Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:1](=[O:2])[CH3:3])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
AcCl (0.063 mL, 0.88 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (252 mg, 0.840 mmol) and DIPEA (0.575 mL, 3.36 mmol) in CH2Cl2 (8.4 mL). The mixture was stirred at rt for 30 min, and aq. sat. NH4Cl was added. The layers were separated, and the org. layer was washed with aq. 1M NaOH, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (190 mg, 66%). LC-MS: tR=1.09 min; ES+: 342.19.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[N:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1nccc1CNc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
Acetic acid (0.87 mL) was added to a chloroform (10 mL) solution that contained 1-methyl-1H-pyrazol-5-carbaldehyde (1.00 g) and 4-aminobenzotrifluoride (1.76 g) at a room temperature, and the obtained solution was then stirred for 10 minutes. Thereafter, sodium triacetoxyborohydride (2.89 g) was added to the reaction solution, and the obtained mixture was then stirred for 5.5 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (1.88 g) in the form of a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:12][C:11]=1[NH:10][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: O=C(Cl)c1cccnc1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3cccnc3)c2)cc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 2, pyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)4-cyanobenzamide to give the title compound in 67% yield; NMR Spectrum: (DMSOd6) 7.57 (d, 1H), 7.59 (m, 1H), 7.73 (d, 1H), 8.01 (d, 2H), 8.10 (m, 3H), 8.34 (d, 1H), 8.79 (d, 1H), 9.15 (d, 1H), 10.33 (s, 1H), 10.66 (s, 1H); Mass Spectrum M+H+ 377.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.S(=O)(=O)(O)[OH:13]>>[OH:13][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1]
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: O=S(=O)(O)O
Product: CC1=CCC(O)(C(C)(C)O)CC1
Reaction time: 20 h

Procedure:
A mixture of 26.0 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene and 250 ml of 1% sulfuric acid was stirred magnetically for 20 hours, then extracted with four 100 ml portions of methylene chloride. The combined methylene chloride extracts was washed, dried, concentrated and Claisen-distilled to give 22.4 g of the desired product, b.p. 78°-81° C. (0.15 mm).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[N:4][C:3]2[C:12]([OH:13])=[N:14][CH:15]=[N:1][C:2]=2[CH:7]=1
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCOC(OCC)OCC
Product: Oc1ncnc2cc(C(F)(F)F)cnc12
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-amino-5-trifluoromethyl-pyridine-2-carboxylic acid amide (500 mg, 2.44 mmol) and triethoxymethane (1.8 g, 12.2 mmol) were heated to 120° C. for 16 h. The mixture was cooled to ambient temperature and treated with low boiling PE. The reaction mixture was stirred for 10 minutes, cooled to 0° C. and the beige solid was collected by filtration (350 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][S-:12].[Na+]>C(O)C>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:12][CH3:11])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: C[S-]
Reactant: Cc1c(N)nnc(Cl)c1C
Agent: [Na+]
Solvent: CCO
Product: CSc1nnc(N)c(C)c1C
Yield: 42.3 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 400 mg, 2.54 mmol, 1.0 eq) and sodium methanethiolate (196 mg, 2.79 mmol, 1.1 eq) in 10.4 mL ethanol were heated for 1 h to 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 50 g SNAP cartridge: DCM/ethanol 95/5→DCM/ethanol 4/1) to give 182 mg (21% yield) of the title compound in 50% purity (UPLC, area-%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.[CH:26]1([CH2:29][NH:30][CH2:31][CH3:32])[CH2:28][CH2:27]1>C(COC)OC>[CH:26]1([CH2:29][N:30]([CH2:31][CH3:32])[C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]1
Reactant: CCNCC1CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCN(CC1CC1)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
To a stirred solution of 15.0 grams (0.05 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 4.97 grams (0.05 mole) of triethylamine in 200 ml. of dimethoxyethane was added, dropwise, 4.28 grams (0.05 mole) of N-cyclopropylmethyl-N-ethylamine at room temperature over a period of 2.5 hours. The resultant mixture was then heated under reflux for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue then dissolved in a mixture of chloroform and water. The organic layer was separated and was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate, and then water. After drying over anhydrous sodium sulfate, the organic solution was evaporated to dryness. The residue was dissolved in hexane and filtered and then evaporated to dryness to give 12.85 grams of the product as as dark, viscous amber liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-]>FC(F)(F)C(O)=O.ClCCl>[CH3:30][C:25]1[C:24]([O:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]3[N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:15]=[CH:16][C:17]=23)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Reaction time: 2.5 h
Yield: 68.8 %

