Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCCCCCCCCN
Reactant: Clc1ccc2c(Cl)ncnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1ccc2c(NCCCCCCCCCNc3ncnc4cc(Cl)ccc34)ncnc2c1

Procedure:
A mixture of 1.99 g. of 4,7-dichloroquinazoline, 0.79 g. of 1,9-diaminononane, 2.5 g. of sodium carbonate and 25 ml. of isopropanol is stirred at room temperature for 2 hours. The reaction mixture is then diluted with 100 ml. of chloroform, filtered and concentrated in vacuo. The solid residue is crystallized from ethanol to obtain N,N'-bis(7-chloro-4-quinazolinyl)-1,9-nonanediamine, m.p. 190°-192°C. which is readily converted into dimethanesulfonate acid addition salt form which melts at 159°-162°C. on crystallization from ethanol/ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:33])[CH2:9][N:10]([CH3:32])[C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([S:29]([CH3:31])=[O:30])=[CH:18][N:19]2[C:22]2[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[CH:15][CH:14]=1)=[O:12].[F:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1B(O)O>C(O)(CC)(C)C.O>[NH2:7][C:8](=[O:33])[CH2:9][N:10]([CH3:32])[C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([S:29]([CH3:31])=[O:30])=[CH:18][N:19]2[C:22]2[N:27]=[CH:26][C:25]([C:36]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:35]=3[F:34])=[CH:24][N:23]=2)=[CH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CN(CC(N)=O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: COc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (110 mg, 0.79 mmol) and (Ataphos)2PdCl2 (19 mg, 0.026 mmol) were added under an inert atmosphere to a solution of 279a) (120 mg, 0.26 mmol) and 2-fluoro-5-methoxyphenylboronic acid (91 mg, 0.53 mmol) in tert-amylalcohol (4.0 mL) and water (0.4 mL). The reaction mixture was stirred for 4 h at 95° C., then cooled to ambient temperature and filtered over celite. The filtrate was evaporated to dryness and the residue was purified by flash column chromatography [silica; methanol/dichloromethane=4:96]. White solid. Yield: 35 mg (27% of theory)
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC>>[OH:4][CH2:3][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[NH:1]1
Reactant: CC(N)(CO)CO
Reactant: CCOC(=O)OCC
Product: CC1(CO)COC(=O)N1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A flask with 2-amino-2-methyl-1,3-propanediol (3.32 g, 31.6 mmol) and diethyl carbonate (10 ml, 83 mmol) was fitted with a Dean-Stark trap and condenser and the suspension heated to 140° C. until 5 ml of liquid had been collected in the trap (˜8 hr). The solution was cooled to RT slowly, and the resulting white, block crystals were filtered off (2.79 g, 21.3 mmol, 67%). The supernatant was purified by flash chromatography to afford the title compound as a white solid (1.04 g, 7.94 mmol, 25%). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.2 (br s, 1H), 3.56 (m, 2H), 4.06 (d, J=8.8 Hz, 1H), 4.33 (d, J=8.8 Hz, 1H), 5.2-5.3 (br s, 1H). ESI/APCI calculated for C5H9NO3: 131.06. Found: 132 (MH+).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]([CH3:27])[CH2:24][O:25][CH3:26])[CH:21]=1)[C:15]([O:17]C)=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C1COCC1>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]([CH3:27])[CH2:24][O:25][CH3:26])[CH:21]=1)[C:15]([OH:17])=[O:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.8 %

Procedure:
Lithium hydroxide monohydrate (1.30 g, 0.03 mol) in water (40 mL) was added to a solution of methyl 3-(benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]benzoate (4.11 g, 0.012 mol) in THF (80 mL) and the reaction mixture stirred for 20 hours at ambient temperature. The THF was removed in vacuo. The aqueous residue was adjusted to pH3 with 1M hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered, and evaporated to give the desired compound (3.79 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:12][C:11]3[CH:14]=[CH:15][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-phenoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH:21]=O)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>C(O)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH2:21][NH:44][C:41]4[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=4)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccncc2N2CCN(c3ccc4ncsc4c3)C2=O)n[nH]1
Yield: 3.2 %

