Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:21]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:5]1[N:4]=[CH:3][C:2]([CH3:21])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Reactant: CB(O)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)cnc1Cl
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of methyl 5-bromo-2-chloronicotinate (1.05 g, 4.19 mmol), K3PO4 (2.95 g, 13.90 mmol), methylboronic acid (0.32 g, 5.26 mmol) and tricyclohexylphosphine (0.11 g, 0.39 mmol) in toluene/water (16 ml/0.8 ml) under nitrogen atmosphere was added Pd(OAc)2 (0.04 g, 0.18 mmol). The mixture was heated at 100° C. overnight under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated in vacuum. Ethyl acetate was added to the residue and this organic layer was washed with water, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to yield the desired product as a yellow oil. Yield=87%
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:1][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:11])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Dioxane (250 mL) is saturated with ammonia and cooled down to 0° C. A solution of benzyl-4-(chlorosulfonyl)piperidine-1-carboxylate (10 g; 31.5 mmol; 1 eq) in dioxane (25 mL) is added dropwise over 10 min. The reaction mixture is stirred at room temperature for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent and the resulting solution is concentrated in vacuo to give a colourless oil. The oil is taken up in MeOH and concentrated in vacuo to give a white foam which is crystallised from EtOAc and Et2O to afford 8.1 g (86%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.40-7.29 (m, 5H), 6.79 (s, 2H), 5.08 (s, 2H), 4.10 (br d, J=13.3 Hz, 2H), 3.05 (tt, J=11.9, 3.6 Hz, 1H), 2.95-2.75 (m, 2H), 2.0 (dd, J=1.8, 11.5 Hz, 2H), 1.46 (dq, J=12.5, 4.4 Hz, 2H). HPLC (max plot) 82%; Rt 3.55 min.
Reaction SMILES: C([O:4][C:5]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:6]=1[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])(=O)C.[OH-].[Na+].Cl>C(O)C.O>[Cl:25][C:24]1[C:5]([OH:4])=[C:6]([CH:21]=[C:22]([Cl:26])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]
Reactant: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
One hundred and eight grams of ethyl ester of N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine were dissolved in 1 L of anhydrous ethyl alcohol and placed in a 2 L round bottomed flask equipped with a magnetic stirring bar and placed in water bath at ambient temperature. Into this mixture a solution of 33.33 g of sodium hydroxide in 37.2 mL of water was added in a single portion and the mixture stirred at ambient temperature for 17 h (overnight). A volume of 68.6 mL of concentrated hydrochloric acid was added under stirring, which was maintained for an additional of 2 h. The precipitated sodium chloride was filtered off and the filtrate evaporated to dryness at 60° C. under 30 T of pressure. The residue of 88.9 g (98% yield) solidified after cooling in form of a colorless glassy product, which was well soluble in toluene or acetonitrile, thereby producing an OTA template (e.g., for use in MIP-OTA production). MS: M+354 and 356 1H NMR (CDCl3, ppm): 12.2 very broad s, 1H, 7.49 d, J 2.4, 1H, 7.35-7.28 m, 3H, 7.20 d, J 2.0, 1H, 7.18-7.16 m, 2H, 6.80 br d, J 6.4, 1H, 6.4 very broad s, 1H, 5.07 dd, 5.2 and 5.2, 1H, 3.34 dd, J 14.0 and 5.2, 1H, 3.27 dd, J 13.6 and 5.2, 1H.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To 4,6-dichloropyrimidine (500.0 mg, 3.36 mmol) and 3-amino-N-methylbenzamide (504 mg, 3.36 mmol) in 2-propanol (5.00 mL) at RT was added N,N-diisopropylethylamine (0.877 mL, 5.03 mmol). The resulting reaction mixture was heated at 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (25 g cartridge, 40 g column, 0 to 100% EtOAc-hexanes then 30-100% 90:10 CH2Cl2-MeOH in CH2Cl2). Fractions with product were combined and concentrated giving 3-(6-chloropyrimidin-4-ylamino)-N-methylbenzamide (815.2 mg).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.C[Si](C)(C)[O-].[K+]>C1COCC1.CCOC(C)=O>[C:18]([O:17][C:15]([N:5]([CH2:4][C:3]([OH:22])=[O:2])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CN(Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of methyl[(tert-butoxycarbonyl)(3,5-difluorobenzyl)amino]acetate from Step B (1.89 g, 5.99 mmol) in THF (60 mL) was added potassium trimethylsilanolate (1.00 g, 7.79 mmol). The reaction mixture was allowed to stir at ambient temperature for 72 hours. The bulk of the THF was then removed in vacuo, and the residue was diluted with water. The aqueous layer was extracted three times with diethyl ether, discarding ether extracts. The aqueous layer was placed under reduce pressure to remove residual ether and then was brought to an acidic pH with aqueous 1 M HCl to obtain an oil. The oil was dissolved in EtOAc and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound. MS: m/z=319 (M+18 (NH4+)).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21](B1OC(C)(C)C(C)(C)O1)([CH3:23])=[CH2:22]>O1CCOCC1.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>[C:21]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:23])=[CH2:22]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Product: C=C(C)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 28.5 %

Procedure:
1-Bromo-4,5-dimethoxy-2-nitro-benzene (6.55 g, 25.0 mmol), potassium carbonate (2 eq, 6.91 g) and tetrakis(triphenylphosphine)palladium(0) (0.125 eq, 3.61 g) were dissolved in dioxane. Isopropenylboronic acid pinacol ester (1 eq, 4.7 ml) was added and the mixture was heated to 100° C. overnight. Upon cooling the mixture was filtered through celite. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (gradient 9:1 to 1:1 Hexanes/Ethyl Acetate) to give 1-isopropenyl-4,5-dimethoxy-2-nitro-benzene (1.59 g, 28.5%) as a yellow oil.
