Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([OH:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.O>C(OCC)C>[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([O:24][CH2:18][C:19]2[O:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncc(Br)c(Cc2ccccc2)n1
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
14.1 mg of 60% oily sodium hydride was added to a mixture of 73.3 mg of 4-benzyl-5-bromo-2-chloropyrimidine (Production Example 15), 1 ml of furfuryl alcohol and 14.8 mg of cuprous iodide at room temperature, followed by stirring at 90° C. for 2 hours. Water and diethyl ether were added to the reaction solution, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10% ethyl acetate/hexane, to give 50.9 mg of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17]([OH:23])=[CH:16][C:15]=2[CH3:24])=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([O:23][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Product: CCOC(=O)COc1cc(C)c(Oc2ccc(OCc3ccccc3)c(C(C)C)c2)c2c1CCC2

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 11 using 7-(4-benzyloxy-3-isopropylphenoxy)-6-methylindan-4-ol instead of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde and using ethyl bromoacetate instead of benzyl bromide.
Reaction SMILES: CN(C=O)C.Cl[C:7]1[C:8]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:9]=2[N:10]([CH3:15])[C:11](=[O:14])[CH2:12][N:13]=1.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.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>[CH3:15][N:10]1[C:9]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:8]=2[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[CH:26]=[O:27])=[N:13][CH2:12][C:11]1=[O:14]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2cccc(C=O)c2)c2cc(-c3ccccc3)ccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To 5 mL of degazed DMF were added 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (200 mg, 0.52 mmol), 3-formylbenzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The title compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=25%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][CH2:21][CH3:22])[CH2:14]2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([N:20]([CH2:21][CH3:22])[C:34]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=1)=[O:35])[CH2:14]2)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a mixture of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (11.0 g; 33 mmol), dissolved in CH2Cl2 (100 mL), is added 4-trifluoromethoxyphenyl isocyanate (10.2 g; 50.2 mmol) and the reaction was allowed to stir at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 11.2 g (62%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid tert butyl ester as a white foam.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: NO
Reactant: CCCC(c1ccc(C=O)cc1)n1ccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(c1ccc(C=NO)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde (see example 6) is dissolved in 2 ml of pyridine and mixed with 0.215 g of hydroxylamine hydrochloride. It was stirred overnight at room temperature and precipitated in 30 ml of water and extracted with ether. After removal of the solvent under vacuum, 0.4 of 1-[1-(4-hydroxyiminomethylphenyl)-butyl]-imidazole is obtained as yellow oil.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=1>CN(C)C=O.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>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[N:18][CH:19]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc([Sn](C)(C)C)cc1OC
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(OC)c(OC)c2)cn1
Temperature: 90 °C

Procedure:
A solution of 2.00 g (6.64 mmol) of 4-trimethylstannylveratrole, 2.49 g (13.2 mmol) of 2-methoxy-5-bromopyridine and 370 mg (0.332 mmol) of Pd (PPh3)4 in 30 mL of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer is back extracted with ethyl acetate (100 mL) and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to give a crude yellow oil. The oil is chromatographed on silica gel (eluting with 95:5 hexane/ethyl acetate and then with 9:1 hexane/ethyl acetate) which gives 5-(3,4-dimethoxy-phenyl)-2-methoxypyridine m.p 83-84° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCOc1ccc2c(c1)c(CC(=O)OC)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (0.35 g), ethyl 5-bromopentanoate (0.232 ml) and potassium carbonate (0.31 g) in methylethylketone (5 ml) was stirred at 80° C. for 18 hours. After an insoluble mass was filtered off, the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and n-hexane. The fractions containing the objective compound were combined and concentrated under reduced pressure. The residue was crystallized with n-hexane and the crystals were collected by filtration and washed with n-hexane to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-methyl}-5-(4-ethoxycarbonylbutoxy)indole-3-acetate (0.23 g).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(OCCn2ncc3ccccc3c2=O)cc1
Yield: 43.4 %

Procedure:
##STR31## The title compound (700 mg, 44%) was prepared from 1(2H)-phthalazinone (800 mg, 5.48 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441), 4-[2-bromoethoxy]benzaldehyde (1.25 g, 5.48 mmol) and K2CO3 (1.5 g, 10.96 mmol) by a similar procedure to that described in preparation 2, mp: 104-106° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.O>[CH3:7][N:6]1[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:3]([CH:9]=[O:10])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nn(C)c(N2CCN(C)CC2)c1C=O
Temperature: 122.5 °C
Yield: 28.7 %

