Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Cl[CH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: ClCc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ncccn3)c3ccccc3c2=O)cc1C
Temperature: 80 °C
Yield: 44.1 %

Procedure:
Compound 4k was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 97 mg (0.35 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 18 mg (0.45 mmol) of 60% sodium hydride and 66 mg (0.51 mmol) of 2-chloromethyl pyrimidine (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) were combined in 1 mL N,N-dimethylformamide and heated at 80° C. for 2 h. The product was purified using reverse phase HPLC (mobile phase with a gradient 10-50% acetonitrile in 50 min), to give 57 mg of a pale yellow solid 4k as trifluoroacetate salt: LC-MSD, m/z for C23H19N3O2 [M+H]+=370.5, HPLC retention time: 2.4 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 7.15-7.2 (m, 1H), 7.25-7.3 (m, 1H), 7.4-7.5 (m, 1H), 7.5-7.55 (m, 1H), 7.6-7.7 (m, 3H), 8.4-8.5 (m, 2H), 8.7-8.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:20])[CH:18]=O)[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][NH2:40])([O-:29])=[O:28].OS(O)(=O)=O>C(O)C.O>[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][N:40]=[CH:18][CH:17]([CH3:20])[N:14]1[C:13]2[CH:21]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([F:22])[C:3]([C:23]([F:26])([F:25])[F:24])=[C:2]([Cl:1])[CH:7]=3)[CH:10]=[CH:11][C:12]=2[N:16]=[N:15]1)([O-:29])=[O:28]
Reactant: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C=NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazol-1-acetaldehyde (0.0294 mole) in ethanol is added to a solution of 2,4-dinitrophenylhydrazine (7 g, 0.035 mole) and conc. H2SO4 (35 ml, 0.63 mole) in H2O at 50° C., allowed to come to room temperature and filtered. The solid filter cake is recrystallized from aqueous acetic acid and from ethanol to afford the title compound, mp 148°-149° C., identified by elemental and NMR analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:12]=1)=[O:5])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH:42][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH2:13][N:11]2[CH:12]=[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:10]2)=[CH:15][CH:16]=1)=[O:20]
Reactant: Cc1oc(-c2ccccc2)nc1CN
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2)nc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82.8 %

Procedure:
A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (500 mg), (5-methyl-2-phenyl-4-oxazolyl)methylamine (260 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained yellow crystals were collected by filtration, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg, yield: 87%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 190–191° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)(=O)C.[O-:16][C:17]#[N:18].[Na+]>O1CCCC1>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:17]([NH2:18])=[O:16]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C(N)=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 25.4 %

Procedure:
A 250-mL round bottom flask was charged with N-methyl-4-nitroaniline (1.94 g, 12.7 mmol) in tetrahydrofuran (50 mL). To this stirred solution at rt was added acetic acid (14.6 mL, 255 mmol) and sodium cyanate (8.29 g, 127.5 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water (100 mL) and the resultant solid was isolated by filtration, washing sequentially with dichloromethane and ethyl acetate to afford the title compound (0.63 g, 25%) as a yellow solid. MW=195.18. 1H NMR (DMSO-d6, 500 MHz) δ 8.19-8.14 (m, 2H), 7.58-7.54 (m, 2H), 6.54 (br s, 2H), 3.27 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH3:26][CH:27]([NH2:29])[CH3:28]>C1COCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([NH:29][CH:27]([CH3:28])[CH3:26])=[O:18])[CH2:14][CH2:15]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1
Reactant: CC(C)N
Reactant: O=C(O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride (0.500 g, 1.487 mmol) was suspended in THF (3 mL). Thionyl chloride (0.434 mL, 5.95 mmol) was added to the suspension, and the reaction mixture was stirred at 20° C. for 2 hours. The resulting mixture was concentrated in vacuo. The solid was resuspended in THF (5 mL) and then propan-2-amine (0.153 mL, 1.785 mmol) was added. The mixture was stirred at RT for 16 hours, and additional propan-2-amine (0.128 mL, 1.487 mmol) was added. Stirring at RT was continued for 1 hour. