Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[CH3:13][C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[C:23]([C@@H:27]([NH2:29])[CH3:28])[CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:29][C@H:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:17]2[CH:18]=[N:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:22]=1)[CH3:28])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: Cc1ccc(Oc2cccc([C@H](C)N)c2)cn1
Product: Cc1ccc(Oc2cccc([C@H](C)NC(=O)C=Cc3ccccc3F)c2)cn1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid following the general procedures as described for Example 1 with the exception that (S)-1-[3-(6-methyl-pyridin-3-yloxy)-phenyl]ethylamine was used.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][OH:19])=[NH:17])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:42]1([O:48]C(Cl)=O)C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[NH:17][C:42](=[O:48])[O:19][N:18]=2)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 89.3 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-trifluoromethyl-benzamidine in 2 ml of anhydrous dichloromethane were added 92 μl pyridine followed by 21.6 μl phenylchloroformate dropwise. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. To a solution of the resulting residue in 2.5 ml of acetonitrile was added 88 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred under microwave heating at 180° C. for 10 minutes (or stirred at room temperature overnight). The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (heptane 1/ethyl acetate 1 then dichloromethane 95/methanol 5 followed by another column with dichloromethane 90/acetone 10) to give 65 mg of 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:9]Br)[C:6]=1[CH2:7]Br.Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[CH2:9][N:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][C:6]=12
Reactant: Clc1scc(CBr)c1CBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2csc(Cl)c2C1
Temperature: 5 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 12.58 g (0.041 mol) of 2-chloro-3,4-bis(bromomethyl)thiophene in 40 ml of dimethylformamide is poured dropwise onto a mixture of 17.77 g of ethyl 2-aminoacetate hydrochloride, 45.5 g of finely powdered potassium carbonate and 80 ml of dimethylformamide, cooled to 5° C. The mixture is stirred at room temperature for 2 h, then poured onto 400 g of a water/ice mixture and stirred for a further 15 min. The mixture is extracted with 5 times 100 ml of diethyl ether, the ether phase is washed with twice 100 ml of salt solution, dried over magnesium sulphate and concentrated. 9.49 g of an oily product are obtained.
Reaction SMILES: [OH:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[CH:27]=[N:26][C:8]2[N:9](COCC[Si](C)(C)C)[C:10]3[CH:15]=[N:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[CH:27]=[N:26][C:8]2[NH:9][C:10]3[CH:15]=[N:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[C:7]=2[CH:6]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1cnc2[nH]c3cnc(C#N)cc3c2c1
Temperature: 60 °C
Yield: 12.2 %

Procedure:
A solution of 3-(3-hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanyl-ethoxymethyl)dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (254 mg, 0.624 mmol) in THF (12 mL) was treated with TBAF (3.7 mL, 12.5 mmol) and heated to 60° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The resultant residue was dissolved in DCM, absorbed onto silica gel, and purified by flash chromatography (Biotage, 25 g, 1-100% EtOAc in heptane). The light orange solid was further purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (21 mg, 12%). 1H NMR (DMSO-D6, 400 MHz,): 12.99 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 5.53 (s, 1H), 1.55 (s, 6H). LCMS (Method D): RT=9.66 min, M+H+=277.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[CH:28][CH:29]=2)[CH:2]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Copper sulfate pentahydrate (70 mg; 0.28 mmol; 0.07 eq.) was added to a solution of 3-ethynyl-5-methyl-1H-indazole (665 mg; 4.26 mmol; 1.00 eq.), 4-(4-azidobenzoyl)morpholine (987 mg; 4.25 mmol; 1.0 eq.) and D-(−)-isoascorbic acid sodium salt (283 mg; 1.43 mmol; 0.34 eq.) in DMF (15 mL) and water (0.5 mL). The reaction suspension was heated in MW at 80° C. for 40 min then poured into HCl solution (1N) and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid (1.38 g, 83%). 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (s, 1H), 9.36 (s, 1H), 8.20-8.10 (m, 3H), 7.68 (d, J=108.7 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.28 (dd, J=1.4, 8.6 Hz, 1H), 3.74-3.36 (m, 8H), 2.48 (s, 3H). HPLC (Condition A): Rt 3.21 min (purity 98.6%). MS (ESI+): 389.2, MS (ESI−): 387.2.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][S:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C[O-].[Na+].CN(C)C=O>O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:5]2[S:4][C:3]3[CH:8]=[CH:9][C:10]4[C:15]([C:2]=3[NH:1][C:6]2=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc3ccccc3c2N1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2c(ccc3ccccc23)SC1=Cc1ccc(Cl)cc1
Yield: 52.8 %

