Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:20]=[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]2=[O:21])[N:13]=1.[H][H]>CO.[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[N:20]=[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]3=[O:21])[N:13]=2)=[C:3]([N:2]([CH3:22])[CH3:1])[CH:8]=1
Reactant: [H][H]
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C1=NC2=NC=NC(=O)C2=N1
Agent: [Ni]
Solvent: CO
Product: CN(C)c1cc(N)ccc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
An amount of 0.9 gm of 8-(2-dimethylamino-4-nitro-phenyl)purin-6-one is hydrogenated in 50 ml of methanol in the presence of 0.5 gm of Raney nickel at ambient temperature and under 5 bars of pressure with hydrogen for three hours until the calculated quantity has been taken up. After the catalyst has been subjected to suction filtration, the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])SC)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH2:15]([O:22][C:23]([N:25]=[C:26]([NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of t-butyl 4-aminobenzoate (2.0 g, 10.3 mmol) in CH2Cl2 (20 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (5.6 g, 15.5 mmol), Et3N (5.0 mL, 36 mmol), and mercuric chloride (3.37 g, 12.4 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite®, and the filtrates were concentrated in vacuo and purified by column chromatography (1:1 CH2Cl2/hexanes to 100% CH2Cl2, and then 10% EtOAc/CH2Cl2) to provide tert-butyl 4-(2,3-bis(benzyloxycarbonyl)guanidino)benzoate (3.9 g, 75%). To a pressure bottle was charged 20% palladium hydroxide on carbon (2 g) followed by a solution of t-butyl 4-(2,3bis(benzyloxycarbonyl)guanidine)benzoate (3.9 g, 7.7 mmol) in EtOAc (80 mL). The mixture was stirred under hydrogen at 50 psi at room temperature overnight. The solution was filtered through Celite® and the filtrate evaporated in vacuo to provide t-butyl guanidinobenzoate (1.8 g, 100%). To the guanidine (855 mg, 3.6 mmol) in EtOAc (50 mL) was add 2M HCl in Et2O (1.9 mL, 3.8 mM). The solution was concentrated and the precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield (840 mg, 85%) of the HCl salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]=[CH:5][CH2:4][O:3]1.C(=O)([O-])[O-:11].[Na+].[Na+].C(#N)C.OO>CO.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]2[CH:5]([O:11]2)[CH2:4][O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCC=CCO1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC1(C)OCC2OC2CO1
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (151.4 g, 1.18 mole) in methanol (500 ml) was added anhydrous sodium carbonate (85 g), followed by acetonitrile (150 ml). This suspension was treated with aqueous hydrogen peroxide (30%; 315 ml, 2.78 mole) dropwise at such a rate that the temperature was maintained at 40°. After 5 hr. at 40°, the reaction mixture was poured into brine (1.5 l) and the solution was extracted with n-butanol. The organic layer was washed with brine, dried, and, then, freed of the solvent in vacuo. Vacuum distillation of the residue yielded the product (III) as a colorless liquid (114 g) (67% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:17]2[CH:16]=[C:15]([C:18]([OH:20])=O)[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(CC)CC>CN(C)C=O.ClCCl>[CH:7]1[C:17]2[CH:16]=[C:15]([C:18]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Reactant: C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C1=Cc2ccccc2Oc2ccccc21)N1CCCCC1
Reaction time: 4 h
Yield: 69 %

Procedure:
1.1 ml (12.59 mmol) of oxalyl chloride and 1 drop of dimethylformamide are added at room temperature to a solution of 3.0 g is (12.59 mmol) of dibenz[b,f]oxepine-10-carboxylic acid in 20 ml of dichloromethane and the mixture is stirred for 4 hours. 1.86 ml (18.88 mmol) of piperidine and 2.62 ml (18.88 mmol) of Et3N are then added and the mixture is stirred at room temperature overnight. The reaction mixture is washed 1× with hydrochloric acid and brine, and the organic phase is dried, concentrated, subjected to column chromatography and crystallised from tert-butyl methyl ether. 2.64 g (8.6 mmol)=69% of dibenz[b,f]oxepin-10-yl-piperidin-1-yl-methanone are obtained in the form of light-yellow crystals; melting point: 127°-128° C.; 1H-NMR (CDCl3, 200 MHz): 1.30-1.50 (mbr, 2H); 1.50-1.70 (mbr, 4H); 3.30-3.45 (mbr, 2H); 363-3.78 (mbr 2H); 6.92 (s, 1H); 7.10-7.40 (m, 8H); MS: 305 (M+), 221, 193, 165; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.32.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1.[Li+].[OH-].O.Cl>C1COCC1>[C:4]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)O)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate prepared above (529 mg, 2.10 mmol) in THF (20 mL), 1N aq. LiOH (7.0 mL, 7.0 mmol) was added. After the mixture was stirred at 40° C. overnight, it was poured into water. The aqueous solution was acidified with 1N HCl to pH 1. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated in vacuo to give 5-ethynyl-thiophene-2-carboxylic acid (316 mg). MS 153 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([S:9]/[CH:10]=[CH:11]/[C:12]3[CH:13]=[N:14][NH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)N[C:38](=[O:40])[CH3:39].[C:43]1([CH2:49][C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.O>O1CCCC1.C(OCC)(=O)C>[C:21]1([CH2:39][C:38]([NH:1][C@@H:2]2[C:33](=[O:34])[N:4]3[C:5]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])=[C:6]([S:9]/[CH:10]=[CH:11]/[C:12]4[CH:13]=[N:14][N:15]([C:50]([CH2:49][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:51])[CH:16]=4)[CH2:7][S:8][C@H:3]23)=[O:40])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C/c3cn[nH]c3)CS[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)N[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C/c3cnn(C(=O)Cc4ccccc4)c3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzhydryl 7β-amino-3-[(E)-2-(4-pyrazolyl)vinylthio]-3-cephem-4-carboxylate (515 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 15 minutes. To the solution was added dropwise a solution of phenylacetyl chloride (146 μl) above at -20° C. for 2 minutes. The mixture was stirred at -20~-15° C. for 1 hour. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with buffer solution (pH 7) and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (eluent: dichloromethane:ethyl acetate=9:1) to give benzhydryl 7β-(2-phenylacetamido)-3-[(E)-2-(1-benzylcarbonylpyrazol-4-yl)vinylthio]-3-cephem-4-carboxylate (93.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1.C1COCC1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CCCCCC[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-chlorobenzoic acid methyl ester (0.5 g, 2.93 mmol), FeCl2 (19 mg, 0.15 mmol), THF (7 mL) and N-methylpyrrolidone (NMP, 1 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1.9 mL, 3.8 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min. Work-up as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (90%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([NH:23]C(=O)OC(C)(C)C)[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5])[NH2:23]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)cn2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-2,2-dimethyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 96, 8.2 mg) in dry dichloromethane (0.5 mL) cooled to 0° C., TFA (57 μl, 0.740 mmol) was added dropwise and the solution was stirred for 3 hours at that temperature. The volatiles were evaporated. The residue was dissolved with dichloromethane (2 mL) and an aqueous saturated solution of NaHCO3 was added (4 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The gathered organic layers were dried over sodium sulphate and evaporated to afford the title compound (6.2 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43]Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][O:29][CH2:41][O:42][CH3:43])[C:17]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(CO)nn(C)c1=O
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.40 g, 5.45 mmol) and diisopropylethylamine (10 ml, 57.4 mmol) in THF (20 ml) was added chloromethyl methyl ether (2.4 ml, 31.6 mmol), and refluxed for 4 hours. After the reaction solution was cooled to room temperature, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.11 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (yield: 80%) as solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]([C:11]1[N:15]([CH3:16])[N:14]([CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)/[C:13](=[N:22]/[C:23](=[O:33])[C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=2F)/[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].CC[O:36]C(C)=O.CO>C1COCC1.CCN(CC)CC>[C:7]([C:11]1[N:15]([CH3:16])[N:14]([CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)/[C:13](=[N:22]/[C:23](=[O:33])[C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=2[O:36][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])/[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C#N)ccc2F)n1CC1CCC1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C#N)ccc2OCC(C)(C)O)n1CC1CCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of Example 81D (0.26 g, 2.9 mmol) in THF (10 mL) at ambient temperature was added potassium tert-butoxide (0.55 g, 4.9 mmol). The mixture was allowed to stir for 20 minutes at ambient temperature then a solution of Example 113D (0.60 g, 1.6 mmol) in THF (5 mL) was added via cannula. The mixture was stirred at ambient temperature for 3 hours then the mixture was quenched with saturated aqueous NaHCO3 (5 mL) and was diluted with EtOAc (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated and purified via column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) to afford the title compound (0.43 g, 0.98 mmol, 60% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (s, 6H) 1.41 (s, 9H) 1.80-1.92 (m, 4H) 1.98-2.07 (m, 2H) 2.53-2.73 (m, 1H) 3.73 (s, 3H) 4.03 (s, 2H) 4.33 (d, J=7.1 Hz, 2H) 6.04 (s, 1H) 6.99 (d, J=8.3 Hz, 1H) 6.99 (s, 1H) 7.56 (dd, J=8.5, 2.2 Hz, 1H) 8.15 (d, J=2.0 Hz, 1H); MS (ESI+) m/z 439 (M+H)+; Anal. calculated for C25H34N4O3: Calc: C, 68.47; H, 7.81; N, 12.78. Found: C, 68.27; H, 7.47; N, 12.68.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[C:33]([CH2:37]I)=[CH:32][N:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[CH2:37][C:33]1[C:34]([Cl:36])=[N:35][C:30]([Cl:29])=[N:31][CH:32]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1c(Cl)cccc1Cl