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine. The organic layer was concentrated in vacuo, and the residual material was purified via silica gel chromatography, eluting with 20-100% EtOAc in hexanes, to yield trans-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as a yellow solid (0.312 g, 61.6% yield). MS m/z=341.0 [M+H], calc 340.81 for C15H21ClN4O3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.C(O)(C)C>CC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:21])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A stirred solution of (9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracene-9-carboxaldehyde prepared as in Example 1i (290.5 g, 1.14 moles) dissolved in acetone (5.0 L) was cooled to 10° C. and treated with Jones Reagent (950 ml, ~ 1.19 moles) over a period of 1 h. The reaction mixture was stirred overnight at room temperature, then analyzed by TLC [silica gel/methylene chloride:hexane (1:1)]. Conversion of the aldehyde (Rf =0.50) to the desired carboxylic acid (Rf =0.0-0.15) was shown to be complete. Isopropanol (150 ml) was added, and the mixture stirred for another 3 h to quench any excess Jones Reagent. The acetone supernatant was decanted away from the green-black sludge that had formed, and the sludge was washed with acetone (2×1 L). The combined acetone solutions were concentrated on the rotary evaporator to a volume of 1.5 L, then poured into ice/water (6 L) with vigorous stirring. A yellow-white gum precipitated and gradually solidified with continued stirring. The solid was collected by filtration, pulverized to a fine off-white powder in a mortar & pestle, then rewashed with cold water (2×1 L). Vacuum drying afforded the title compound as an off-white powder (304.8 g, 98.7%), mp 175°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13](=[CH2:15])[CH3:14].[C:16](C1C=CC(O)=CC=1)([CH3:18])=[CH2:17]>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:14])[CH3:12].[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][C:9]=1[C:13]([CH3:14])([CH3:12])[CH3:15])[C:1]([CH3:4])([CH3:2])[CH2:3][C:16]2([CH3:18])[CH3:17]
Reactant: C=C(C)C
Reactant: C=C(C)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1cc2c(cc1O)C(C)(C)CC2(C)C
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
150 g (1 mol) of 4-tert.-butylphenol and 400 g of an acid-activated fuller's earth are introduced into an autoclave. 1650 g (29.5 mol) of isobutylene and 2600 g (9.7 mol) of molten dimeric 4-isopropenylphenol are then simultaneously pumped in over a period of about 4 to 5 hours at a temperature of around 180° C. The mixture is then left to react for 4 hours at around 180° C. The hot reaction mixture is then filtered off from the catalyst under suction, 4184 g of crude product being obtained in this way. Fractional distillation gives 1980 g (10.4 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane and 564 g (2.3 mol) of 5-hydroxy-6-tert.-butyl-1,1,3,3-tetramethyl indane.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Br-]>CN(C=O)C>[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 28) (7.27 g, 18.5 mmol) in anhydrous DMF (60 ml), sodium azide (2.33 g, 37 mmol) was added and the mixture was stirred at room temperature for 2 hour. The TLC of the RM showed the complete disappearance of the starting bromide. The reaction mixture was poured into ice water (300 ml) and extracted with EtOAc (3×100 ml). The organic layer was washed with water (100 ml), brine (100 ml) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 30% EtOAc in hexanes as eluent to isolate 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (6.16 g, 94%) as a low melting solid. 1H NMR (300 MHz) δ 0.57 (d, 3H), 1.07 (d, 3H), 2.50-2.74 (m, 1H), 2.98 (s, 3H), 3.71 (d, 1H), 5.05 (d, 1H), 5.78 (d, 1H), 7.12-7.40 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)C.O.[Li+].[OH-].Cl>C1COCC1.CCO>[Cl:11][C:9]1[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)n1
Temperature: 55 °C

Procedure:
To a solution of 5-chloro-6-{4-[6-(4-fluoro-phenyl)2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (427 mg, 0.813 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H20 (350 mg, 8.13 mmol) followed by a small amount of EtOH. Heat the mixture at 55° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue, followed by 8.13 mmol of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15].N1C=CC=CC=1>CN(C=O)C>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:15]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
To a solution of 5-aminoindan (4.66 g, 35.0 mmol) in anhydrous DMF (26 ml) was slowly added methoxyacetyl chloride (5.70 g, 52.50 mmol) followed by pyridine (8.5 ml, 105.0 mmol). The red solution was stirred at room temperature for 3.5 hours under argon, then it was partitioned between ethyl acetate (200 ml) and 1N HCl (120 ml). The organic layer was washed with more 1N HCl (120 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with diethyl ether; the white precipitate was collected by filtration, washed with diethyl ether to afford the title compound (5.93 g, 83%), m.p. 104-105° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.06 (m, 2H, 2-CH2), 2.87 (m, 4H, 1-CH2 and 3-CH2), 3.50 (s, 3H, OCH3), 4.00 (s, 2H, 2≧CH2OMe), 7.22 (m (overlap with CHCl3 peak), 2H, 6-H, 7-H), 7.52 (s, 1H, 4-H), 8.18 (s, 1H, CONH); MS (ESI, m/z): 432 [(2M+Na)+, 30%], 206 [(M+H)+, 100%]; Found C, 70.10; H, 7.38; N, 6.81. C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1.I[CH3:14]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]2[N:12]([CH3:14])[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Sodium hydride (60%, 670 mg, 16.8 mmol) was added to a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (3.00 g, 15.2 mmol) in DMF (20 mL) at 0° C., and the reaction mixture was stirred for 30 minutes. Iodomethane (1.05 mL, 16.8 mmol) was added. The reaction mixture was subsequently stirred for 30 minutes while warming to RT, diluted with EtOAc, quenched and washed with brine. