Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:41](B(CC)CC)[CH3:42]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:41][CH3:42])=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Reactant: CCB(CC)CC
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: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To the mixture of 0.3g (0.59 mmol, 1.0 eqv) of ethyl 6-chloro-7-(2-chloro-4-bromophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 0.32 g (2.3 mmol) of potassium carbonate, 68 mg (0.059 mmol ) of tetrakistriphenyl-phosphinepalladium (0), and 2.5 mL of anhydrous DMF under nitrogen was added 0.83 mL (0.83 mmol, 1.0 M in THF) of triethylborane. The mixture was heated to 110° C. and shaken for five hrs. LC-MS indicated that the reaction was completed. After cooling to room temperature, the reaction was added to 50 mL of ethyl acetate. The resulting organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane to afford 0.23 g (84.7%) of a light yellow solid. The product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][CH:3]=1
Reactant: CC(O)(CO)c1nc(Br)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propane-1,2-diol (18.29 g, 73.1 mmol) in dichloromethane (350 ml) was added triethylamine (20.39 ml, 146 mmol). Methanesulfonyl chloride (6.27 ml, 80 mmol) was added dropwise at 0° C. over 10 minutes. Stirring was continued at 0° C. for 30 minutes. The reaction mixture was washed with sat. sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 31.46 g (crude, used without further purification in the next step). LCMS RtH5=0.81 min. (ES+ 328, 330); 1H-NMR (360 MHz, CDCl3): 7.52 (dd, 1H), 7.41 (dd, 1H), 5.13 (s, 1H, OH), 4.61 (d, 1H), 4.45 (d, 1H), 3.05 (s, 3H, CH3SO2), 1.61 (s, 3H, CH3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]#[N:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: COc1ccc(C=CC#N)cc1
Yield: 59.5 %

Procedure:
A solution of 4-iodoanisole (1 g, 4.2 mmol), acrylonitrile (0.3 ml, 4.7 mmol), tri-o-tolylphosphine (243 mg, 0.4 mmol), palladium (II) acetate (90 mg, 0.4 mmol) and triethylamine (1.78 ml, 12 mmol) in acetonitrile (20 ml) was refluxed under nitrogen for 14 hours. The reaction mixture was diluted with EtOAc (50 ml) and washed with 2M sodium hydrogen carbonate (100 ml), the organic layer was dried over magnessium sulphate and filtered. The filtrate was evaporated in vacuo and purified by column chromatography using pentane, then 95:5 pentane:ethyl acetate, then 90:10 pentane:ethyl acetate to give the title compound (414 mg, 2.5 mmol) as a mixture of cis and trans isomers as yellow crystals, 1H NMR (CDCl3 400 MHz) δ: 3.8 (s, 3H), 5.7 (d, 1H), 6.9 (d, 1H), 7.2 (d, 1H), 7.4 (d, 2H); LRMS: m/z 176 (M+NH4+); Anal. Found C, 74.44; H, 5.66; N, 8.36. C10H39NO.0.1H2O requires C, 74.42; H, 5.65; N, 8.41%.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: P([O-])([O-])([O-])=O.[B+3].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[NH3:19]>>[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]#[N:19])=[CH:10][CH:9]=1.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: N
Agent: CCOC(=O)c1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [B+3]
Product: N#Cc1ccc(O)cc1
Reaction time: 0 h

Procedure:
A reaction tube having an inside diameter of 5 cm was filled with 440 g of a supported catalyst composed of 4.35% by weight of boron phosphate (P2O5 /B2O3 mole ratio=1) deposited on the same silica carrier as in Example 1. Ethyl p-hydroxybenzoate, ammonia and steam were introduced into the reaction tube at a rate of 71.6 g/hr, 281.9 g/hr and 43.4 g/hr, respectively, and reacted in the vapor phase at 410° C. The mole ratio of ammonia, steam and ethyl p-hydroxybenzoate in the gaseous mixture was 38.5:5.6:1, and the contact time was 7.5 seconds. When the reaction was continued for 92 hours, 4.477 kg of p-hydroxybenzonitrile was obtained from 6.587 kg of ethyl p-hydroxybenzoate. The yield of the product was 94.8% by weight. Gas-chromatographic analysis showed that only 1.2% by weight of phenol was formed as a by-product. The amount of p-hydroxybenzonitrile obtained was more than 10.1 parts by weight per part by weight of the supported catalyst.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[N+:14]([C:17]1[CH:18]=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1)([O-:16])=[O:15]>C(Cl)(Cl)Cl>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:24](=[O:23])[C:19]4=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=[C:20]4[C:21]3=[O:22])[CH2:3][CH2:4]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCN(C2CCCCC2)CC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(C2CCCCC2)CC1