Procedure:
To a solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (25.4 g, 0.16 mol) in HMPA (25 mL) and water (25 mL) was added 1-methylpiperazine (40 g, 0.4 mol, 2.5 equiv), and the mixture was heated at 120-125° C. for 25 h. When the reaction was completed, the reaction mixture was poured into water (500 mL), and potassium carbonate was added to make the medium strongly alkaline. The mixture was extracted with dichloromethane (5×100 mL). The combined organic extracts were washed twice with water and dried with sodium sulfate, and the solvent evaporated. The residue was purified chromatographically on silica gel with gradient elution from dichloromethane to methanol, affording 10.2 g (29%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.26 (s, 3H), 2.44 (m, 4H), 3.16 (m, 4H), 3.59 (s, 3H), 9.88 (s, 1H). LC-MS (API-ES) calcd for C11H18N4O: 222.15, found (M+H+): 223.1 m/z.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH3:12]>CO>[CH3:1][C:2]1[S:3][C:4]([S:8]([NH2:12])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: N
Solvent: CO
Product: Cc1nc(C)c(S(N)(=O)=O)s1
Yield: 34 %

Procedure:
According to Reference Example 9-7, by use of 2,4-dimethylthiazole-5-sulfonyl chloride (250 mg, 1.1 mmol) and a 7 mol/L solution of ammonia in methanol (2 mL), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 20/1) was performed to give 2,4-dimethylthiazole-5-sulfonamide (Compound FL) (60 mg, yield: 34%).
Reaction SMILES: I[Si](C)(C)C.[O:6]=[S:7]1(=[O:41])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[C:21]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][O:38]C)[CH:34]=3)[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:41]=[S:7]1(=[O:6])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[C:21]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][OH:38])[CH:34]=3)[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OCCCS4(=O)=O)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Iodotrimethylsilane (0.416 mL, 2.92 mmol) was added to a solution of 3-[(5,5-dioxido-3,4-dihydro-2H-1,5-benzoxathiepin-8-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (150 mg, 0.29 mmol) in acetonitrile (7 mL) and the reaction stirred at RT overnight. Methanol (35 mL) was added, the reaction stirred for 1 hour, then a saturated aqueous solution of sodium thiosulphate (30 mL) was added and the reaction stirred for a further 20 minutes. The mixture was evaporated in vacuo, and the product was extracted away from the inorganic residues by the addition of 20% methanol in DCM (40 mL) with stirring. The organics were reduced in vacuo to a volume of approximately 5 mL. The residue was chromatographed on silica, eluting with 0-20% methanol in DCM, to give the desired compound as a cream solid (79 mg).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:32])[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1
Reactant: CI
Reactant: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(N(C)S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The title compound of Example 102 (56 mg, 0.13 mmol) in DMF (0.2 mL) was treated with NaH (60% dispersion in oil, 6 mg, 0.16 mmol). After about 15 min, methyl iodide (0.012 mL, 0.2 mmol) was added. After complete reaction, silica gel chromatography gave the title compound (55 mg, 0.13 mmol) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96-2.17 (s, 3H) 2.98 (s, 3H) 3.25 (s, 3H) 3.49 (s, 3H) 6.82 (d, J=8.84 Hz, 1H) 7.21-7.40 (m, 3H) 7.40-7.54 (m, 2H) 7.59 (s, 1H) 7.82 (d, J=2.53 Hz, 1H) LCMS (M+H)+ 435
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCl
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cn1nnnc1-c1ccccc1
Yield: 18.1 %

