Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[N:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:7]1[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(Br)n1
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: [Na+]
Solvent: CC#N
Product: Nc1cccc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 153.7 %

Procedure:
To a stirred degassed suspension of a mixture of 2-amino-6-bromopyridine (5.38 g, 31.09 mmol), 2,4,6-(3-pyridinyl)-cyclotriboroxane (3.80 g, 12.07 mmol) and aqueous Na2CO3 (100 mL, 0.4M) in acetonitrile (100 mL) at room temperature Pd(PPh3)4 (1.70 g, 1.47 mmol) was added. The reaction mixture was heated at 95° for 1 to 2 days under nitrogen, cooled to the room temperature and filtered. The filtrate was concentrated purified by flash chromatography on silica gel (MeOH/CH2Cl2: 5/95→10/90 plus a few drops of NH4OH) and co-precipitated with a mixture of AcOEt/CH2Cl2/hexane to afford the title compound 11 (4.091 g, 23.90 mmol, 77% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.16 (dd, J=2.2, 0.8 Hz, 1H), 8.57 (dd, J=4.7, 1.6 Hz 1H), 8.33-8.28 (m, 1H), 7.54-7.44 (m, 2H), 7.14 (dd, J=7.3, 0.5 Hz, 1H), 6.49 (dd, J=8.2, 0.4 Hz 1H), 6.12 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][C:24]([NH:26][OH:27])=[NH:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:28]1([C:31](O)=O)[CH2:30][CH2:29]1>>[CH:28]1([C:31]2[O:27][N:26]=[C:24]([CH2:23][CH:11]3[CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]3[S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[N:25]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CC(=N)NO)CCC2c2ccc(F)cc2)cc1
Reactant: O=C(O)C1CC1
Product: Cc1ccc(S(=O)(=O)N2C(Cc3noc(C4CC4)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=442.3 (M+H+) was prepared in accordance with the general method of example 13 from (2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine and cyclopropyl-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[S:24]>O1CCCC1.C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24]
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: S=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc(CNC(=S)Nc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and 2-chlorophenylisothiocyanate (0.09 g) in dry tetrahydrofuran (10 ml) was added 10 drops of triethylamine. The mixture was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo and the residue extracted with ethyl acetate and washed with 2M hydrochloric acid. The layers were separated and the organic phase was evaporated to dryness to give the title product, m.p. 126° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:26].O1CCOCC1>ClCCl>[ClH:26].[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15](=[O:25])[N:14]2[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:18][CH:19]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccc(C#N)cc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)N(C1CCNCC1)C(=O)C2
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of N-Boc 4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine (D136, 400 mg, 1.172 mmol) in dichloromethane (5 mL) was treated with 4M HCl in dioxane (5 mL, 20.00 mmol). After 4 h at room temperature, evaporation and crystallisation from diethyl ether gave white crystals of 4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine hydrochloride (270 mg, 0.972 mmol, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-n2ccc(NC(=O)c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.17 g, 0.50 mmol) and 4-dimethylaminopyridine (0.01 g) in pyridine (10 mL) was added benzoyl chloride (0.07 mL, 0.60 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours, and water (100 mL) was added. The title compound was precipitated as a solid which was collected by filtration and washed with water and t-butylmethyl ether (0.17 g, 76%): mp 246-248° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.78 (t, J=5.7 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.66-7.47 (m, 3H), 7.35-7.18 (m, 6H), 6.94 (dd, J=7.8, 2.1 Hz, 1H), 4.39 (d, J=5.7 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 161.9, 161.0, 153.8, 150.3, 149.4, 139.8, 134.1, 132.9, 131.6, 129.0, 128.7, 128.4, 127.7, 127.2, 123.9, 104.2, 103.9, 43.1, 17.5; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:13](=[O:22])[C@H:12]([N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:23][C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][N:14]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:13]1=[O:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Yield: 0.1 %