Procedure:
6.85 Grams of 4-amino-1-cyclohexylpiperidine were added to 7.26 grams of 4-nitrophthalic anhydride in 100 milliliters of chloroform and the solution was evaporated to dryness. 50 millilters of acetic anhydride were then added and the solution was heated on a steam bath for half an hour. The excess acetic anhydride was evaporated off and the residue dissolved in 40 millilters of isopropyl alcohol and the product crystallised out. This was filtered, dried and dissolved in the least amount of ethanol and ethereal hydrogen chloride added to give 2.85 grams of the title compound which was collected as the monohydrochloride. Melting Point: 265°-270° C.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-:26].[Na+].[O-]Cl.[Na+]>C(OCC)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:26])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: [OH-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -10 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A flask equipped with a stirrer is charged with ethyl acetate (140 ml). Under mixing, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]thio]-1H-benzimidazole VI (5 g, 13.6 mmol) is added to the flask followed by 18.8% aq. NaOH (11.5 ml, d=1.16 g ml−1, 4.9 eq.). The reactor is cooled to −10° C. 9.7% NaOCl (9.7 ml, d=1.16 g ml−1, 1.04 eq.) is added dropwise over 15 min. The two-phase mixture is stirred at room temperature for 3 h. The phases are then separated, and 27% aq. sodium metabisulfite (Na2S2O5) (7 ml) is added to the aqueous phase to quench unreacted oxidant. The organic phase is washed with water, and the aqueous phase is washed twice with ethyl acetate. The organic phases are combined, dried over sodium sulfate (Na2SO4), and evaporated under 20 mm Hg vacuum. The resulting oil is triturated with methyl t-butyl ether and filtered to obtain pantoprazole (3.7 g, yield 71%) which contains 0.04% sulfone and 0.03% compound VI as within the limit of UV detection.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:16]([NH:23][C:24]([NH2:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:26][C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Reactant: NC(=O)NCc1ccccc1
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2c1

Procedure:
The title compound was prepared from dimethyl 2-bromoterephthalate (2.4 g, 8.8 mmol) and benzylurea (1.7 g, 11.4 mmol) following the procedure outlined in Example 14, step 1 (1.8 g, 66%). LC-MS: (FA) ES+ 311.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH:30][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCCc1oc(-c2ccccc2)nc1C(=O)O
Product: CCCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-propyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-phenyl-5-propyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:15]>C(O)CCC>[CH3:13][O:12][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:15])[C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: [NH4+]
Reactant: COc1ncnc(F)c1C(F)(F)F
Agent: [OH-]
Solvent: CCCCO
Product: COc1ncnc(N)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-6-methoxy-5-(trifluoromethyl)pyrimidine (N-2) (1.10 g, 5.61 mmol) in n-butanol (4 mL) in a pressure vessel, ammonium hydroxide (5 mL) is added and the resulting mixture is stirred at 90° C. for 1 h. The mixture is allowed to cool to RT, quenched with water, and extracted with ethyl acetate (100 mL×2). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product 6-methoxy-5-(trifluoromethyl)pyrimidin-4-amine (N-3) as an off-white solid. The product is used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(Cl)cc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 29.7 %

Procedure:
The acid from Step 1 (9.01 g, 29.6 mmol) and triethylamine (3.03 g, 29.9 mmol) were dissolved in 45 mL of anhydrous toluene, cooled to 0° C. and treated with diphenylphosphoryl azide (8.22 g, 29.9 mmol). The solution was maintained at 0° C. for 10 minutes and warmed to room temperature for 2 hours. The reaction was poured into water, extracted with ether, dried over anhydrous MgSO4, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to 90° C. for 15 minutes. Tert-Butyl alcohol (10 mL) was added to the reaction mixture. After an additional twenty minutes, concentrated hydrochloric acid (8 mL) was cautiously added and the reaction maintained at 90° C. for 15 minutes. The solution was cooled to room temperature and a precipitate formed that was isolated by filtration, washed with ether and air dried to provide the desired ketone as a white solid (2.43 g, 30%): mp 143°-147.5° C. 1H NMR (CDCl3) 300 MHz 8.08 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.24 (m, 4H), 4.35 (s, 2H), 2.05 (s, 3H). Mass spectrum: M+H=277.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:21]1[CH:26]=[CH:25][C:24]([O:27][Si](C(C)(C)C)(C)C)=[CH:23][CH:22]=1)[N:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:5]([CH:4]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[C:3]([O:2][CH3:1])=[O:35])[CH3:6])(=[O:9])=[O:8])=[CH:11][CH:12]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55769.2 %