Procedure:
3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.308 mmol) was reacted with NaBH(OAc)3 (131 mg, 0.616 mmol), 5-methyl-1H-pyrazol-3-ylamine (40 mg, 0.370 mmol) and acetic acid (10 mL) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3), followed by preparative HPLC afforded 4 mg of the product (7.7% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH:28]=[O:29])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=2)=[C:21]([CH:28]=[O:29])[CH:20]=1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2C=O)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate, prepared as in Example 1, (1.5 g, 5.0 mmol), (4-chloro-2-formylphenyl)boronic acid (1.0 g, 5.5 mmol), Pd(dppf)Cl2 (408 mg, 0.5 mmol), and K2CO3 (1.4 g, 10.0 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[N:23]=1)([OH:21])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=1)(=[O:12])=[O:11])[CH3:9])(=O)C.C(N(CC)CC)C.O>CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:8]([CH2:7][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[N:23]=2)([OH:21])[CH2:5][OH:4])[CH3:9])(=[O:11])=[O:12])=[CH:14][C:15]=1[CH3:20]
Reactant: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1ccc(Cl)c(C)c1)c1cccc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(S(=O)(=O)N(C)CC(O)(CO)c2cccc(Cl)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A mixture of 1.5 g of 1-acetoxy-3-[N-(4-chloro-3-methylbenzenesulfonyl)-N-methylamino]-2-(6-chloropyridin-2-yl)-2-hydroxypropane, 1 ml of triethylamine, 1 ml of water and 2 ml of methanol was stirred at room temperature for 4 hours. The reaction mixture was left to stand overnight, and the deposited crystals were filtered out and washed with water-containing methanol to obtain 1.17 g of the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[N:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23](O)[N:22]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:23]1[N:22]=[N:21][C:26]([OH:27])=[CH:25][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Oc1ccc(O)nn1
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(O)nn1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 5, from (1R,2R)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, Example 69, Step 4) and pyridazine-3,6-diol to afford the desired product as a white gum. MS (EI): 385.3 (M−H)−.
Reaction SMILES: C(O)C.[Na].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[C:18](=O)([O:22]CC)[O:19][CH2:20][CH3:21]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH2:20]([O:19][C:18](=[O:22])[CH:15]([C:16]#[N:17])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)[CH3:21]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1
Temperature: 85 °C
Yield: 440.1 %

Procedure:
Ethanol (13 mL, 225) was added to a suspension of sodium (3.6 g, 157 mmol) in toluene (125 mL) with stirring at 85° C. The reaction mixture turned to a slightly turbid white mixture. 3,4-Dimethoxy phenylacetonitrile (26.6 g, 150 mmol) was added to the reaction mixture at one time and the mixture was stirred at 85° C. for 30 minutes. Diethyl carbonate (20 mL, 16.5 mmol) was added to the mixture. The mixture was heated at 110° C. for 5 hrs. The solvent was evaporated and ice (250 g) was added. The mixture was neutralized to pH=7 by addition of acetic acid (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded cyano-(3,4-dimethoxy-phenyl)-acetic acid ethyl ester (18.1 g, 49% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10](=O)[C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[C:3]1=O.C1C=CC=CC=1>Cl.C(O)C>[CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[CH2:3]1
Reactant: Cc1cc(C)c2c(c1C)C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1cc(C)c2c(c1C)CC(C)(C)C2
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 22.32 g of the 2,2,4,6,7-pentamethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 15.67 g of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]#[CH:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][CH3:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C2=O
Yield: 42.4 %

Procedure:
A mixture of 7-chloro-5-ethynyl-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 0.1 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.015 g, 43%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.23 (t, 3H), 2.69 (q, 2H), 4.20 (s, 2H), 4.81 (s, 2H), 7.09 (s, 1H), 7.24 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H). GC-MS: m/z 353 (M)+, 334 (M−29)+, 284 (M−50)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:56]>O1CCCC1.CC(C)=O>[ClH:56].[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCNC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 65 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.610 g, 21.49 mmol) in tetrahydrofuran (200 mL) was added rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (6.039 g, 32.25 mmol), triphenylphosphine (11.273 g, 42.98 mmol), and diethyl azodicarboxylate (7.485 g, 6.77 mL, 42.98 mmol). The reaction mixture was stirred at room temperature for 6 days and then concentrated to afford an orange-brown oil. Acetone (100 mL) and 5 N hydrochloric acid (50 mL) were added and the solution was heated at 40° C. for 18 h and then cooled to room temperature. The resulting yellow precipitate was filtered, and the filter cake was washed with diethyl ether and dried to afford rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride as an off-white solid (5.153 g, 65%). RP-HPLC Rt 4.079 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 331 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:38][CH2:39][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:41][CH2:42]1)=[O:36]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(=O)c5ccco5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(2-furoyl)piperazine hydrochloride (109 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with ethyl acetate-diisopropylether to give N-[4-[1-(2-furoyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 44) (112 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C1(OC(=O)OC2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(=O)=O.C[N:44](C=O)C>>[CH3:1][C:2]1[C:3]([NH2:44])=[N:4][C:5](=[O:17])[NH:6][CH:16]=1
Reactant: CN(C)C=O
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Product: Cc1c[nH]c(=O)nc1N
Reaction time: 1 h

