Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: CNCCc1ccccn1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCc1ccccn1)C(=O)c1ccc(N)cc1
Reaction time: 3 h

Procedure:
p-Aminobenzoic acid (1 g, 0.0073 mol) was dissolved in DMF (15 ml), methyl-(2-pyridin-2-yl-ethyl)amine (5 ml, 5 eq) was added, followed by DIPEA (1.91 ml, 1.5 eq), and HATU (4.1 g, 1.5 eq). After stirring for 3 h, TLC showed complete consumption of starting material. Water was added and the mixture extracted with CH2Cl2, the organic extracts were washed with NaHCO3 (sat), NH4Cl (sat), dried (MgSO4), concentrated under reduced pressure, and purified by flash chromatography (SiO2, EtOAc-EtOAc/MeOH 95:5) to give 1.43 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzamide. Step B: Preparation 1B (100 mg, 0.371 mmol) and the product of step A (142 mg, 1.5 eq) were dissolved in DMF (2 ml), potassium tert-butoxide (91 mg, 2.2 eq) was added and the mixture allowed to stir overnight. Water was added and the mixture extracted with EtOAc, dried (MgSO4), concentrated under reduced pressure, and the residue purified by flash chromatography (SiO2, hexane-EtOAc) to give 56 mg of the title compound. LCMS: MH+=489.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:11]4([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (915 mg, 1.59 mmol) in DCM (15 mL) was added TFA (3 mL) and the resulting mixture allowed to stir at r.t. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-(2-Ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (775 mg, quant.). LCMS (method H): RT 1.95 min, [M+H]+ 477.3
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:18]([OH:20])=O.CN(C(ON1[N:37]=[N:36][C:31]2C=[CH:33][CH:34]=[CH:35][C:30]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NN1CCCCC1.O>CN(C=O)C>[N:36]1([NH:37][C:18]([C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:15])([F:17])[F:16])=[CH:11][CH:12]=3)[NH:6][C:2]=2[CH3:1])=[O:20])[CH2:33][CH2:34][CH2:35][CH2:30][CH2:31]1
Reactant: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)NN1CCCCC1
Reaction time: 0.02 h
Yield: 89.5 %

Procedure:
To 1 g of 5-methyl-2-(4-trifluoromethoxy-phenyl)-1H-imidazole-4-carboxylic acid in 50 ml of DMF was added 1.12 g of TBTU and 3.0 ml of Hünigs' base and the reaction mixture was stirred for 1 minute. Then 0.38 ml of 1-aminopiperidine (as R1R2NH) was added and the reaction mixture was stirred for 4.5 hour at room temperature. After such time the reaction mixture was poured onto 250 ml of water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were then washed with water (2×100 ml) and brine (50 ml), dried (MgSO4) and after filtration, concentrated in vacuo to yield an oil which crystallized during concentration. The residue (about 30 ml volume) was then treated with heptane (200 ml), the solid was filtered and dried to yield 1.15 g of the title compound, MS (ISP) 369.0 (M+H)+.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(C(C)C)CC)(C)C.C(#N)C>ClCCl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@@:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH2:52][CH2:53][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][N:17]4[CH:21]=[CH:20][CH:19]=[N:18]4)[C:13]4[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:42]1)=[O:40]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1cccn1
Agent: I
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCn3cccn3)CC2)(c2ccccc2)C1
Yield: 50.3 %

Procedure:
Reflux a mixture of 2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazole dihydroiodide (0.48 g, 0.84 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.40 g, 0.84 mmol, example 47.2), diisopropylethylamine (0.44 g, 3.37 mmol) and acetonitrile (20 mL) for 12 hours. Cool and dilute with dichloromethane (150 mL), wash the organic phase with water (2×10 mL), dry (MgSO4) the organic phase, filter and evaporate. Purify the residue by silica gel chromatography eluting with 0.5% methanol in dichloromethane to afford 0.29 g of the title compound, Rf=0.18 (silica gel, 0.5% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1nncs1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1nncs1)C(=O)OCC