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were dried over MgSO4, concentrated, and purified by silica gel chromatography (50% EtOAc/DCM) to give the title compound as a white solid (2.98 g, 93%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38 (d, 1H, J=2.0 Hz), 8.21 (d, 1H, J=2.0 Hz), 7.65 (d, 1H, J=3.5 Hz), 6.57 (d, 1H, J=3.5 Hz), 3.81 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C8H7BrN2, 211, 213; found 211, 213.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (1.00 g, 4.66 mmol) in methanol (10.0 mL) was treated with SOCl2 (0.68 mL, 9.32 mmol). After stirring overnight at ambient temperature, the solution was concentrated in vacuo and taken on without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.04 (d, J=2.3 Hz, 1 H) 7.89 (dd, J=8.7, 2.1 Hz, 1 H) 6.93 (d, J=8.6 Hz, 1 H) 4.66 (qq, J=6.1 Hz, 1 H) 3.88 (s, 3 H) 1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 229 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-:3])=[O:2].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.Cl>CN(C)C=O.O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:11]#[N:12])[N:18]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(C(C#N)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
50 g (0.31 M) of 2-(2-nitrophenyl)acetonitrile was dissolved in 500 ml of dimethylformamide. Thereto was added 24.7 g (0.62 M) of 60% sodium hydride. The mixture was stirred at room temperature for 2 hours. Then, 68 g (0.31 M) of 4,6-dimethoxy-2-methanesulfonylpyrimidine was added. The mixture was stirred at 80° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by neutralization with dilute hydrochloric acid. The mixture was subjected to extraction with ethyl acetate. The extract was washed with water, dried and subjected to vacuum distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 73.3 g (yield: 79%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile as a white powder (melting point: 88 to 89° C.).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[CH2:18]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=N)CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
610 mg of (2S, 4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4-nitrobenzyloxycarbonylacetimidoylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 1.19 ml of anisole, and 4.23 ml of trifluoroacetic acid and 193 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 1 hour under the same conditions and then at room temperature for a further 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane and with diethyl ether and dried by evaporation under reduced pressure, to convert it to the trifluoromethanesulfonate in the form of a powder. Ethyl acetate was added to the whole of this compound, followed by sufficient of a saturated aqueous solution of sodium hydrogencarbonate to make it alkaline. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure, to give 448 mg of the title compound as a powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][SH:79]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccccn1
Reactant: SCc1ccccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(C(F)(F)F)c(SCc2ccccc2Cl)s1)c1ccccn1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial was charged with N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)picolinamide (0.06 g, 0.2 mmol), diisopropylethylamine (59 μL, 0.34 mmol), Pd2(dba)3 (0.0048 g, 0.0085 mmol), Xantphos (0.0099 g, 0.017 mmol), 1,4-dioxane (0.6 mL) and 2-chlorophenylmethanethiol (22 μL, 0.17 mmol). The reaction mixture was purged with argon for 5 min; the vial was capped and heated at 100° C. for 15 h. the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered, washing with ethyl acetate (10 mL) and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 30% to give the product.
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O.CCOC(C)=O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[CH:7]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[O:10][N:9]=3)=[O:13])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)C(O)c1cc(C(=O)O)no1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Yield: 1.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid (2.160 mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.800 mmol, 0.502 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2 M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.0146 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 0.89 (d, 3H), 0.92-0.98 (m, 3H), 1.26 (d, 3H), 2.01-2.13 (m, 1H), 4.28-4.45 (m, 2H), 4.51-4.64 (m, 2H), 6.53 (d, 1H), 6.79 (d, 1H), 7.68-7.77 (m, 2H), 7.91 (s, 1H).