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 2,6-dichloro-phenylacetic acid methyl ester (2.19 g, 10.0 mmol) (TCI-US) in tetrahydrofliran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(2,6-dichloro-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.57 g, 82.6%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17][NH2:18]>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([NH:18][CH2:17][C:16]2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=2)=[O:10])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)nc1Cl
Yield: 61 %

Procedure:
The title compound was prepared as described in Example 1, but employing 2,4-dichloropyrimidine-5-carbonylchloride (0.10 g, 0.40 mmol) and 3,5-bistrifluoromethylbenzylamine (0.10 g, 0.45 mmol) to give the compound in a 61% yield (0.12 g); m.p. 144°-145° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:28][C:27]=1[O:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1
Reactant: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)cc1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ccc(COc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)ccc2Cl)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in general procedure A. Purification on silica yielded 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]1([C:14](Cl)=O)[CH2:13][CH2:12]1>O1CCOCC1.CN(C)C=O>[CH:11]1([C:14]2[N:1]=[C:2]3[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]([OH:9])[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(O)n2nc(C3CC3)nc2n1

Procedure:
To a solution of Intermediate 1 (0.5 g, 3.57 mmol) in a mixture of 1,4-dioxane (4 mL) and N,N-dimethylformamide (1 mL), cyclopropanecarbonyl chloride (ALDRICH, 0.49 mL, 5.35 mmol) was added and the resulting mixture was heated under reflux overnight. The reaction was then concentrated under vacuum yielding a pale yellow solid which was purified by flash chromatography (Si, eluting with DCM:MeOH mixtures, gradient from 100:0% to 90:10%) to yield a beige solid which was re-purified by flash chromatography (Si, eluting with DCM:MeOH mixtures from 100:0 to 85:15%). The title compound was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([C:31]([OH:33])=O)[CH2:19]3)[C:5]2=[N:6][CH:7]=1.Cl.CN(C)[CH2:37][CH2:38][CH2:39][N:40]=[C:41]=[N:42][CH2:43][CH3:44].O[N:47]1[C:51]2C=[CH:53][CH:54]=[CH:55][C:50]=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@@H:20]([C:31]([N:47]4[CH2:53][CH2:54][CH2:55][CH2:50][CH:51]4[CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[CH:41]4)=[O:33])[CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)C[C@@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)C[C@@H]1C(=O)N1CCCCC1CCCn1ccnc1

Procedure:
1,1-dimethylethyl 4-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6] cyclohepta[ 1,2-b]pyridin-11-yl)-2(R)-carboxy-1-piperazinecarboxylate (0.7225 g, 1.3 mmoles) (prepared as described in Preparative Example 6), the title compound from Preparative Example 8, Step B (0.3382 g, 1.7 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.3354 g, 1.7 mmoles), 1-hydroxybenzotriazole (0.2364 g, 1.7 mmoles) and 4-methylmorpholine (0.192 mL, 1.7 mmoles) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25° C. for 319 h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the partially purified title compounds. The appropriate fractions were rechromatographed using 1.5% (10% conc. NH4OH-methanol)-dichloromethane as the eluant to give title compound as a mixture of 4 diastereoisomers (0.3718 g, 39%): FABMS: m/z 711.4 (MH+); δH (CDCl3) 1.39 (9H, s, CH3), 6.91, 7.08, 7.13, 7.17, 7.56, 7.67 (Ar—H), 6.97 (1H, s, Im-H5), 7.04 (1H, s, Im-H4), 7.58 (1H, s, Im-H2) and 8.38 ppm (1H, m, Ar—H2); δC(CDCl3) CH3: 28.3/28.4, 28.3/28.4, 28.3/28.4; CH2: 18.9, 24.9/25.0/25.5, 26.8, 30.2, 30.5, 36.2, 40.1, 42.7/43.0, 46.5/46.7, 50.1/50.3/50.7, 52.7/52.9; CH: 46.9, 51.6/52.0, 78.5, 119.0, 126.2/126.3, 128.6, 130.8/130.9, 132.6, 137.0, 141.5, 146.9/147.2; C: 80.2, ˜120.1, 134.3, 134.9, 137.6, 140.8, ˜155.1/156.1, ˜156.8, ˜170.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (74.9 g, 299.8 mmol) in methanol (900 mL) was added hydroxylamine hydrochloride (104 g, 1.49 mol) followed by sodium hydroxide (600 mL, 10% aqueous, 1.5 mol). The resultant suspension was heated to reflux for 2 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue taken up in ether and water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g, 86%) as a white solid. 1H NMR (CDCl3): δ 8.69 (s, 1 H), 7.71 (dd, 2 H), 7.53 (t, 1 H), 7.18–7.16 (m, 2 H), 7.03 (t, 2 H), 4.37 (s, 2 H); 19F NMR (CDCl3) δ −111.77; MS m/z 265 (M+1).