Procedure:
2-amino-1,3,4-thiadiazole (5 g) was reacted with diethyl ethoxymethylenemalonate (26.5 g) in ethanol (20 ml) at the reflux temperature for 23 hours. After cooling the precipitate was filtered and purified with hexane to give diethyl N-(1,3,4-thiadiazol-2-yl)-aminomethylenemalonate, m.p. 107°-111° C. (10 g), which was treated with polyphosphoric acid (57.6 g; 30.8 g of 99% H3PO4 and 26.8 g of P2O5) and POCl3 (25 g) under stirring at 120° C. for 30 minutes.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=O)=[N:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C.O.C(OCC)(=O)C>[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH2:1])=[N:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reaction time: 0.42 h

Procedure:
Methyl(triphenyl)phosphonium bromide (774 mg, 2.166 mmol) was suspended in anhydrous diethyl ether (5 mL) and potassium tert-butoxide (2.311 mmol, 1.78 M in THF, 1.29 mL) was added at 0° C. dropwise. The suspension was left 25 min at the same temperature (solution became orange-brown). A solution of diethyl ether (1 ml) and ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (500 mg, 1.444 mmol) was added dropwise at 0° C. The mixture was left at the same temperature for 30 min, allowed to reach room temperature, left under stirring additional 90 min, diluted with water and taken up in ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 10% EtOAc in hexanes) to afford ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]-cyclohexanecarboxylate (62%) as an oil. MS ESI calc'd. for C14H18BrNO2S for [M+H]+ 344, 346. found 344, 346. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 5.60 (s, 1H), 5.19 (s, 1H), 4.04 (q, J=7.0, 2H), 2.62-2.78 (m, 1H), 2.20-2.30 (m, 1H), 1.90-2.02 (m, 3H), 1.50-1.60 (m, 2H), 1.10-1.30 (m, 2H), 1.17 (t, J=7.0, 3H), 0.72-0.82 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is added dropwise to 100 g of 37% hydrochloric acid and 200 ml of water in the course of 1 hour, in a manner ensuring that the temperature does not exceed 80° C. The mixture is then cooled to 20°-25° C., and 69.5 g (1.0 mol) of hydroxylamine hydrochloride is added. There is subsequently added during one hour, with water-bath cooling, about 92 g (2.3 mols) of solid sodium hydroxide until the pH value of the aqueous solution is 10-11. The organic phase which precipitates is separated, and washed free from salt with water. Distillation yields 245 g (0.92 mole) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-oxime; b.p. 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([C:17]([OH:19])=O)[NH:15][CH:16]=2)=[CH:4][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([C@H:48]([NH2:51])[CH2:49][OH:50])[CH:42]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:47][C:45]1[CH:44]=[C:43]([CH:48]([NH:51][C:17]([C:14]2[NH:15][CH:16]=[C:12]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][CH:9]([CH3:10])[CH3:11])[CH:4]=3)[CH:13]=2)=[O:19])[CH2:49][OH:50])[CH:42]=[CH:41][CH:46]=1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Reactant: CC(C)Nc1cc(-c2c[nH]c(C(=O)O)c2)c(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(-c2c[nH]c(C(=O)NC(CO)c3cccc(Cl)c3)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a suspension of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid (1.93 g, 6.9 mmol, 1.0 equivalent) in DMF (5.0 mL) was added EDCI (1.45 g, 7.6 mmol, 1.1 equivalents), HOBt (0.94 g, 6.9 mmol, 1.0 equivalent) and (S)-3-chlorophenylglycynol (1.58 g, 7.6 mmol, 1.1 equivalents). Diisopropylethylamine (2.7 mL) was then added and the resulting mixture was stirred a room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the crude was adsorbed on silica gel. Purification was effected by flash chromatography on silica, eluting with mixtures of hexanes/acetone (from 80:20 to 60:40) to afford the title compound as white solid (1.9 g, 64%). Rt(min) 4.981 s. FIA MS: 433.1 ES+; 431.2 ES−. 1HNMR (CD3OD) δ 1.31 (d, 6H), 3.85 (m, 3H), 5.15 (t, 1H), 7.01 (s, 1H), 7.25 (m, 3H), 7.4 (s, 1H), 7.45 (s, 1H), 7.7 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClC[CH2:34][S:35](C)(=[O:37])=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:34][S:35]([CH2:18][CH2:17][N:16]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)(=[O:37])=[O:36]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CS(=O)(=O)CCCl