Procedure:
5-Methyluridine (ribosylthymine, commercially available through Yamasa, Choshi, Japan) (72.0 g, 0.279M), diphenylcarbonate (90.0 g, 0.420M) and sodium bicarbonate (2.0 g, 0.024M) were added to DMF (300 mL). The mixture was heated to reflux, with stirring, allowing the evolved carbon dioxide gas to be released in a controlled manner. After 1 hour, the slightly darkened solution was concentrated under reduced pressure. The resulting syrup was poured into diethylether (2.5L), with stirring. The product formed a gum. The ether was decanted and the residue was dissolved in a minimum amount of methanol (ca. 400 mL). The solution was poured into fresh ether (2.5L) to yield a stiff gum. The ether was decanted and the gum was dried in a vacuum oven (60° C. at 1 mm Hg for 24 h) to give a solid which was crushed to a light tan powder (57 g, 85% crude yield). The material was used as is for further reactions.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][CH:5]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Cl)(C)C>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:5][N:6]=1
Reactant: CNOC
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: -30 °C
Yield: 88.4 %

Procedure:
6-Chloro-nicotinic acid methyl ester (6 g, 34.97 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (5.12 g, 52.46 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (52 mL, 2M in THF, 105 mmol) is slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride is added with stirring. The reaction is diluted with diethyl ether and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The 6-chloro-N-methoxy-N-methyl-nicotinamide (6.20 g, 30.90 mmol) is obtained in pure form after flash column chromatography. 1H NMR (CDCL3, 400 MHz): δ 8.78 (d, J=1.5 Hz, 1H), 8.02 (dd, J=1.5 and 8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 3.57 (s, 3H), 3.40 (s, 3H); MS m/z 218, 201, 188, 171.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([O:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])[CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:41][C:42](OC(C)=O)=[O:43].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CCOC(C)=O.O>[C:42]([O:38][CH2:37][C:36]([O:35][C@@H:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Cl:1])[CH2:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:40])[CH3:39])(=[O:43])[CH3:41]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(C)(C)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)O[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1c(C)cc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At 23° C., a flask containing (S)-2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-1-ol (1.31 g, 2.21 mmol) was charged with Ac2O (5.00 mL) immediately followed by pyridine (5.00 mL). 4-(N,N-dimethylamino)-pyridine (20 mg, 0.164 mmol) was added. After 1.5 h, the reaction was poured onto 50 mL of crushed ice and H2O. A white precipitate developed. EtOAc (50 mL) was added after several hours had passed. Solid NaHCO3 was added portionwise (bubbling) until the aq. layer had a pH of 9. The slurry was extracted with EtOAc (2×25 mL). The combined organic layers were washed with 1.0 M aq. CuSO4 monohydrate (3×25 mL) and H2O (25 mL). The final organic phase was dried over Na2SO4, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.52-7.41 (m, 9H), 7.26-7.16 (m, 9H), 5.99 (dd, J=8.2, 4.7 Hz, 1H), 4.02 (app. s, 2H), 3.55 (dd, J=8.6, 8.4 Hz, 1H), 3.12 (dd, J=9.8 Hz, 4.7 Hz, 1H), 2.52 (s, 3H), 1.86 (s, 3H), 1.32 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][N:15]([CH3:21])[C:10]1[N:9]=[C:8]([C:4]2[S:3][C:2]([NH:1][C:22](=[O:24])[CH3:23])=[N:6][C:5]=2[CH3:7])[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2sc(N)nc2C)nc(N(C)CCN(C)C)n1
Product: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1

Procedure:
N-[4-(2-Amino-4-methyl-thiazol-5-yl)-6-methyl-pyrimidin-2-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine (0.020 g, 0.065 mmol) in acetic anhydride (1 ml) is heated at 60° C. for 2 hours. When cool, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate (30 ml) and water (30 ml). The organic extract is removed, dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18]O)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18][Cl:22])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cn2cccc(OCc3ccccc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: ClCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
A mixture of 8-benzyloxy-2-hydroxymethylimidazo[1,2-a]pyridine (2 g) and phosphorylchloride (10 ml) was heated on a steam bath for 1 hr. Excess phosphoryl chloride was distilled off in vacuo, the solid residue triturated with acetonitrile and the mixture filtered to give the title product as the hydrochloride salt.