Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.CCO>[OH:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C=Cc2ncccc2OCc2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
Methyl 4-[2-(3-benzyloxy-2-pyridyl)ethenyl]benzoate (2.0 g, 5.8 nnol) was partially dissolved in EtOAc (20 ml) and EtOH (10 ml). The reaction vessel was flushed with argon, palladium-on-carbon (0.2 g, 10%) was added and the reaction was flushed with argon followed by hydrogen. The reaction was stirred at ambient temperature for 18 hours, filtered and evaporated to give methyl 4-[2-(3-hydroxy-2-pyridyl)ethyl]benzoate as a pale orange solid (1.3 g, 90%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:4][CH:3]=1.[CH2:19]([C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:18][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[N:29][C:21]=3[CH2:19][CH3:20])=[C:10]([NH:14][CH:15]3[CH2:16][CH2:17]3)[N:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CCc1ncccc1C(=O)Cl
Reactant: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
6-(4-Chlorophenyl)-N-cyclopropylpyrimidine-4,5-diamine (1.00 g, 3.83 mmol) was initially charged in a mixture of DCM (3.20 ml) and pyridine (0.93 ml) and cooled to 0° C. Solid 2-ethylnicotinoyl chloride (780 mg, 4.60 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another hour. After addition of semisaturated NaHCO3 solution, the organic phase was separated off and concentrated under reduced pressure.
Reaction SMILES: O[C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)CC1CCc2sc3ncnc(O)c3c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC1CCc2sc3ncnc(Cl)c3c2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (10.10 g, 34.55 mmol, 1.00 equiv) in POCl3 (80 g, 521.75 mmol, 15.00 equiv) was stirred for 1 h at 90° C. in an oil bath under nitrogen. The resulting mixture was concentrated under vacuum. The residue was added dropwise to a cooled saturated aqueous sodium bicarbonate and extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (6.67 g, 62%) as a yellow solid. MS: m/z 311, 313 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C@H:24]([CH2:26][CH3:27])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@@H:22]([C@@H:24]([CH3:25])[CH2:26][CH3:27])[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:28]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of Example 28A (12.1 g) in methanol (20 mL) was added L-isoleucine tert-butyl ester hydrochloride (13.0 g, 58 mmol), sodium cyanoborohydride (7.3 g, 116 mmol), and acetic acid (2 mL). The resulting solution was stirred for 3 hrs at 25° C. and the methanol removed under vacuum, dichloromethane (500 mL) added, and the solution washed with aqueous NaHCO3 (2×300 mL). The organic layer was concentrated to give 12.9 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22])=[CH2:18].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]1([CH2:1][N:8]2[CH2:12][CH2:18][CH:17]([C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1C#N
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (16.62 g,70.0 mmol) in dichloromethane (15 mL) are added dropwise, over a 45-minute period, to a solution of 2-ethenylbenzonitrile (6.00 g, 46.0 retool) and trifluoroacetic acid (0.57 g, 5.0 retool) in dichloromethane (55 mL). The resulting solution was stirred at room temperature for an additional 10 to15 minutes, and then heated with saturated aqueous sodium bicarbonate solution (ca 10-15 mL). The organic layer was decanted, washed with water,and dried over anhydrous magnesium sulfate. Filtration and concentration ofthe solution provided an orange oil which was chromatographed (silica-gel, hexanes-ethyl acetate 5:1) to afford the title compound (6.95 g, 58%) as apale yellow oil. 1H-NMR (300 MHz, CDCl3): δ=1.80-1.92 (1H,m), 2.43-2.55 (1H, m), 2.63-2.75 (2H, m), 2.88-2.96 (2H, m), 3.71 (2H, AB quartet, JAB =13.0 Hz), 3.78-3.86 (1H, m), 7.25-7.41 (6H, m), 7.53-7.66 (3H, m).
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH:4]=[O:5].N1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].COC(C)(C)C>C1COCC1>[OH:10][CH:9]1[O:11][C@H:13]2[CH2:14][C:3]([CH:4]=[O:5])=[CH:2][C@H:12]2[CH2:8]1
Reactant: O=CCCC=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The solution of succinaldehyde 8 (57.5 g, 668 mmol) in THF (334 ml) obtained in Example 1B was stirred at r.t. (S)-Proline (1.54 g, 13.4 mmol, 0.02 eq.) was added as a solid and the reaction stirred at r.t. for 20 h. THF (334 ml) was added, followed by [Bn2NH2][OCOCF3] (4.16 g, 13.4 mmol, 0.02 eq.). The reaction was stirred for a further 14 h. The volume of the reaction mixture was reduced by half under reduced pressure. tert-Butyl methyl ether (TBME) (334 ml) was added and the mixture stirred for 20 min before filtration of the resulting solids (through a sinter funnel). The solids were washed with TBME (3×50 ml) and the filtrate was concentrated under reduced pressure. (Note: During concentration of the filtrate, for the purposes of this example it is important not to heat the water bath of the rotary evaporator). The material was purified by column chromatography (˜350 g silica), eluting with petrol/EtOAc (6:4 to 4:6), to give the lactol 7 (as an approximately 2:1 mixture of diastereoisomers, 16%), as a brown oil. This material is of sufficient purity to take forward for the next transformation (see Example 3C). While it does contain some unreacted succinaldehyde and oligomeric side-products these do not interfere with the subsequent transformation and purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:23](=[O:24])[C@H:22]([NH:21][C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[C:13]([Cl:12])[C:14]=2[CH3:29])[C@H:26]([OH:28])[CH3:27])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 92.7 %