Procedure:
A solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 710 mg, 1.7 mmol) in 20% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 40 min, then the solvents were evaporated and the residue held under high vacuum to give a pale yellow thick oil. SiliaBond Carbonate (Silicycle, Quebec City, Canada; 4 equivalents) was added and the mixture was stirred slowly for 2.5 h, then filtered. The filtrate was evaporated and held under high vacuum to give 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (363 mg, 68%) as a white solid.
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].Cl.[NH2:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>C(O)C.C(O)C.O>[O:15]=[C:14]1[NH:16][C:17](=[O:18])[CH2:19][N:13]1[N:12]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1]
Reactant: NN1CC(=O)NC1=O
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#CC=CC(=O)C=NN1CC(=O)NC1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A solution of 5-azido-2-furaldehyde (240 mg, 1.75 millimole (mmole)) in 20 milliliters (ml) of ethanol was added dropwise over 10-20 minutes to a solution of 1-aminohydantoin hydrochloride (320 mg, 2.1 mmole) in 25 ml of ethanol:water (4:1) and the mixture was chilled in an ice bath. The reaction mixture turned into a yellow-orange suspension within thirty minutes and was gradually heated to about 60° C. to form a complete solution. The heating continued for another 24 hours after which time it was allowed to cool and evaporated to dryness. The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper. The filtrate was evaporated to dryness. The residue was dissolved in 3 ml of acetone and streaked on two preparative silica gel TLC plates (EM Science, Cat # 5717-7) and developed with ethyl acetate: petroleum ether (3:1). The fast moving major band (Rf around 0.51) detected under UV light was stripped, and the silica gel was ground to a fine powder and eluted with acetone. The acetone eluent was evaporated to give a pale yellow solid which showed a homogeneous single spot on TLC (137 mg, 0.67 mmole, 38% yield). Alternatively the crude reaction product can be purified by silica gel column chromatography and further recrystallized from 30% ethyl acetate/hexanes to give the pure desired product (mp 171-173° C.). Elemental analysis supported a molecular formula of C8H6N4O3. 0.15 EtOAc. The structure of compound 1 was established by 1H and 13C NMR analysis as shown in FIGS. 1-4. 1H NMR analysis of 1 revealed that the acrylonitrile moiety has a trans (E)-configuration (coupling constant J=16.5 Hz). MALDI-TOF mass spectral analysis confirmed structure 1 with the M+1 peak of 207.22
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl)-amide (500 mg; 2.27 mmol) was dissolved in 5 ml of pyridine, treated with acetic anhydride (240 μl, 2.5 mmol) then stirred at room temperature overnight. The solvent was removed by evaporation then dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water then dried under vacuum. The product was isolated as an off white solid (275 mg). (LC/MS: Rt 2.96, [M+H]+ 262.91).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25]([O:27]CC)=O>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 65.1 %

Procedure:
A solution of 12.63 g of aniline and 10.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 7.55 g (65%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-phenyl-3-quinolinecarboxamide, m.p. 120° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([Cl:14])=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([O:21][CH3:22])[NH:18][N:17]=2)[N:3]=1.Cl.[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:5]1[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:7][C:2]([NH:33][C@H:31]([C:28]2[N:29]=[CH:30][C:25]([F:24])=[CH:26][N:27]=2)[CH3:32])=[N:3][C:4]=1[NH:15][C:16]1[CH:20]=[C:19]([O:21][CH3:22])[NH:18][N:17]=1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 76.8 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide (Method 25, 63.8 mg, 0.174 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 61.7 mg, 0.348 mmol), and DIPEA (0.122 ml, 0.693 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (63.1 mg, 77%). LC-MS: 472 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 11.71 (s, 1H), 9.40 (s, 1H), 8.77 (s, 2H), 7.91 (s, 1H), 5.65 (s, 1H), 5.07-5.10 (m, 1H), 3.79 (s, 3H), 3.01 (s, 6H), 1.54 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
13 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is heated to reflux with 9 g of propargyl alcohol and 0.1 g of p-toluenesulphonic acid. The excess propargyl alcohol is thereupon slowly (5 hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether phase is dried with sodium sulfate and evaporated. There is obtained dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester which is purified on Kieselgel.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[OH:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>O1CCCC1>[CH3:1][O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)(C)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl formamide (100 ml) and tetrahydrofuran (300 ml) were placed in a 1000 ml three-neck round-bottom flask equipped with a thermometer, a mechanical stirrer, and a dropping funnel. An 80% dispersion of sodium hydride in oil (19.80 g, 0.66 mol) was added to form a gray suspension. The suspension was cooled in an ice-water bath. Methyl hydroxyisobutyrate (70.8 g, 0.60 mol) was dissolved in tetrahydrofuran (50 ml) and added slowly to the cooled sodium hydride suspension while the temperature was held below 15° C. The resulting suspension was stirred for one hour. Methyl iodide (freshly distilled, 108.75 g, 0.75 mol) in tetrahydrofuran (25 ml) was slowly added to the cooled suspension. The addition took 1.5 hours, during which the temperature was held below 15° C. The suspension was stirred and allowed to warm to room temperature for 15 hours. The suspension was poured into ethyl acetate (300 ml) and water (300 ml). The clear layers were separated and the aqueous phase was extracted with ethyl acetate (300 ml). The combined organic layers were decolorized with water (200 ml) containing sodium bisulfite (10 g). The organic phase was separated and dried over magnesium sulfate. The solvent was mostly removed by rotary evaporation (25 mm Hg, 30° C.). The resulting solution was distilled at atmospheric pressure and the product collected at 137°-146° C. The product was contaminated with DMF, but by NMR the yield of product was 48.8 g (61%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>O1CCOCC1>[Cl:3][CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Solvent: C1COCCO1
Product: O=c1[nH]cc(CCl)c(=O)[nH]1
Yield: 100 %