Procedure:
Two grams of 5-phenyltetrazole (13.68 mM) were slowly added to 5 ml of a methanol solution containing 770 mg (13.68 mM) of potassium hydroxide at room temperature. Two milli liters of a methanol solution containing 1.48 g (13.68 mM) of methyl chloroacetate were dropwise added to the resultant solution at room temperature. After the completion of the addition, the reaction solution was refluxed for 20 hours and cooled. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elute is chloroform), to give 0.54 g of methyl 5-phenyl-1-tetrazoleacetate (yield: 18.1%).
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][OH:14])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CO)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 6a, starting from 5.6 g (0.02782 mol) of trans-3-(N-BOC-amino)-cyclobutanemethanol, 4.54 g (0.02783 mol) of N-hydroxyphthalimide, 7.3 g (0.02783 mol) of triphenylphosphine and 5.12 ml (0.0306 mol) of diethyl azodicarboxylate (93%), the title compound is obtained, m.p. 120°-122° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCOCC1>[CH2:14]([O:21][C:22]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 500 mg (4.95 mmol) azetidine-3-carboxylic acid was added 10 mL dioxane and 10 mL H2O and the solution cooled to 0° C. 1.38 g (10 mmol) potassium carbonate was added followed by 0.78 mL (11 mmol) benzylchloroformate, and the reaction stirred at room temperature for 18 hours. The mixture was acidified with 25 mL 1 M HCl, extracted with DCM (2×20 mL), the combined organic layers dried over Na2SO4. After filtration the solvent was evaporated to give the desired product which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[N:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[N:18]=[C:19]([CH3:20])[C:11]=12>CCCCCC.O1CCCC1>[CH3:20][C:19]1[C:11]2[C:12](=[N:13][C:14]([CH3:16])=[CH:15][C:10]=2[O:3][CH:4]2[CH2:8][CH2:7][O:6][CH2:5]2)[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:18]=1
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)cc(C)nc32)c(C)c1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2nc(C)c3c(OC4CCOC4)cc(C)nc32)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in oil, 176 mg, 4.4 mmol) was washed with hexane and suspended in 2 ml of tetrahydrofuran. 3-Hydroxytetrahydrofuran (1 ml) was added and stirred at room temperature for 5 minutes. A solution of 4-chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.665 mmol) in 1 ml of THF was added and the resulting mixture was heated at reflux for 8 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give 334 mg of crude product. The crude material was purified through silica gel column chromatography using 1% methanol in chloroform as eluent to give 127 mg of a beige solid, mp 117-119° C.; IR(KBr) 2950, 1600, 1580 cm−1; high MS, calc. 351.1941, found, 351.19386; 1H NMR (CDCl3): 6.90 (s, 2H), 6.15 (s, 1H), 5.07 (m, 1H), 3.9-4.05 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.2-2.3 (m, 2H), 1.98 (s, 3H), 1.96 (s, 3H) ppm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=[O:17].C(OCC)(=O)C.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:24]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=[O:17])#[N:25]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nc2ccc(I)cc2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A suspension of ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (2.00 g, 5.81 mmol), zinc cyanide (375 mg, 3.19 mmol) and tetrakis(triphenylphosphine)palladium (336 mg, 0.29 mmol) in DMF (10 mL) was stirred at 80° C. for 5 hr under argon atmosphere. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The precipitated solid was collected by filtration, washed with ethyl acetate, diisopropyl ether and water, dried over diphosphorus pentaoxide under reduced pressure to give the title compound as a pale-yellow powder (965 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.O1CCOC[CH2:15]1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1COCCO1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(F)c1

Procedure:
A solution of 5.0 g (29.1 mmol) of 3,5-difluorophenylacetic acid and a solution of 20 mL (80 mmol) of HCl in dioxane (4M) in 60 mL of methanol was heated at reflux for 6 h. After cooling, the solution was concentrated and the residue poured into 200 mL of ether/ethyl acetate (1/1). The organic layer was washed with 20 mL of water, dried over Na2S04 and concentrated to afford the title compound.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])[CH2:6]1)C.[CH3:22][NH:23][C:24]([NH2:26])=[NH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:22][NH:23][C:24]1[N:26]=[CH:4][C:5]2[CH2:6][N:7]([C:12]3[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=3[CH3:21])[CH2:8][CH2:9][C:10]=2[N:25]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Reactant: CNC(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1ncc2c(n1)CCN(c1cc([N+](=O)[O-])ccc1C)C2
Temperature: 25 °C

Procedure:
To a solution of 3-Dimethylaminomethylene-1-(2-methyl-5-nitrophenyl)piperidin-4-one (12.06 gm, 41.7 mmol)[as prepared in reference 1] in Ethanol (250 ml) were added N-Methyl guanidine (12.20 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried [sodium sulfate] and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 5-10% Methanol/Chloroform as eluent to give pure desired product [41] i.e., Methyl-[6-(2-methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amine as yellow solid. (Yield: 2.47 gm, 19.8%).