Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][O:13][C:12](=[O:16])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.O.CCOCC>[OH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][O:13][C:12](=[O:16])[N:11]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25].[Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][O:13][C:12](=[O:16])[N:11]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCCI
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCOC(=O)N1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1CO
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazinan-2-one (0.51 g, 2.078 mmol) in DMF (10 mL) at rt under N2 was added KHMDS (0.5 M in toluene, 5 mL) dropwise (gel like precipitation formation) and the mixture was stirred for 10 min. Isopropyl 7-iodoheptanoate (1.24 g, 4.16 mmol, 2 eq) was then added in one portion and the mixture stirred at 65° C. for an additional 5 h and cooled to rt, diluted with water/ether. The layers were separated and the aqueous layer extracted with ether. The organic layers were combined, washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (15-30% acetone/toluene) to give desired product isopropyl 7-[(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxo-1,3-oxazinan-3-yl]heptanoate as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ4.98-4.90 (1H, m), 4.38-4.30 (1 H, m), 4.16-4.12 (1 H, m), 3.83-3.77 (2 H, m), 3.56-3.48 (2 H, m), 3.15-3.07 (1 H, m), 2.26 (2 H, t), 2.11-2.09 (2 H, m), 1.69-1.53 (4 H, m), 1.41-1.27 (4 H, m), 1.21 (6 H, d), 0.92 (9 H, s), 0.12 (6 H, s).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N(C(C)C)CC)(C)C.[C:69]1([CH2:75][C:76](Cl)=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:76](=[O:77])[CH2:75][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) (100 mg, 0-2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, 1 mmol) and phenylacetyl chloride (0.026 ml, 0.2 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane (2 ml) and washed with dilute hydrochloric acid (2 ml). The organic layer is separated and evaporated under reduced pressure to afford the title compound (114 mg). LCMS (electrospray): m/z [MH+] 583.27
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:12][C:4]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Reactant: C1CCNCC1
Product: CCOC(=O)c1c(C)nc2ncccc2c1N1CCCCC1
Temperature: 80 °C
Yield: 63.3 %

Procedure:
In a screw cap pressure tube ethyl 4-chloro-2-methyl-1,8-naphthyridine-3-carboxylate (250 mg, 1.0 mmol) was suspended in piperidine (2.0 ml, 20 mmol). The tube was sealed and the mixture heated to 80° C. for 1.0 h. The mixture was then adsorbed on silica and chromatographed (CH2Cl2/MeOH 98:2→97:3) giving 189.4 mg (63%) of the title compound.
Reaction SMILES: [Na+].[N:2]1([CH2:22][C:23]([O-:25])=[O:24])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]([O-:17])=[O:16])[CH2:7][CH2:6][N:5]([CH2:18][C:19]([O-:21])=[O:20])[CH2:4][CH2:3]1.[Na+].[Na+].[CH2:28]1[O:31][CH:29]1[CH3:30].[Gd:32]>>[CH3:28][CH:29]([OH:31])[CH2:30][N:11]1[CH2:10][CH2:9][N:8]([CH2:14][C:15]([O-:17])=[O:16])[CH2:7][CH2:6][N:5]([CH2:18][C:19]([O-:21])=[O:20])[CH2:4][CH2:3][N:2]([CH2:22][C:23]([O-:25])=[O:24])[CH2:13][CH2:12]1.[Gd+3:32]
Reactant: [Gd]
Reactant: CC1CO1
Reactant: O=C([O-])CN1CCNCCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Agent: [Na+]
Product: CC(O)CN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Product: [Gd+3]