Procedure:
A mixture of 1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (5.17 g), 4-chlorobenzaldehyde (5.62 g), sodium methoxide (1.73 g) and dimethylformamide (80 ml) is refluxed for 4.5 hours. After cooling, the reaction mixture is poured into water and the resulting precipitate is separated by filtration, washed and dried and then is recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorobenzylidene)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (4.28 g). M.p. 277°-279° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][C:24]4[C:23]([F:22])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])[CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(N2CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 2,4,6-trifluorobenzaldehyde (28 mg, 0.18 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol) and acetic acid (6 μL, 0.1 mmol). The reaction was stirred at room temperature for overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=30:70, 40:60) to afford 2-furan-2-yl-6-[4-(2,4,6-trifluoro-benzyl)-piperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (35 mg, 56%). 1H NMR (300 MHz, CDCl3) δ2.66 (t, J=4.5 Hz, 4H), 3.34 (t, J=4.5 Hz, 4H), 3.73 (s, 2H),5.61 (s, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.26 (s, 1H), 7.57 (d, J=1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ46.53, 48.35, 51.56, 95.63, 99.82, 100.10, 100.38, 110.29, 111.73, 134.80, 143.80, 146.00, 146.42, 149.06, 155.13.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][N:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]3=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCBr)S(C)(=O)=O)cc2C1=O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)OC(C)(C)C)C3=O)S(C)(=O)=O)CC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (300 mg, 0.650 mmol) in acetonitrile (15 ml), K2CO3 (135 mg, 0.975 mmol) and 1-methylpiperazine (0.080 ml, 0.715 mmol) were added, and the resulting mixture was heated under MW irradiation at 130° C. for 1 hour. Additional K2CO3 (44.8 mg, 0.325 mmol) and 1-methylpiperazine (0.036 ml, 0.325 mmol) were added, and the reaction was submitted to a second microwave cycle at 130° C. for 1 hour. The mixture was diluted with acetonitrile, the insoluble inorganic salts were filtered off, and the filtrate was evaporated under vacuum. Purification by flash chromatography (DCM/MeOH 95/5) afforded tert-butyl 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (149 mg, 0.310 mmol, 47.7% yield, MS/ESI+ 480.9 [MH]+).
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:9]#[N:10].[NH4+]>>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: O=C(O)CC(=O)CCl
Reactant: C#N
Agent: [NH4+]
Product: N#CC(O)(CCl)CC(=O)O

Procedure:
In an alternate procedure, the 3-oxo-4-chlorobutyric acid from 11 is reacted at 12 directly with HCN in the absence of ammonium or metal cations to produce 3-cyano-3-hydroxy-4-chlorobutyric acid for feed to hydrolysis step 15.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:19][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[Cl:12])=[N:6][CH:5]=1
Reactant: O=Cc1ccncc1Cl
Reactant: COC(=O)c1ccc(N)nc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NCc2ccncc2Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To 6-amino-nicotinic acid methyl ester (553, 2.15 g, 0.014 mol) in acetonitrile (60.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), triethylsilane (11.00 mL, 0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80° C. overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (555, 1.5 g, 38.2%). MS (ESI) [M+H+]+=278.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:26]([C:30]1[CH:31]=[CH:32][C:33]([C:36](Cl)=[O:37])=[N:34][CH:35]=1)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[O:37])=[N:34][CH:35]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1ccc(C(=O)Cl)nc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: CCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)nc1
Yield: 60 %

Procedure:
The compound of example 648 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available 5-butylpicolinoyl chloride (Sigma Chemical Company, USA).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]3OCC[O:20]3)[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)cc1OC
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of compound 6 (5.6 g, 13.23 mmol) in THF (50 mL) at 0° C. was added 2N HCl (50 mL). The resulting mixture was stirred at rt O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 7 (3.0 g, 60%) as a pale yellow solid.
Reaction SMILES: [Li]C(CC)C.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1.CN(C)CCN(C)C.CN([CH:26]=[O:27])C>C1COCC1>[O:6]1[C:10]2[C:11]([CH:26]=[O:27])=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2c1OCC2
Reaction time: 1 h