Procedure:
Thionyl chloride ((10 ml) was added to a suspension of 5-(hydroxymethyl)-2,4(1H,3H)-pyrimidinedione (0.60 g, 4.2 mmol)from step (11a) in dioxane (15 ml). The reaction was heated to reflux for 4 h, allowed to cool, and concentrated in vacuo to give the 5-(chloromethyl)-2,4(1H,3H)-pyrimidinedione (0.62 g, 100%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>CC(N(C)C)=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(CCc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 145.8 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(3-phenylpropionylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (490 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (250 mg) prepared in Example 1 with 3-phenylpropionyl chloride (132 mg) according to a similar manner to that of Example 17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[NH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>>[OH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=1[C:9]([NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: NCc1cccnc1
Reactant: COc1ccc2c(c1)C(=O)OC2
Product: COc1ccc(CO)c(C(=O)NCc2cccnc2)c1
Temperature: 150 °C
Yield: 91.8 %

Procedure:
A mixture of 919 mg of 6-methoxyisobenzofuran-1 (3H)-one and 1.82 g of 3-aminomethylpyridine was heated at 150° C. without solvent for 3 hours under stirring. After finishing the reaction, the mixture was chromatographed on a column of silica gel, eluting with ethyl acetate and then with tetrahydrofuran to give 1.40 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: C1CNCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1.[I-:20].[Na+].COC(C)(C)C>CC(C)=O>[I:20][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: [I-]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CI

Procedure:
A suspension of 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (3.2 g, 11 mmol; example 19 a]) and sodium iodide (8.25 g, 55 mmol) in acetone (56 ml) was heated under reflux conditions for 30 min. Tert butyl methyl ether was added, the solid was filtered off and the filtrate was brought to dryness under reduced pressure. The residue was dissolved in tert butyl methyl ether, washed with ice water/brine 1/1 and the aqueous layer was extracted two times with tert butyl methyl ether. The combined extracts were washed with aqueous sodium thiosulfate solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([CH2:14][F:15])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:20]O>>[NH2:1][C:2]([CH2:14][F:15])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([O:5][CH3:20])=[O:4]
Reactant: NC(CF)(Cc1cccc(O)c1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)(CF)Cc1cccc(O)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 2-amino-2-(fluoromethyl)-3-(3-hydroxyphenyl)propanoic acid (1 g, 4.7 mmol) in MeOH (10 mL) was added thionyl chloride (3.9 mL, 54 mmol) dropwise and the reaction mixture was heated to 60° C. for 48 h. Additional thionyl chloride (2 mL) was added and the reaction continued for 48 h. Quenching with H2O, concentration and trituration from MeCN gave methyl 2-amino-2-(fluoromethyl)-3-(3-hydroxyphenyl)propanoate. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 2H), 6.66 (m, 2H), 4.83-4.37 (ABX, J=46 Hz, J=8.8 Hz, 2H), 3.76 (s, 3H), 3.04 (d, J=13 Hz, 1H), 2.69 (d, J=13 Hz, 1H).