Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C@@H:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5])[CH3:2].[ClH:20]>O1CCOCC1>[ClH:20].[NH:10]1[CH2:11][CH2:12][C@@H:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9]1
Reactant: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CO[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3R)-3-(ethoxycarbonylmethoxy)pyrrolidine-1-carboxylate (4.0 g, 15.42 mmol) was dissolved in 4N HCl in 1,4-dioxane (50 mL), stirred at ambient temperature for 3 hrs, evaporated, co-evaporated with 1,4-dioxane (3×50 mL) and dried under high vacuum to give (R)-ethyl 2-(pyrrolidin-3-yloxy)acetate hydrochloride as an orange oil that solidified on standing. (3.2 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.I[CH3:23]>>[CH3:23][O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Reactant: CI
Product: COC(=O)CCc1ccc(C#Cc2cccc(OC)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (41 mg, 0.20 mol) and iodomethane (60 μL, 0.97 mmol) according to the general procedure IV to give 38 mg (69%) of a pure yellow oil. Rf=0.37 (EtOAc:PE, 1:3); 1H NMR (CDCl3): δ 7.45 (dt, J=8.3 Hz, 2.0 Hz, 2H), 7.27-7.23 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 7.12 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.05 (dd, J=2.8 Hz, 1.5 Hz, 1H), 6.88 (ddd, J=8.4 Hz, 2.4 Hz, 1.0 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.1, 159.3, 140.9, 131.8, 129.4, 128.3, 124.3, 124.1, 121.1, 116.3, 114.8, 89.1, 89.0, 55.3, 51.6, 35.4, 30.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH:26]=[O:27].O>CC(=O)CC>[CH2:24]([O:25][C:26](=[O:27])[NH:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=[CH:13][N:12]=1)[CH3:23]
Reactant: O=COCCCl
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a mixture of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (1.0 g, 4.9 mmol) and potassium carbonate (4.0 g, 29 mmol) in 2-butanone (10 ml), chloroethylformate (0.50 ml, 4.9 mmol) was added and the mixture was refluxed for 3 hours at 80° C. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.60 g of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:28][C:21]2[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[Cl:19])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1c(F)cc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(F)cc(F)cc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 99.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.22 g of 2-chloro-4,6-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.34 g of 4-(2-butynyloxy)-6-(2-chloro-4,6-difluorophenoxy)pyrimidine (the present compound (47)).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[CH2:36][NH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][CH:40]=[C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3cccc(-c4ccccc4)c3)c2CC1)C(F)(F)F
Yield: 79.3 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.3 g, 0.706 mmol) with 3-phenyl-benzylamine (0.388 g, 2.117 mmol) using palladium(II) acetate (32 mg, 0.141 mmol), tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.070 mmol), BINAP (264 mg, 0.424 mmol) and cesium carbonate (460 mg, 1.412 mmol) in toluene (12 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1) to give 7-chloro-6-(3-phenyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (0.257 g, 79%). MS (ES+) m/z: 459 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22](C(OCC)=O)[CH2:21][C:19]=2[N:20]=1.ClC1N=[C:39](N2CCOCC2)[C:40]2CN(C(C)C)C[C:41]=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([CH:40]([CH3:41])[CH3:39])[CH2:21][C:19]=2[N:20]=1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOCC3)c2C1