Procedure:
The solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt is directly reacted, as described in EP 292689, with propylene oxide to give the alkylated product, which can easily be complexed with gadolinium to give the final Gadoteridol.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]#[N:29].[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35]Br)[CH3:31]>C1COCC1>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][CH:27]([C:28]#[N:29])[C:21]1[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:26])[CH3:31]
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCC(C#N)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
A solution of diisopropylamine (19.2 mL, 0.135 mol) in THF (75 mL) was added dropwise at room temperature to n-BuLi in hexane (67.5 mL, 0.135 mol) under argon atmosphere. The mixture was stirred for 0.5 h and then brought to -78° C.C. A solution of 2,6-dichlorophenyl acetonitrile (25 g, 0.135 mol) in THF (50 mL) was added dropwise while the reaction mixture was maintained at -78° C.C. The resulting mixture was stirred for 1 h, whereafter a solution of ethyl-3-bromoproionate (17.2 mL, 0.135 mol) in THF (50 mL) was added dropwise. The resulting mixture was stirred for 1 h, and then allowed to reach room temperature. After an additional 1 h at 25° C.C., the mixture was quenched with 10% aqueous hydrochloride solution. The phases were separated and the aqueous phase was extracted with diethyl ether (3×75 mL). The combined organic phases were dried (MgSO4), filtered, and concen-trated in vacuo affording ethyl-4-cyano-4-(2,6-dichlorophenyl)-butanoate (37 g) as an oil. A solution of the butanoate (3.53 g, 15 mmol) in HCl-saturated ethanol (100 mL) was hydrogenated at 50 psi over PtO2 (0.9 g) in a Parr apparatus. Removal of the catalyst by filtration, followed by evaporation of the EtOH, yielded an oily residue. The oil was taken up in 15% NaOH and was extracted with diethylether (3×30 mL), dried, filtered, and concentrated in vacuo. The oily residue was purified by flash chromatography using CH2Cl2 /MeOH (19/1) as eluent, affording pure racemic-69 (0.9 g, 85%): MS m/e 244.95 (M+ +1, 15.1), 243.95 (M+, 3.5), 242.95 (M+ -1, 24.1), 208.00 (19.3), 179.00 (29.3), 173.9 (61.3), 171.9 (100), 137.00 (31.6), 115.00 (20.5)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[N:24]=[CH:23][C:22]([CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:48][C:17]([C:19]4[N:24]=[CH:23][C:22]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)[CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
To a solution (5 mL) of diethyl (6-{5-[4-(cyclopropylsulfonyl)phenyl]-4-oxo-6-(tetrahydro-2H-pyran-4-yl)hexanoyl}pyridin-3-yl)malonate (150 mg) in acetic acid was added ammonium acetate (300 mg), and the mixture was stirred at 110° C. for 40 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (120 mg, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1.5:1, volume ratio). MS: 595 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[N:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M78) (0.35 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzoic acid (0.6 g, 2.53 mmol) and dichloromethane (10 mL). Cool in an ice bath. Add dropwise oxalyl chloride (0.64 mL, 5.0 mmol) followed by dimethylformamide (1 drop). Warm to ambient temperature. After 3 hours, evaporate invcuo and dry to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:11]=1)=[N:8][S:9][N:10]=2.C(O)C.[C-:15]#[N:16].[K+]>O>[N:10]1[S:9][N:8]=[C:7]2[CH:11]=[C:3]([CH2:2][C:15]#[N:16])[CH:4]=[CH:5][C:6]=12
Reactant: BrCc1ccc2nsnc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc2nsnc2c1
Yield: 53.3 %