Reaction SMILES: CC1(C)[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)C(=O)C2C=CC=CC=2O1.[ClH:28]>>[ClH:28].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N2C(=O)c3ccccc3OC2(C)C)nc1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(N)nc1
Temperature: 100 °C

Procedure:
A stirred mixture of ethyl 2-[6-(2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-3-yl)-pyridin-3-yl]-2-methylpropanoate (13.3 g, 36.1 mmol) in concentrated HCl (50 mL) was heated at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the residue washed exhaustively with chloroform to give the title compound as a solid (6.90 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:49][N:50]2[CH:54]=[N:53][CH:52]=[N:51]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:47])[CH:40](OS(C)(=O)=O)[CH3:41])[C:35]5=[O:48])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[N-:55]=[N+:56]=[N-:57].[Na+].O>CN(C=O)C>[N:55]([CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:48])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:49][N:50]6[CH:54]=[N:53][CH:52]=[N:51]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[CH:38]=[N:37]1)[CH3:47])=[N+:56]=[N-:57]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of [2S-[2α,4α(S*,S*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-3H-1,2,4-triazol-3-one (0.0039 mol) and NaN3 (0.005 mol) in DMF (50 ml) was stirred at 85° C. for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (41%) of [2S-[2α,4α(R*,S*)]]-2-(2-azido-1-methylpropyl)-4-[4-[4-[4-[[2-(2,4difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; (compound 19).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22]>CS(C)=O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:19][CH2:20][CH2:21][OH:22])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: NCCO
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: CS(C)=O
Product: OCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethanol (Example 49A) is prepared in analogy to Example 36A from 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]-pyrimidine (Example 6A) (200 mg, 0.7 mmol) and 2-aminoethanol (82 mg, 1.3 mmol) in DMSO (80° C., 4 h). Removal of the solvent results in a crude product which is precipitated from dichloromethane. The product is filtered off with suction and dried. 216 mg (99% of theory) of product are obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1.[CH3:15]S(C)=O.CN>CN(C)C(=O)C.O>[CH3:15][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(C)=O
Agent: CN
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1nc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-amino-6-methyl-3,5-dinitropyridine (24.9 g, 0.125 mole) and 175 ml dimethylsulfoxide in a 500 ml Parr bottle was added a solution of methylamine (20 g, 0.65 mole) in 75 ml N, N-dimethylacetamide. The reaction was shaken for 6 hours at ambient temperature and then heated 15 hours at 70° C. Upon cooling, the mixture was diluted with water, filtered, washed with methanol-water (1v/1v) and dried. 2-(methylamino)-6-methyl-3,5-dinitropyridine was obtained as a yellow solid (82% yield). Anal. Calcd. for C7H8N4O4 : C, 39.6; H, 3.8; N, 26.4. Found: C, 39.6; H, 3.9; N, 26.3.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25](C(O)=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:2]3[C:3](=[O:14])[C:4]4[C:9]([C:10](=[O:13])[C:11]=3[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
A mixture of 2,3-dichloro-1,4-naphthoquinone (5 gm), trans 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (6.06 gm) and silver nitrate (2.47 gm) is taken in acetonitrile (60 ml) and the mixture is heated to reflux, maintaining good stirring. Then a solution of ammonium persulphate (14.23 gm) in water (77 ml) is added through a dropping funnel over a period of 1-2 hrs. The mixture refluxed for 4 hrs. Then it is cooled in ice for about 1 hr after which it is filtered. The solid is extracted with hot methylene chloride (100 ml×3). The organic layer is dried over anhydrous sodium sulphate and concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the trans compound as yellow crystals (1.5 gm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:47]
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Product: COC1CCN(c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2C)CCC1N