Procedure:
A solution of di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate (0.481 g, 0.895 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (3 mL). After lh the reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2×). The organic washes were combined, dried over magnesium sulfate, and concentrated to afford the title compound (0.30 mg). MS 338.2 (M+1).
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>C1COCC1.CCOCC>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH:14]([CH3:16])[CH3:15])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (2.0 g, 11.2 mmol) in THF (20 mL) was heated under an atmosphere of nitrogen at reflux. To this solution was added slowly a solution of isopropyl magnesium chloride (39.3 mmol) in THF (ca. 20 ml). This solution had been prepared from the commercial solution (19.6 ml 2N solution in ether), from which the solvent had been removed in vacuum, and where the residue was made up with THF to a volume of 20 ml). After the addition of the Grignard reagent was completed, the mixture was stirred for another 30 minutes, and then allowed to cool to ambient temperature. To the mixture was then added a 10% solution of ammonium chloride (ca. 30 ml). The aqueous layer was removed, and re-extracted with TBME (ca. 20 ml). From the combined organic layers the solvent was removed, and the residue was redissolved in TBME (ca. 50 ml). After washing with water and brine, the organic layer was dried (Na2SO4). Removal of the solvent left the product as an oil, 2.2 g (88%). There was only one isomer present by 13C-NMR, which turned out to be the (S,S)-diol. 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.783 (d, J=6.7 Hz)/20.02 (CH3); 1.065 (d, J=6.5 Hz)/18.99 (CH3); 2.02 (m)/35.29 (CHMe2); 4.60 (d, J=7.6 Hz)/76.51 (CH(OH)); 2.38 br s (OH); 7.20-7.26 (m)/126.75 (Ar ortho-CH); 7.33-7.39 (m)/127.55 (Ar meta-CH); 141.41 (Ar ipso-C).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:12][C:5]1([O:6][CH3:7])[C:8]([OH:9])=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[CH2:4]1
Reactant: ClCl
Reactant: COc1cc(C=O)ccc1O
Solvent: ClC(Cl)Cl
Product: COC1(Cl)CC(C=O)=CC=C1O
Yield: 94 %

Procedure:
Vanillin (100 g) is dissolved in chloroform (800 ml), and thereto is blown with stirring chlorine gas at room temperature for about one hour to give the white solid. The compressed air is blown into the mixture to remove the chlorine being dissolved therein, and the precipitated solid is collected by filtration, washed, and dried. The mother liquor is concentrated, and triturated with diethyl ether, and the precipitates are collected by filtration, washed, and dried. The former precipitated solid and the powder thus obtained are combined to give 3-chlorovanillin (115.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11]Cl)[C:6]=2[CH:13]=1.[CH3:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11][NH:15][CH3:14])[C:6]=2[CH:13]=1
Reactant: CN
Reactant: ClCC1=CCOc2ccc(Cl)cc21
Product: CNCC1=CCOc2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
500 ml of 33% ethanolic methylamine are added dropwise under ice-water cooling to 105 g 6-chloro-4-chloromethyl-2H-1-benzopyrane. Reaction is continued for 8 hours at room temperature, the mixture concentrated by evaporation and the residue taken up in dichloromethane. The mixture is washed with 500 ml each of 1 N NaOH and water, dried over MgSO4 and concentrated by evaporation. Distillation of the residue yields the title product b.p. 116°-120°/13.3 pascal.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:29]=[N+:30]=[N-:31])[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)=O.O>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:29]=[N+:30]=[N-:31])[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C2OC(C)(C)OC21)OCC
Solvent: O=CO
Solvent: O
Product: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C(O)C1O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 48.4 (130 mg, 0.29 mmol) was dissolved in 90% formic acid in water (2.8 mL). The solution was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was used in the next step reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC1CCOCC1)c1ccccc1
Yield: 91.2 %