Procedure:
To a solution of 6.0 g (0.012 mmol) of [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester in 100 mL of THF was added 11.6 mL of a 1.0M solution of tetrabutylammonium fluoride in THF. The reaction was stirred for 1 h at room temperature and then acidified with 5% HCl solution and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to give 2.7 g of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate as a white solid. . Electrospray Mass Spec 404.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20]([N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 4-hydroxypiperidine (50 mg, 0.49 mL) in anhydrous DMSO (3 mL) was heated at 100° C. under nitrogen for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 55 mg, 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: COC(=O)Cc1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Compound 50.1 (4 g, 10 mmol) in THF (12 mL) was added dropwise to LDA in THF (1M, 12 mL) at −78° C. The resulting mixture was stirred for 30 min. before tert-butyl bromoacetate (2.15 g, 11 mmol) in THF (2 mL) was added over 10 min. The reaction mixture was stirred for 2 h at −78° C. and allowed to warm slowly to 0° C. The reaction was quenched with saturated aqueous NH4Cl (20 mL). The organic phase was extracted with ethyl acetate (25 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 3.3 g of 50.2. MS ESI (pos.) m/e: 537 (M+Na). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.68 (1H, s); 7.58-7.49 (3H, m); 7.25-7.24 (2H, m); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04-4.0 (1H, m); 3.7 (3H, s); 3.1 (1H, m); 2.63 (1H, m); 1.42 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:25]([CH3:27])[CH3:26])[C:13]([NH:15][C:16]1[C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:14])[NH:15][C:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:21]=1[C:22](=[O:24])[NH:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1ccncc1C(=O)O
Reactant: NCc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1ccncc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
Formulae 508 and 509 where R1, R3 and R4 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; W, Y and Z are —C═; and X is —N═: A solution of dichloromethane (200 mL), 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid (10.0 g, 26.9 mmol) and EDC (7.74 g, 40.4 mmol) was stirred at room temperature for 2 hours until the complete consumption of the starting material was observed by reverse phase HPLC. Benzylamine (5.88 mL, 53.8 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:2) as eluents to obtain the uncyclized product of Formula 508, [1-(3-benzylcarbamoyl-pyridin-4-ylcarbamoyl)-2-methyl-propyl]carbamic acid benzyl ester (4.45 g, 35.9%) and the cyclized product of Formula 509, [1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propyl]-carbamic acid benzyl ester (1.85 g, 15.5%). 508: MS (Cl) M/E: 461.2; 509: MS (Cl) M/E: 443.2.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1)([O:13][CH3:14])=[O:12]>>[C:11]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:25])=[CH:21][CH:22]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: Cc1nc(C(O)CN)cs1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using ethyl acetate/methanol=9:1 as eluant.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:42])[CH2:39][CH2:40][CH3:41]>>[CH2:38]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCO
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CCCCOc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) with 2 equivalents each of n-butyl lithium and n-butanol by the procedure described in Reference Examples 6 and 7 to afford 2-(2-n-butyloxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=500 (M++1); Rt=4.34 min. 1H-NMR 500 MHz (CDCl3): δ 0.93 (t, 3H), 1.40-1.46 (m, 2H), 1.70-1.75 (m, 2H), 4.22-4.26 (t, 2H), 7.18-7.30 (m, 7H), 7.40-7.42 (m, 1H), 7.57-7.60 (m, 1H), 8.54-8.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:10][C@@H:9]1[CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1COS(C)(=O)=O
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10.85 g, 50.0 mmol) in pyridine (50 mL) was added methanesulfonyl chloride (10.8 mL, 140 mmol) over a period of 20 min. After stirring for 16 h, the reaction mixture was concentrated to dryness, diluted with satd. aq. Na2CO3 and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered and concentrated to provide the title compound as an oil that slowly solidified (14.4 g, 84%). 1H NMR (400 MHz, CDCl3): 5.24-5.20 (m, 1H), 4.72-4.47 (m, 1H), 4.32-4.17 (m, 2H), 4.01-3.75 (m, 1H), 3.63-3.48 (m, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.60-2.25 (m, 2H), 1.48 (s, 9H).