Yield: 40 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave 325 (70.8 mg, 40% over two steps). 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.48 (s, 1H), 7.40 (s, 2H), 7.23 (d, J=9.0 Hz, 2H), 3.64 (s, 3H), 3.24 (s, 4H), 3.23-2.86 (m, 8H), 2.37 (s, 3H), 2.11-1.95 (m, 1H), 1.91-1.79 (m, 1H), 1.79-1.53 (m, 2H). LCMS (ES+) m/z 474 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=1.[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([OH:42])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:42][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=2)=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.30 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (3.10 g, yield 92%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(Cl)c2c(n1)CCC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(SC)nc2c1CCC2
Reaction time: 2 h

Procedure:
18.05 g (90 mmol) of 4-chloro-2-methylthio-6,7-dihydro-5H-cyclopentapyrimidine were dissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide (as 30% strength solution in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33]Br)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:29]=[CH:30][CH:31]=1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: Clc1cccc(CCBr)c1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(CCc3cccc(Cl)c3)c12
Yield: 73 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 2-(3-chlorophenyl)ethyl bromide as starting materials, the title compound was obtained in a yield of 73% as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11].[CH:19]([C:21]1[CH:22]=[C:23]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:24]=[CH:25][CH:26]=1)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.CO.C(O)(=O)C>[NH2:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:24]=[CH:25][CH:26]=2)=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product from step (v) (Ig) was dissolved in THF (30 mL) then acetic acid (0.239 g, 0.23 ml) and methyl 2-(3-formylphenyl)acetate (0.709 g) were added followed by MeOH (0.5 mL). The reaction mixture was stirred at rt for 72 h then sodium borohydride (0.1506 g) was added. After 2 h a further portion of sodium borohydride (0.0452 g) was added and the reaction mixture stirred for 16 h. A further portion of sodium borohydride (0.1506 g) was added and stirred for 2 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc. The solvents were evaporated and the product was purified by chromatography eluting with DCM:MeOH 97:3 to 80:20 to give the title compound 0.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].S(=O)(=O)(O)O.[CH:24]([C:26]([CH3:28])=O)=[CH2:25]>CN(C)C=O>[CH3:25][C:24]1[C:26]([CH3:28])=[N:18][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]=2[N:1]=1
Reactant: C=CC(C)=O
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: Cc1nc2ccc3c(c2nc1C)C(=O)c1ccccc1C3=O
Reaction time: 72 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after methyl vinyl ketone (0.36 g, 5 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 24, and the production rate is 25%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7](Cl)(=[O:25])[CH2:8][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][CH3:24]>N1C=CC=CC=1.CN(C=O)C>[C:7]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])(=[O:25])[CH2:8][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][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCC(O)CO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)NCC(O)CO
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of 3-amino-1,2-propanediol (32 g, 0.35 mol) in 100 mL of pyridine and 250 mL of DMF was added a solution of stearoyl chloride (100.0 g, 0.33 mol) in 150 mL of DMF. After stirring for 1 h, precipitation occurred and an additional 100 mL of DMF was added. After 2 h, the gelatinous mass was filtered, washed with water, and air dried. The solid was recrystallized successively from EtOH, isopropanol, and chloroform to give 74 g (63%) as a white powder (mp 111.5-113.5° C.). 1H-NMR: 0.86 (t, 3H, CH3), 1.25 (broad m, 28H, (CH2)14), 1.55 (m, 2H, NHCOCH2CH2), 2.20 (t, 2H NHCOCH2), 3.4 (m, 2H, CH2NH), 3.55 (d, 2H, CH2OH). 3.75 (m, 1H, CH), 5.8 (m, 1H, NH).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: C#CCCc1nc2ncccc2o1
Reactant: Ic1ccccn1
Product: C(#Cc1ccccn1)CCc1nc2ncccc2o1
Yield: 28.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (100 mg, 0.49 mmol) and 2-(but-3-ynyl)oxazolo[4,5-b]pyridine (100 mg, 0.58 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 35 mg (0.14 mmol, 29%) of 2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine as a brown semi-solid with a purity of 86%.