Procedure:
A mixture of 5-bromomethyl-benzo[1,2,5]thiadiazole [RN65858-50-6](7.0 g, 30 mmol), ethanol (50 ml)and a solution of potassium cyanide (2.3 g, 36 mmol) in water (25 ml) was stirred at 50° C. for 15 hours. The alcoholic solution was concentrated and the residue suspended in water. The solid was collected by filtration, washed with water and dried in vacuo to give benzo[1,2,5]thiadiazol-5-yl-acetonitrile (2.8 g, 47%)
Reaction SMILES: [NH2:1][CH:2](O)[CH2:3][C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.[CH3:15][N:16]([CH2:23][C:24](=O)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+].C[OH:32]>>[CH3:15][N:16]([CH2:23][CH:24]([NH:1][CH2:2][CH:3]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)[OH:32])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CN(C)c1ccccc1
Reactant: CO
Reactant: NC(=O)c1cc(CC(N)O)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(CN(C)c1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
To To a solution of 20 mmol 5-(2-amino-hydroxyethyl)salicylamide and 3.26 g (20 mmol) N-methylanilino acetone in 100 ml methanol add 2.51 g (40 mmol) NaCNBH3. Stir 16 hrs., concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Dry and concentrate the organic layer. Dissolve the foam in CHCl3, and wash with water. Filter the solid which forms and recrystallize from EtOAc to give a white solid, mp 143°-5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.CO.[C:24]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1cccc(-c2cncc(Br)c2)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(-c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [3-(5-bromo-pyridin-3-yl)-phenyl]-acetic acid (Intermediate 94) (1 eq, 4.1 mmol, 1.2 g) in THF (15 ml) is added thionyl chloride (1.5 eq, 6.16 mmol, 0.45 ml), and the resulting mixture is stirred for 30 min at r.t. Then MeOH (3 eq, 12.3 mmol, 0.5 ml) is added and stirring is continued for another 20 h. Addition of 10% aqueous NaHCO3 solution is followed by extraction with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification or the crude mixture by column chromatography (hexane/EtOAc) gives the title compound; [M+H]+=306/308.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C[I:15].[CH2:16](O)C>O>[I-:15].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]2[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCO
Reactant: CI
Reactant: N#Cc1ccc(-n2ccnc2)cc1
Solvent: O
Product: Cn1cc[n+](-c2ccc(C#N)cc2)c1
Product: [I-]
Reaction time: 48 h

Procedure:
56 g (0.33 mol) of 1-(4-cyanophenyl)imidazole are dissolved in 560 ml water-free tetrahydrofuran in a 2000 ml one-necked flask with condenser, admixed with 234.2 g (1.65 mol) of methyl iodide, stirred briefly and allowed to stand for 48 hours without further stirring. The solid contents of the flask are subsequently slurried with ethanol, filtered off with suction and washed with ethanol until the washings are virtually colorless. The residue is dried at 70° C. under reduced pressure. The yield is 81.54 g (80% of theory).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]2[CH2:24][CH2:25][C:26](=[O:27])[C:11]=2[CH:10]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[NH:9]1.CI>CN(C)C=O>[CH3:8][N:9]1[CH:10]([C:28]2[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=2)[C:11]2[C:26](=[O:27])[CH2:25][CH2:24][C:12]=2[N:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)[C:1]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (82 mg, 0.25 mmol) is added to a solution of 4-(2,5-Dioxo-1-(2-(tri-fluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 15.5, 50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL). Methyl iodide (28 mg, 0.20 mmol) is added, and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 43 mg; ESI mass spectrum [M+H]+=413; Retention time HPLC: 0.78 min (005_CA01).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4]([O:22]C)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl>O>[N:24]1([C:2]2[NH:7][C:6]3[N:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]=[CH:14][CH:13]=4)[CH:9]=[N:10][C:5]=3[C:4](=[O:22])[CH:3]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: COc1cc(Cl)nc2c1ncn2Cc1cccc2ccccc12
Agent: Cl
Solvent: O
Product: O=c1cc(N2CCOCC2)[nH]c2c1ncn2Cc1cccc2ccccc12
Yield: 28.2 %