Procedure:
Following general procedure A: ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (269 mg, 1.14 mmol), tetrahydro-4H-pyran-4-one (0.12 ml, 1.3 mmol) and NaBH(OAc)3 (340 mg, 1.60 mmol) in CH2Cl2 (8.0 ml) was stirred at room temperature for 18 hours. Standard work-up and purification by flash column chromatography on silica (CH2Cl2/MeOH, 19:1) gave [(R)-1-phenyl-2-(tetrahydro-pyran-4-ylamino)-ethyl]-carbamic acid tert-butyl ester as a colorless oil (333 mg, 91%). 1H NMR (CDCl3) δ 0.80-1.36 (m, 3H), 1.41 (s, 9H), 1.68-1.82 (m, 2H), 2.61 (tt, 1H, J=10.3, 4.1 Hz), 2.93 (d, 2H, J=5.1 Hz), 3.35 (tdd, 2H, J=11.6, 5.6, 2.2 Hz), 3.88-3.96 (m, 2H), 4.74 (br s, 1H), 5.45 (br d, 1H, J=5.7 Hz), 7.22-7.35 (m, 5H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[N:6]([S:7]([O-:10])(=[O:9])=[O:8])[C:5](=[O:11])[CH:4]1[NH:12][C:13](=[O:61])[C:14]([C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)=[N:15][O:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)=O>[Cl:1][CH2:2][C@H:3]1[N:6]([S:7]([OH:10])(=[O:8])=[O:9])[C:5](=[O:11])[C@H:4]1[NH:12][C:13](=[O:61])[C:14]([C:36]1[N:37]=[C:38]([NH2:41])[S:39][CH:40]=1)=[N:15][OH:16]
Reactant: O=C(NC1C(=O)N(S(=O)(=O)[O-])C1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1cc[nH+]cc1
Solvent: O=CO
Product: Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CCl)cs1
Temperature: 60 °C

Procedure:
A suspension of 1.02 g of the product of Step B in 9.1 ml of formic acid containing 33% water was heated at 60° C. for 15 minutes and was reacted as in Step C of Example 3 to obtain 119 mg of racemate of syn isomer of cis 4-chloromethyl-3-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-2-oxo-azetidine-1sulfonic acid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][CH2:14][CH2:15][CH:16]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CCCCCC(CCCCl)OC1CCCCO1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CCCCCC(CCCN1C(=O)c2ccccc2C1=O)OC1CCCCO1
Temperature: 95 °C
Yield: 45 %

Procedure:
Sodium hydride (53%) (1.5 g. excess) is washed with benzene three times by decantation, then dimethyl formamide (100 ml.) is added. To this stirred suspension is added a solution of phthalimide (4.3 g., 0.03 mole) in dimethyl formamide (50 ml.) at such a rate as to keep the temperature below 35°C. A clear solution is obtained and to it is added 1-chloro-4-(2-tetrahydropyranyloxy)-nonane (7.8 g., 0.03 mole) and the resulting clear solution is stirred and heated at 95°C. for 20 hours. The reaction is then concentrated to one half its volume in vacuo, poured into ice water (200 ml.) and extracted with ether (2 × 150 ml.). The ether is washed with 5% sodium hydroxide (2 × 50 ml.), saturated sodium chloride solution (2 × 50 ml.) then dried over sodium sulfate. Evaporation of the ether affords 4.5 g. (45% yield) of N-[4-(2-tetrahydropyranyloxy)nonyl]phthalimide melting 59°- 61°C. After recrystallization from cyclohexane, the product melts at 62°-63°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.CC([O-])(C)C.[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: Clc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cncc(Oc2ccccn2)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-pyridin-3-ol (1000 mg, 7.72 mmol), potassium tert-butylate (866 mg, 7.72 mmol) and 2-chloro-pyridine (730 g, 7.72 mmol) in DMF (6 mL) was stirred at 130° C. for 3 h. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and 2 N NaOH solution (50 mL). After extraction of the aqueous layer with DCM (6×50 mL) the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane and EA) to give the title compound. MS (m/z): 207.2 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Yield: 99.7 %