Procedure:
Method as (S)-ethyl 2-(2-fluoro-4-(3-(2-fluoroethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (Example 168) using 4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 34).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[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]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[CH3:28])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccncc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 70 mg, 0.151 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49.7 mg, 0.227 mmol), Pd(Ph3P)4 (17.48 mg, 0.015 mmol) and K3PO4 (96 mg, 0.454 mmol) were added to a vial, flushed with argon, treated with toluene (1 mL), and stirred at 110° C. for 2 h followed by 4 h at 130° C. Dioxane (1 mL) was added and the RM was stirred for an additional 3 days at 130° C. The RM was diluted with dioxane and filtered on a pad of Hyflo®, followed by Si-Thiol scavenger treatment. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min). The purified product was lyophilized in water/min. vol. MeCN to afford the title product as an off-white powder. UPLC-MS (Condition 3), tR=0.97 min, m/z=475.1/477.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.62-1.89 (m, 2H) 2.02/2.14 (s, 3H) 2.70-3.35 (m, 4H) 4.09-4.24 (m, 1H) 4.79-4.96 (m, 1H) 7.27-7.42 (m, J=8.66 Hz, 3H) 7.86 (d, J=7.91 Hz, 2H) 7.91-8.00 (m, 1H) 8.41-8.61 (m, 2H) 8.77 (br. s, 1H) 10.11-10.19 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH:23][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12]
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1nccc(I)c1C(=O)NNc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 4-iodo-2-methoxynicotinic acid (1.00 g) obtained in Step C of Example 6 in DMA (10 mL) were added (2,6-difluorophenyl)hydrazine hydrochloride (647 mg), EDCI hydrochloride (824 mg) and HOBt (581 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (1.32 g).
Reaction SMILES: [CH3:1][C:2]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[N:3]O.Cl>C(O)C.O=[Pt]=O>[CH3:1][CH:2]([NH2:3])[C:5]12[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: CC(=NO)C12CC3CC(CC(C3)C1)C2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CC(N)C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h
Yield: 54 %

Procedure:
1-Adamantyl methyl ketoxime, 2.0 g, was dissolved in 200 ml of ethanol and mixed with 1.0 ml of conc. hydrochloric acid. This solution was poured into a Parr hydrogenation flask, and 1.0 g of PtO2 was added. Hydrogenation under 35 psia (240 KPa) and at room temperature proceeded slowly. After two days of hydrogenation, the catalyst was removed. The filtrate was distilled to dryness and 100 ml water was added to the residue. The insoluble material was removed by filtration and the aqueous layer was basified with sodium hydroxide. The aqueous layer was extracted with ether and the ether layer was separated. The ether layer was then dried over potassium hydroxide pellets and then magnesium sulfate. The resultant ether solution was distilled to remove the solvent providing 1.0 g rimantadine free base (54% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34]N)=[CH:33][C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCO2
Yield: 16 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 16% yield. MS: M=425.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23](B(O)O)=[C:22]([CH3:30])[CH:21]=1)[CH3:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH3:30])[C:23]([C:2]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[C:24]([CH3:26])[CH:25]=1)[CH3:15]
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Reactant: CCOCCOc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cc(C(=O)OC)ccc2OC)c(C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
A mixture of methyl 3-bromo-4-methoxybenzoate (0.90 g, 3.67 mmol), [4-(2-ethoxyethoxy)-2,6-dimethylphenyl]boronic acid (0.87 g, 3.67 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.15 mmol), 2-(dicyclohexylphosphino)biphenyl (79 mg, 0.22 mmol), tripotassium phosphate (1.56 g, 7.34 mmol) and toluene (20 mL) was stirred under a nitrogen atmosphere at 90° C. for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (0.71 g, yield 54%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred suspension of 3-chloro-2-hydroxy-5-nitropyridine (10 g, 57.3 mmol) and K2CO3 (15.84 g, 115 mmol) in DMF (100 mL) under Ar was added MeI (5.37 mL, 86 mmol) at 0° C. The reaction mixture was stirred for 1 hr at rt, concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, and evaporated to afford the title product (10.38 g, 55.0 mmol, 96% yield) as a yellow solid. tR: 2.90 min (HPLC 1).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+].Cl>O.CO>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a mixture of 4-[(2-phenyl-4-thiazolyl)methoxy]benzaldehyde (6.35 g), tetrahydrofuran (30 ml) and methanol (20 mL) was added sodium borohydride (0.45 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Dilute hydrochloric acid and water were added to acidify the reaction mixture. The precipitated solid was collected by filtration, and dried with air to give crystals (5.76 g, 90%) of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 145-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[N:19]3[N:20]=[CH:21][N:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(Br)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-bromophenol (1.73 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred for 1 hour 30 minutes at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 4:6 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.28 g, (m.p. 121°-124° C.).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[CH:18]=2)[CH2:12]1.O=S(Cl)[Cl:37]>C(Cl)(Cl)Cl>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[C:18]=2[Cl:37])[CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: O=C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Cl)c(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 4 (40 mg, 0.1 mmol) in CHCl3 (2 mL) was treated with SOCl2 (200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MS to give the title compound 7. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.73 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 5.32-5.42 (m, 2H), 3.43 (s, 3H), 3.33-3.40 (m, 2H), 3.17 (m, 2H), 2.87 (s, 1H), 2.08 (m, 1H), 1.70 (m, 1H), 1.32-1.43 (m, 2H). MS (ES) [m+H] calc'd for C18H21ClN5O2, 374.1; found, 374.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH3:22]>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([C:18]1[C:17]([CH3:20])=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:13][CH3:12])[CH:19]=1)=[O:6]
Reactant: COc1ccc(C)cc1OC
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC

Procedure:
Reaction of 9.5 g (0.05 mol) of 2,6-dichlorobenzoic acid and 7.5 g (0.05 mol) of 1,2-dimethoxy-4-methylbenzene, in a manner analogous to that of Example 3(a), yields (2,6-dichlorophenyl)-(3,4-dimethoxy-6-methyl-phenyl)-methanone as colourless crystals, m.p. 101°-103° C.
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11](COCC[Si](C)(C)C)[C:12]([C:16]([C:18]4[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])=[N:13]3)=[C:9]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.Cl>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12]([C:16]([C:18]4[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])=[N:13]3)=[C:9]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)c2nc3nc(N4CCOCC4)nc(N4CCOCC4)c3n2COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C(=O)c2nc3nc(N4CCOCC4)nc(N4CCOCC4)c3[nH]2)c1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
[2,6-Di-morpholin-4-yl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purin-8-yl]-m-tolyl-methanone (185 mg, 0.34 mmol) was dissolved in ethanol (10 ml) and 2N HCl (4 mL). The resulting suspension was heated to reflux for 4 hrs then cooled to room temperature. After neutralization with 2N NaOH, ethanol was removed under reduced pressure and ethyl acetate (100 mL) was added. The ethyl acetate layer was washed with water (3×50 mL), dried over MgSO4 then evaporated to dryness. The crude product was purified by silcagel column chromatography. Elution with a gradient of 25% ethyl aceate/hexane to ethyl acetate to 10% methanol/ethyl aceate produced (2,6-di-morpholin-4-yl-7H-purin-8-yl)-m-tolyl-methanone (80 mg, 57% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CN(C)C(=O)c1ccccc1NCCCCl
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2ccccc2C(=O)N(C)C)CC1
Yield: 40.6 %

Procedure:
A mixture of 1-(5-chloro-2-methoxyphenyl)piperazine (365 mg, 1.6 mmol), prepared as in Example 2, 2-(3-chloropropyl)amino-N,N-dimethylbenzamide (385 mg of crude mixture), prepared as in Example 28, potassium carbonate (550 mg, 3.98 mmol) and sodium iodide (240 mg, 1.6 mmol) in 20 mL of acetonitrile was heated at reflux for 18 hours. The mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-{3-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl ]propylamino}-N,N-dimethylbenzamide (280 mg, 0.65 mmol).
Reaction SMILES: [C:1](OC(C1CCCN1C(=O)C(NC(=O)C1C=CC(N)=C(Cl)C=1)C)=O)(C)([CH3:3])[CH3:2].[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35]CC2C=CC=CC=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[CH2:35]([O:34][CH:32]1[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(C)COC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 38 %

Procedure:
Prepared from 97a and syn-(2-isobutoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 93 mg (38% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 0.74-0.76 (t, 0.6H), 0.80-1.00 (m, 5.4H), 1.40-1.50 (m, 3H), 1.90-2.22 (m, 3H), 2.33-2.45 (m, H), 2.80-2.90 (m, H), 3.32-3.38 (m, H), 3.55-3.80 (m, 3H), 4.38 (br, H), 4.50-4.60 (m, H), 4.70-4.80 (m, H), 4.90-5.00 (m, H), 5.42-5.45 (m, H), 6.74-6.76 (d, H), 6.86-6.88 (d, H), 7.31-7.33 (d, H), 7.51-7.53 (m, H), 7.74-7.75 (d, H); retention time on analytical HPLC: 9.63 & 9.80 min; LC-MS: m/z=495 (M+H+).