Procedure:
sec-BuLi (20.00 ml, 1.4 M in cyclohexane, 28.00 mmol) was added to a solution of 2,3-dihydro-benzofuran (2.40 mL, 21.30 mmol) and tetramethylethylenediamine (TMEDA, 10.00 mL) in THF at −20° C. The resulting mixture was stirred for 1 hour, then DMF (3.00 mL, 38.75 mmol) was added and stirring was continued for another 30 minutes. The reaction mixture was quenched with water and diluted with ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated to afford the desired title aldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: CN1OC2(CC(C3CCOCC3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCOCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.8 %

Procedure:
A mixture of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.131 mmol), 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1H-NMR (CDCl3): 1.54 (m, 2H), 1.62 (m, 1H), 1.88 (m, 1H), 2.10 (m, 1H), 2.48 (m, 1H), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)([CH3:20])[CH3:19]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[CH:18]([CH3:20])[CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Mg]Cl
Reactant: COCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
A solution of 3-(methoxymethylcarbamoyl)azetidine-1-carboxylic acid tert-butyl ester (1.06 g, 4.34 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 4° C. under argon gas. 2M solution of isopropyl magnesium chloride (4.35 mL, 8.68 mmol) was added dropwise and the resulting reaction mixture was stirred at 4° C. for 5 min. The temperature was allowed to rise to RT and stirred for 1 h then the mixture was stirred at 40° C. for 1 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride (5 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulfate, filtered and the solvents reduced in vacuo to afford the title compound as a pale yellow oil (950 mg, 96%) 1H NMR (400 MHz, CDCl3): δ 4.03-4.01 (4H, m), 3.59-3.59 (1H, m), 2.61-2.61 (1H, m), 1.43 (9H), 1.11 (6H, d, J=6.94 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([N:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:17][CH:18]([OH:20])[CH2:19][NH:16][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: COc1ccc(O)c(C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C)c1C
Temperature: 140 °C
Yield: 72.5 %

Procedure:
A mixture of 9.1 parts of 2,3-dimethyl-4-methoxyphenol, 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction product was dissolved in 100 parts of 2 N-hydrochloric acid aqueous solution and washed twice with 100 parts of ether. The water layer was made alkaline with 4 N-sodium hydroxide aqueous solution, and the resulting crystals were recovered by filtration and dried. Then the crystals were dissolved in 100 parts of ether and decolored. The decolored liquid was concentrated and allowed to cool. As a result, 10.2 parts of 1-(2',3'-dimethyl-4'-methoxyphenoxy)-3-(tert.-butylamino)-2-propanol melting at 73°-75° C. were obtained. The yield was 72.5%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: Br[C:2]1[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]2[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: [O-][n+]1nccnc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNc1nccn[n+]1[O-])c1ccc(F)cc1
Yield: 41.6 %

Procedure:
A solution of 3-bromo-1,2,4-triazin-2-oxide (2.0 g, 11 mmol), (2-(4-fluorophenyl)-2-methylpropan-1-amine (3.0 g, 17 mmol), and diisopropylethylamine (3.0 mL, 17 mmol) in CH3CN (20 mL) was stirred at rt for 24 h. The solvents were removed and the residue dissolved in EtOAc. The solution was washed with saturated NaHCO3, dried over Na2SO4, and evaporated to dryness. The residue was mixed with ether and then filtered to give the desired product (1.2 g) as a yellow solid.
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([CH3:4])=O.[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>CO.CO.CO>[CH3:4][C:2]1[C:1](=[O:6])[NH:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1cccnc1N
Solvent: CO
Product: Cc1nc2cccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
Ethyl pyruvate (1.22 mL) was dissolved in methanol (10 mL) and added to a cold solution of 2,3-diaminopyridine (1.09 g) in methanol MeOH (20 mL) and the mixture was stirred at ambient temperature. The solid was filtered off and washed with cold methanol to afford 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (1.1 g) as a grey solid. 1.0 g of this material was suspended in acetonitrile (10 mL) and phosphoryl chloride (1.16 mL) was added. The mixture was heated at 120° C. for 0.5 h under MW conditions. The crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford IIId (460 mg) as a red solid sufficiently pure for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)[CH:29]=[CH:28][CH:27]=1
Reactant: NCc1nc(NCC(c2cccc(Cl)c2)c2cccc(Cl)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Product: CC(C)N(CCNC(=O)NCc1nc(NCC(c2cccc(Cl)c2)c2cccc(Cl)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(3-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 62) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) in a similar procedure to that used in Example 36.