RT over 2 h. The solvent was evaporated and the residue triturated with Et2O, filtered washed with Et2O and dried to give the bis-HCl Salt of the desired product (2.62 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=219; tR=0.36.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)[CH:5]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(-c3ccc(C(N)=O)cc3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 35.4 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-2-fluorobenzonitrile (400 mg, 1.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (397.0 mg, 2.41 mmol), Pd(PPh3)4 (185 mg, 0.16 mmol), and Na2CO3 (427 mg, 4.02 mmol) in 1,4-dioxane (60 mL) and water (20.0 mL) was stirred and heated at 110° C. for 1 hour under nitrogen. The mixture was cooled to room temperature and concentrated, and the resulting residue was portioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic layers were dried Na2CO3, filtered and concentrated to dryness. Purification by SiO2 chromatography using 4:1 petroleum ether/THF as eluent afforded the title compound (190 mg) as a white solid. LC-MS (ES) m/z=334 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C:20]#[CH:21].C(N(CC)CC)C.C(=O)(O)[O-]>CO.ClCCl.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.CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:23]([NH:22][CH2:19][C:20]#[C:21][C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:28]
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C#CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 67 %

Procedure:
A 100-mL three-necked flask was charged with 5-iodocytidine (2.66 g, 7.00 mmol, 1.00 equiv.), cuprous iodide (0.267 g, 1.40 mmol, 0.20 equiv.) and dry DMF (35 mL). After complete dissolution of the reaction mixture, propargyltrifluoroacetamide (3.17 g, 21.00 mmol, 3.00 equiv.), triethylamine (1.42 g, 14.00 mmol, 2.00 equiv.) and finally tetrakis(triphenylphosphine)palladium(0) (0.809 g, 0.70 mmol, 0.10 equiv.) were added to the reaction mixture under N2. The reaction was stirred at ambient temperature (around 19° C. to around 22° C.) under N2 for 18-24 h. The reaction was then diluted with 70 mL of 1:1 methanol-dichloromethane and the bicarbonate form of AGI X8 resin (12.00 g) was added. After stirring for about one h, the reaction mixture was filtered and the resin was washed with 1:1 methanol-dichloromethane. The combined filtrates were rapidly concentrated with a rotary evaporator. The residue was immediately purified by flash chromatography. Removal of solvent from the appropriate fractions afforded 1.84 g (67%) of 5-[3-(trifluoroacetamido)propynyl]cytidine as a light brown solid, which was confirmed by 1H-NMR.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C(Br)Br.[CH:16]12CC(CC1)C=[CH:17]2.C=CC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:10]1[C:9]2[NH:8][C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]=2[CH:16]=[CH:12][CH:11]=1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: C1=CC2CCC1C2
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: BrCBr
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To an ampoule, Cu(I)Br (1 mmol), 2,2′-bipyridine (1 mmol), norbornene methylene bromide (NBMBr)(1 mmol) and styrene (St) (100 mmol) were added in 10 mL toluene. The heterogeneous mixture was placed under vacuum and degassed via a freeze-pump-thaw cycle thrice. After degassing, the reaction mixture in ampoule was stirred at 100° C. for 12 hrs. The macromonomer containing polystyrene segments (NBMPStBr) was precipitated from methanol. Polymer was dissolved in THF and reprecipitated from methanol three times. Number average molecular weight of (NBMPStBr) is 160000 and PDI is 1.28(by GPC).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:26][CH2:27][C@H:28]([OH:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O:20]CC)=[O:19])=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+:39]>C(O)C>[OH:1][CH2:2][C@@H:3]([NH:26][CH2:27][C@H:28]([OH:37])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O-:20])=[O:19])=[O:13])=[CH:7][CH:6]=1.[Na+:39]
Reactant: CCOC(=O)c1cccc(NC(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1)Nc1cccc(C(=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-amino]carbonyl]amino]benzoate (148 mg) in ethanol (2.0 ml) was added 1N sodium hydroxide solution (292 μl) and the solution was refluxed for 4 hours. An additional portion of 1N sodium hydroxide solution (58.3 μl) was added and the whole was refluxed for 3 hours. After cooling to room temperature, the solvent was removed by evaporation to give sodium 3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]amino)-benzoate (158 mg) as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:52]=[CH:51][C:36]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][C:44]([OH:50])=[C:45]([O:48][CH3:49])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[C:35]([F:53])[CH:34]=1.[C:54]([O:58][C:59]([NH:61][CH2:62][CH2:63]O)=[O:60])([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[C:54]([O:58][C:59]([NH:61][CH2:62][CH2:63][O:50][C:44]1[CH:43]=[C:42]2[C:47]([C:38]([NH:37][C:36]3[CH:51]=[CH:52][C:33]([Cl:32])=[CH:34][C:35]=3[F:53])=[N:39][CH:40]=[N:41]2)=[CH:46][C:45]=1[O:48][CH3:49])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
Diethyl azodicarboxylate (0.94 ml, 6 mmol) was added dropwise to a mixture of triphenylphosphine (1.57 g, 6 mmol), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), (prepared as described for the starting material in Example 2), and N-(tert-butoxycarbonyl)ethanolamine (0.354 g, 2.2 mmol) in methylene chloride (20 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium hydrogen carbonate solution, water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The product was recrystallised from acetonitrile, collected by filtration, washed with ethyl acetate and dried to give 7-(2-[N-tert-butoxycarbonylamino]ethoxy)4-(4-chloro-2-fluoroanilino)6-methoxyquinazoline (235 mg, 25%).