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CS(=O)(=O)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-2-methanesulfonyl-ethane (Prepared as described in Chem. Ber. 1894, 27, 3048) and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Cl.[CH2:2]([CH:10]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[NH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([N:20]([CH2:23][CH3:24])CC)C.CN([CH:28]=[O:29])C>>[C:23]([C:24]1[CH:12]=[CH:10][C:2]([C:28]([NH:11][CH:10]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[O:29])=[CH:3][CH:4]=1)#[N:20]
Reactant: CCN(CC)CC
Reactant: CC(C)(C(=O)O)C(N)CCc1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Product: CC(C)(C(=O)O)C(CCc1ccccc1)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
β-Phenethyl-α,α-dimethyl-β-alanine hydrochloride (600 mg, 2.33 mmol) was dissolved in DMF (100 ml). To the resulting solution, triethylamine (Et3N) (0.98 ml, 6.99 mmol) and 4-cyanobenzoyl-OSu (630 mg, 2.56 mmol) were added under cooling with ice and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in a 2N aqueous solution of sodium carbonate and washed with hexane. The aqueous layer was adjusted to pH 3 with citric acid and extracted with ethyl acetate. The collected ethyl acetate layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained crude N-4-cyanobenzoyl-β-phenethyl-α,α-dimethyl-β-alanine (200 mg, 0.57 mmol) was derivatized to N-4-cyanobenzoyl-β-phenethyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (212 mg, 65.8%) by the same procedure as in Example 2-(6-2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 145 °C
Yield: 69.5 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (300 mg, 1.84 mmol) in THF (4 mL) were added tert-butyl piperazine-1-carboxylate (376 mg, 2.02 mmol) and DIPEA (0.48 mL, 2.76 mmol), and the reaction was heated at 145° C. under microwave irradiation for 30 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound (400 mg, 70%) as an off-white solid. LCMS (ES+) 313.0 (M+H)+, RT 3.63 minutes (Method 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
To a solution of methyl 2,2′-dimethyl-1,1′-biphenyl-4-carboxylate of Step A (24.7 g, 103 mmol) in 5:1 tetrahydrofuran:methanol (200 mL) was added 1 M aqueous sodium hydroxide (108 mL, 108 mmol). The reaction mixture heated at reflux for 1 hour, cooled and then concentrated in vacuo to remove organic solvents. The resulting aqueous solution was cooled to 0° C. and 2 M aqueous hydrochloric acid (60 mL, 120 mmol) added slowly followed by water (60 mL) to facilitate stirring of the precipitated product. The suspension was stirred for 1 h at 0° C. then filtered to afford the title compound (22.6 g) as a white solid, m. p. 140-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].C1C2C(=CC=CC=2)C=C1.CCOCC.ClCC[N:33]1CC[O:36][CH2:35][CH2:34]1.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[N:33]1[CH2:34][CH2:35][O:36][CH:12]([CH2:13][CH3:14])[CH2:11]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: [Li]CCCC
Reactant: ClCCN1CCOCC1
Reactant: CC1=Cc2ccccc2C1
Agent: C1=Cc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC1CN(C2=C(C)Cc3ccccc32)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