Procedure:
A mixture of 5-chloro-7-(methyloxy)-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (140 mg, 0.432 mmol) and morpholine (2.5 mL, 28.7 mmol) was irradiated in a microwave oven for 4 h at 200° C. The mixture was diluted with water and the pH was adjusted to ca. 7 by the addition of 1 N HCl. The precipitate formed was collected, washed with water and air dried. It was then dissolved in DMSO and purified by RP-HPLC (Gilson, 25-80% AcCN in water plus 0.1% TFA). The fractions containing product were collected, neutralized by the addition of aqueous NaHCO3 sat sol and the volume was reduced to ½-⅓ of the original. The precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven at 45° C. to give 5-(4-morpholinyl)-3-(1-naphthalenylmethyl)-3,4-dihydro-7H-imidazo[4,5-b]pyridin-7-one (45 mg, 0.122 mmol, 28.3% yield). MS (ES+) m/e 361 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (br. s., 1H), 8.32-8.47 (m, 1H), 8.00 (s, 1H), 7.94-7.98 (m, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.52-7.61 (m, 2H), 7.47 (dd, J=8.08, 7.07 Hz, 1H), 7.35 (d, J=6.32 Hz, 1H), 6.07 (s, 1H), 5.77 (s, 2H), 3.65-3.75 (m, 4H), 3.35-3.43 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH:9]=O)=[CH:8][C:4]=2[CH:3]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1C=CC=CC=1.N1CCCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7](/[CH:9]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2cc(Cl)ccc2s1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc2cc(Cl)ccc2s1
Temperature: 110 °C

Procedure:
A mixture containing 5-chlorobenzo[b]thiophene-2-carboxaldehyde (Matsunaga Bioorg. Med. Chem. 2004, 12, 2251), malonic acid (1.4 equiv), pyridine (2.5 equiv) and piperidine (0.1 equiv) was heated at 110° C. for a period of 4 h. The reaction mixture was cooled, poured into H2O and filtered to provide the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2].C(O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:44][C:45]([F:56])([F:55])[C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:49]2[CH:50]=[CH:51][C:46]([C:45]([F:56])([F:55])[F:44])=[CH:47][CH:48]=2)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COCCOCN(c1c(I)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To 2-[(5-{{[4-(tert-butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino)-4-iodo-1-methyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 14) (300 mg) in solution in toluene (5 ml) were successively added ethanol (1 ml), cesium carbonate (805 mg) in water (2 ml), and 4-(trifluoromethyl)phenylboronic acid (187 mg) at room temperature. The reaction mixture was degassed (vacuum followed by nitrogen atmosphere). This operation was repeated 5 times. The tetrakis(triphenylphosphine)-palladium(0) (15 mg) was then added and the reaction mixture degassed twice. The reaction mixture was refluxed for 1.5 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and a saturated solution of sodium carbonate (20 ml). The organic layer was separated and washed with a saturated solution of sodium carbonate (10 ml) and then brine (10 ml). The solution was dried on magnesium sulfate, the solution filtered on celite and concentrated under reduced pressure. The crude material was purified by chromatography on a suction column packed with silica eluted with ethyl acetate:hexane (1:2 to 3:1 gradually) to yield the desired product as an off white solid (200 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:40])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:41]([O:48]CC)([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44]>>[CH2:43]([O:42][P:41]([CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:40])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:48])[O:45][CH2:46][CH3:47])[CH3:44]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCP(=O)(OCC)OCC)cc(C(=O)OCc2ccccc2)c1
Yield: 59.6 %

Procedure:
A mixture of 4.91 g (7.95 mmol) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester and 1.5ml (8.74 mmol) of triethyl phosphite was stirred and heated at 150° for 32 horns. Purification by chromatography on 250 g of silica gel gave 3.2 g (60% yield) of 3-[3-(octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonic aciddiethyl ester as an oil. The structure was confirmed by the nmr spectrum.
Reaction SMILES: O[CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](CBr)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
1,1-Dimethylethyl (2S)-2-(hydroxymethyl)-4-morpholinecarboxylate (18.5 g, 0.080 mol) and carbon tetrabromide (34.5 g, 0.104 mol) were dissolved in methylene chloride (400 mL) and cooled in an ice bath. A solution of triphenylphosphine (22 g, 0.084 mol) in methylene chloride (150 ml) was added dropwise over 30 min. After 1 hr at 0° C., the reaction was allowed warm to room temp and was stirred overnight. The reaction volume was reduced by ½ in vacuo and poured onto a pad of silica gel and the product eluted with 15% ethyl acetate in hexane. The filtrate was concentrated in vacuo to afford the desired compound as an oil (12 g, 55%). MS (ES)+ m/e 281 [M+H]+.