Procedure:
By reaction of 17 g (82 mmol) of methyl 3-tert-butyl-4-hydroxybenzoate with 10.7 ml (82 mmol) of benzyl bromide in a manner analogous to Example 1(a), 24.4 g (100%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@:8]1([C:14]([OH:16])=[O:15])[C@H:12]([CH3:13])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])([C:14]([OH:16])=[O:15])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
A mixture of (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 1i (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8 mmol), acetic acid (0.635 ml, 11.1 mmol), sodium triacetoxyborohydride (3.14 g, 14.8 mmol) and methanol (35 ml) was heated at 40° C. for 38 hours and 30 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title compound as Lot A (584 mg) and Lot B (708 mg).
Reaction SMILES: [CH3:1][C:2](=[CH2:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)=[O:4].C(O)(C(F)(F)F)=[O:20].OO>C(Cl)Cl>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([C:2]2([CH3:1])[CH2:18][O:20]2)=[O:4])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:13]
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: OO
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reaction time: 8 h

Procedure:
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0 mmol) in CH2Cl2 (15 ml) was treated by TFA (3.0 ml) at 0° C. To the reaction mixture was then added H2O2 (30%, 1.0 ml, 10.0 mmol) dropwise. The reaction mixture was stirred overnight and quenched by NaHCO3, then extracted by ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using hexanes:ethyl acetate 4:1 as eluent to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>CCOC(C)=O>[CH2:17]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14])[CH:16]=[CH2:15]
Reactant: CCCc1c(Br)ccc2c1COC2=O
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1CCC)COC2=O
Yield: 54.4 %

Procedure:
To a flask charged with 5-bromo-4-propyl-2-benzofuran-1(3H)-one (130 mg, 0.51 mmol) and a stir bar was added allyl tri-n-butyltin (0.24 mL, 0.76 mmol), PdCl2(dppf)-DCM complex (42 mg, 0.051 mmol), lithium chloride (65 mg, 1.5 mmol), and tolene (5 mL). The mixture was sealed with a condensor, purged with nitrogen three times, and heated to reflux for 5 hours. The crude reaction was diluted with EtOAc, adsorbed onto silica gel, and purified by MPLC. Removal of solvent gave rise to 5-allyl-4-propyl-2-benzofuran-1(3H)-one (60 mg, 44% yield) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=O)[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.B.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CCc3cnccc3C2=NN1c1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Clc1cccc(N2CCC3CCc4cnccc4C3=N2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
2-(3-Chlorophenyl)-4,4a,5,6-tetrahydropyrido[3,4-h]cinnolin-3(2H)-one (from Example 5 above; 66 mg) was placed in a flask under nitrogen. Borane tetrahydrofuran complex (1.0M in THF; 3 ml) was added and the solution stirred for 16 hours at ambient temperature. The mixture was added to methanol (3 ml) with stirring and then concentrated hydrochloric acid (0.5 ml) was added cautiously. The mixture was heated under reflux for 30 minutes, then cooled to room temperature and the volatiles removed on a rotary evaporator. The resultant product was partitioned between NaHCO3 (aqueous) and ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated to give a solid which was chromatographed eluting with ethyl acetate to give a solid which was recrystallised from isopropanol to yield the title compound as yellow crystals (14 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15]CC)=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:15])[CH2:12][NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)Nc1cccc(I)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1c1cccc(I)c1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A solution of ethyl N-{[(3-iodophenyl)amino]carbonyl}glycinate (9.42 g) in DMF (60 ml) was treated with sodium hydride (60% oil dispersion, 1.2 g) at 20° C. After 2 h the reaction mixture was treated with aqueous 2M HCl (200 ml) and stirred overnight. The solid was collected by filtration, washed with water and dried to give the title compound (6.9 g) LCMS RT=2.45 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[C:38]([F:41])([F:40])[F:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:42]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:42])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[C:38]([F:40])([F:39])[F:41])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(F)cc1C(F)(F)F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Temperature: 127.5 °C
Reaction time: 4 h

Procedure:
A mixture of 2.22 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 168 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125-130° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [Silica gel, eluent: ethyl acetate/cyclohexane, elution gradient of 0/100 (v/v) to 70/30 (v/v)] to yield the title product.