Procedure:
4-Chloro-N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide was prepared using 4-chlorobenzoic hydrazide (4.42 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.02 mmol, 1.0 equiv.) according to the procedure as described for intermediate 5a. The crude off-white solid was recrystallized using hot methylene chloride to provide the desired product as a white solid (1.57 g, 93% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.94 (br. s, 1H), 9.48 (br. s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.55 (m, 3H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d., J=7.1 Hz, 1H), 4.25 (m, 1H), 4.13 (m, 1H), 2.35 (s, 3H), 1.37 (d, J=6.4 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18Cl2N4O3 [M]+421.28, found 421.3; TLC Rf=0.32, 100% EtOAc, vanillin stain.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>C(OCC)(=O)C>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:21][O:22][C:2]1[C:3]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN1CCCC(O)(c2nccnc2Cl)C1
Agent: O=C(O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1nccnc1C1=CCCN(C)C1

Procedure:
A mixture of 0.32 g of (1) (0.0014 mol) and 10 ml of thionyl chloride was heated to reflux for 1.5 h. The excess thionyl chloride was evaporated, the residue treated with ice-water and made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was dissolved in 5 ml of methanol and added to 25 ml of methanol that had reacted with 0.35 g of Na (0.015 mol). The reaction was heated to reflux for 1.5 h. The solvent was evaporated, the residue was treated with ice-water and the mixture extracted 3× with 25 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark liquid, 0.15 g. The liquid was dissolved in ethyl acetate and treated with oxalic acid to give 0.05 g of (2) after recrystallization from ethyl acetate, mp 150°-151° C. NMR ppm (D2O) 2.6-2.9 (2H, m), 3.1 (3H, s), 3.3 (1H, m), 3.65 (1H, m), 4.0 (3H, s), 4.05 (1H, dd), 4.35 (1H, d), 6.95 (1H, bs), 8.07 (1H, d), 8.1 (1H, d). Anal. C11H15N3O-C2H2O4 requires C: 52.88; H: 5.80; N: 14.23%. Found C: 52.66; H: 5.94; N: 14.04%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(OC(C)C)(C)C>CN(C)C=O>[I:15][C:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:11][NH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
2.1 g (11 mmol) of 3-(3-nitrophenyl)-1H-pyrazole were dissolved in 25 ml of dry dimethylformamide and 2.63 g (11.7 mmol) of N-iodosuccinimide were added. After 5 hours under stirring at 70° C. the most part of solvent was removed in vacuo and an aqueous solution of sodium thiosulphate was added and the product extracted several times with dichloromethane. The organic phase was then dried over sodium sulphate and evaporated to give, after trituration with diisopropylether, 2.6 g (74%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5](C#N)[CH:6]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])C.O.OS(O)(=O)=O>C(O)(=O)C>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[CH2:5][C:4]([OH:24])=[O:3])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccc(Br)cc1)c1ccc(F)cc1F
Temperature: 120 °C