16.4 g (0.126 mol) 2-methylindene was taken up in 150 ml dry ether under nitrogen atmosphere. A solution of 9.6 g (0.15 mol) n-butyl lithium (2.1 M) in hexane (62 ml) was added dropwise to the indene/ether solution. The resulting solution was stirred at room temperature for 2 hours and a solution of 3.5 g (0.18 mol) N-(2-chloroethyl)morpholine in 100 ml ether was added and stirred overnight. Saturated solution of ammonium chloride was added to the reaction mixture and the ether layer was extracted with 2N HCl. The acidic aqueous layer was then washed with ether twice and cooled in an ice bath, then neutralized with 35% sodium hydroxide and extracted with ether to give 16.3 g (54%) of the 2-methyl-3-(2-ethyl N-morpholinyl)indene (Formula II Rz=methyl; R3=R4=hydrogen; Alk=1,2-ethylene).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]1[N:26]2[N:27]=[CH:28][CH:29]=[C:25]2[C:24]([C:30]#[N:31])=[C:23](O)[CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[NH2:73][C@H:74]1[CH2:79][CH2:78][C@H:77]([NH2:80])[CH2:76][CH2:75]1>O1CCOCC1.C(OCC)(=O)C>[NH2:73][C@H:74]1[CH2:79][CH2:78][C@H:77]([NH:80][C:23]2[CH:22]=[C:21]([N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[N:26]3[N:27]=[CH:28][CH:29]=[C:25]3[C:24]=2[C:30]#[N:31])[CH2:76][CH2:75]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)OC(=O)N(c1ccc(-c2ccccc2)cc1)c1cc(O)c(C#N)c2ccnn12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(c1ccc(-c2ccccc2)cc1)c1cc(N[C@H]2CC[C@H](N)CC2)c(C#N)c2ccnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(tert-Butoxy)-N-[4-cyano-5-hydroxy(pyrazolo[1,5-a]pyridin-7-yl)]7-N-(4-biphenylyl)carboxamide (40) (27 mg) was dissolved in 1,4-dioxane (600 μL)and to this solution were added triethylamine (22 μL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (36 mg). This mixture was stirred at room temperature for 10 min. Trans-1,4-Diaminocyclohexane (145 mg) was added and the mixture was further stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with thin layer silica gel column chromatography (ethyl acetate/2 mol/L methanolic ammonia solution=5/1) to obtain the title compound (46).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][S:5][C:6]=1[C:7](OCC)=[O:8].C(O)(=O)C.[CH:29](N)=[NH:30]>C(O)C>[O:8]=[C:7]1[NH:30][CH:29]=[N:1][C:2]2[C:3]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)=[CH:4][S:5][C:6]1=2
Reactant: N=CN
Reactant: CCOC(=O)c1scc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2csc3c(=O)[nH]cnc23)CC1
Yield: 21.4 %

Procedure:
tert-Butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (307 mg, 0.87 mmol) was dissolved in ethanol (8 mL), and then formamidine acetate (542 mg, 5.20 mmol) was added, followed by heating under reflux for 36 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (62.5 mg, 21.5%) as a pale yellow amorphous.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(#N)C>[C:29]([O:21][CH2:20][C@H:17]1[O:16][C@@H:15]([N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][CH:13]=[N:14][C:6]=3[NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:19][CH2:18]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reaction time: 4 h
Yield: 52.5 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.290 g, 1 mmoles), 4-dimethylaminopyridine (10.2 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (620 μl, 4.4 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. The flask was chilled in an ice bath and acetyl chloride (150 μl, 2.1 mmoles, Aldrich Chemical Co., Madison, Wis.) was added. The reaction was brought to room temperature and stirred for 4 hours. Additional aliquots of triethylamine (620 μl, 4.4 mmoles) and acetyl chloride (150 μl, 2.1 mmoles) were added and the reaction was stirred overnight. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was suspended in 25 mL ethyl acetate and salts were removed by filtration. Solvent was evaporated in vacuo and the remaining material was chromatographed on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (7:3). Lyophilization afforded 0.174 g of 9-[(2R,5S)-5-(acetoxymethyl)-tetrahydro-2-furyl]-6-(cyclopropylmethylamino)-9H-purine as an oil (51% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])=[N+:13]=[N-:14]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (1 eq) in DMSO at 10° C. is vigorously stirred and sodium azide (1.25 eq) is added. The mixture is stirred for 1 hour then quenched with water and extracted with ethyl acetate (2×). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give 2-azido-1-(4-fluoro-phenyl)-ethanone.