Procedure:
To a solution of 3-(4-bromo-phenyl)-2-cyano-3-(2,4-difluoro-phenyl)-propionic acid ethyl ester (2.4 g) in acetic acid (11 mL) was added water (6 mL) and concentrated H2SO4 (6.83 mL) at 0° C. The reaction mixture was heated to 120° C. overnight, then cooled and poured on ice and extracted with ethyl acetate (3×100 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude reaction product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:0 to 1:1) to provide the title compound as an off-white solid. MS (ESI−): m/z=339.0 ([M−H]−).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[F-:20].[K+].C(O)CO>C(O)COCCO>[F:20][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5]
Reactant: [F-]
Reactant: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Solvent: OCCOCCO
Solvent: OCCO
Product: CC(O)(CCF)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A mixture of 27.9 g. of 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, 8.7 g. of KF, 10 ml. of ethylene glycol and 5 ml. of diethylene glycol is heated to 140° - 150° for 8 hours. It is cooled and worked up in the customary manner and gives 1-fluoro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 90° - 92°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1F)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(Cl)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.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>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a flask charged with Pd(PPh3)4 (46 mg, 0.040 mmol) under nitrogen was added a solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL). The system was purged with nitrogen gas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 h. Then the reaction mixture was cooled to rt, 3N HCl was added and the mixture was stirred for additional 4 h. Water was added and the product was then extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 120 mg (90%) of the title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 4-(4-aminophenylsulfonyl)butanoate (Intermediate 48, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(C)=O>CN(C=O)C>[NH:38]([C:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)CC(=O)NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)Nc3ccccc3)cc2)nc1N(C)CC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
A solution of methyl {2-(4-aminobenzyl)-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)-amino]pyrimidin-5-yl}acetate (0.050 g, 0.11 mmol) in DMF (2 mL) was treated with phenyl isocyanate (0.022 mL, 0.20 mmol). After stirring at room temperature for 18 hours, EtOAc was added and the organic phase was washed with 8% NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product thus obtained was triturated with CH2Cl2 and diisopropyl ether to give methyl {2-{4-[(anilinocarbonyl)amino]benzyl}-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)amino]pyrimidin-5-yl}acetate (0.055 g, 87% yield) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(O)cc(OCc2ccccc2)c1
Yield: 29.4 %

Procedure:
To a mixture of 3,5-dihydroxybenzonitrile (1.08 g, 8 mmol) and K2CO3 (1.104 g, 8 mmol) in CH3CN (50 mL), benzyl bromide (1.438 g, 8 mmol) was added. The mixture was heated to reflux for 2 hours. Solvent was evaporated under vacuum. The residue was treated with EtOAc (200 mL) and 1M HCl (200 mL). The organic layer was washed, dried, and evaporated in vacuo. The residue was chromatographed (gradient, Hexanes-CH2Cl2-MeOH) to give 3-benzyloxy-5-hydroxybenzonitrile (529 mg, 29%), 3,5-dibenzyloxybenzonitryl (784 mg, 31%) and 256 mg (23.7 mg, 24%) of the starting material. The product 3-benzyloxy-5-hydroxybenzonitrile had: MP 144-145° C.; 1H NMR δ 9.15 (s, 1H, OH), 7.47 (d, 2H, J=7.0 Hz, 2′ and 6′), 7.40 (ddd, 2H, J=7.0, 7.0, 2.0 Hz, 3′ and 5′), 7.34 (dd, 1H, J=7.7 and 2.1 Hz, 4′), 6.89 (dd, 1H, J=1.5 Hz, 4), 6.78 (d, 2H, J=1.8 Hz), 5.16 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[S:22][C:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][C:25]=1[CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C=O>[CH2:27]([C:23]1[S:22][C:21]([CH3:20])=[C:25]([CH3:26])[C:24]=1[C:5]([C:4]1[CH:8]=[C:9]([CH3:13])[C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8) in anhydrous methylene chloride (200 mL) at room temperature under nitrogen was added oxalyl chloride (9.6 mL, 110 mmol) and N,N-dimethylformamide (5 drops). After two hours the solvent was removed. The resulting residue was dissolved in anhydrous methylene chloride (200 mL), and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen. The resulting mixture was, cooled to −78° C., and tin(IV) chloride (10.8 mL, 92.8 mmol) was added quickly. The −78° C. bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then poured onto ice water (1 L), and the resulting mixture was extracted once with diethyl ether (700 mL), and a second time with diethyl ether (400 mL). The combined diethyl ether extracts were washed with ice water(500 mL), dilute sodium bicarbonate (500 mL), water (500 mL), brine (mL), and then dried (Na2SO4). Concentration under reduced pressure gave the title compound as a yellow oil (25.2 g, 82%): NMR (DMSO-d6): δ 7.40 (s, 2H), 7.24-7.15 (m, 3H), 7.06 (d, 2H), 3.83 (s, 2H), 3.70 (s, 3H), 2.28 (s, 3H), 2.26 (s, 6H), 1.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[S:20][C:19]([CH2:21][CH2:22][OH:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:15][C:16]1[S:20][C:19]([CH2:21][CH2:22][O:23][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:18][CH:17]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCc1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1c2cc(OCCc3ccc(Cl)s3)nc(=O)n2CC1(C)C
Temperature: 130 °C
Reaction time: 5 h

Procedure:
To a solution of 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (90.0 mg, 0.421 mmol) and 2-(5-chlorothiophen-2-yl)ethanol (68.5 mg, 0.421 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added Cs2CO3 (274 mg, 0.842 mmol). The reaction mixture was stirred at 130° C. for 5 h, quenched with water. Purification via MDAP afforded the title product as a white solid.