Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([NH:17][C:3]1[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:12]([CH3:13])[C@@H:10]([O:11][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:8]2[O:9][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5](=[O:16])[N:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)c3ccccc3)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
5'-Deoxy-5-fluorocytidine (245 mg), benzoyl chloride (400 μl) and 4-dimethylaminopyridine (122 mg) were dissolved in dry pyridine (5 ml). After stirring for 3 hours at room temperature pyridine was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methanol to give N4,2'-O,3'-O-tribenzoyl-5'-deoxy-5-fluorocytidine (280 mg), mp 158°~160° C.; MS 558 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon, a mixture of 9.0 g (37.9 mmol) of 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 10.25 g (45.5 mmol) of 4-bromobenzotrifluoride, 1.39 g (1.89 mmol) of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and 20.11 g (189 mmol) of sodium carbonate in 200 mL of DMSO and 70 mL of water is stirred at 90° C. overnight. After the reaction has ended, the mixture is cooled to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic phase is once more washed with water, dried with sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate gradient). This gives 5.28 g (53% of theory) of 5-fluoro-4′-(trifluoromethyl)biphenyl-2-amine having a content of 97% according to LC-MS and a logP (acidic) of 3.52.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[C:15](OC(=O)C)(=O)C.C(Cl)(=O)C>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COC(=O)CCc1ccccc1C(=O)O

Procedure:
2-carboxybenzenepropanoic acid (9.7 g., 0.05 mole), acetic anhydride (15.5 g., 0.15 mole) and acetyl chloride (0.5 g) in dichloromethane (200 ml) was boiled at reflux under nitrogen for 16 hr. The solvents were removed at high vacuum and the residual cyclic anhydride was heated at reflux with methanol (250 ml) for 2 hrs. Evaporation of solvent gave the sub-title compound as an oil which crystallised with petroleum ether (b.p.60°-80°) to a solid (6.3 g) mp 76°-79°. This was further purified by continuous extraction of the crude product with boiling petroleum (b.p.40°-60°) in a Soxhlet apparatus. The pure compound, mp 79°-81° separated from the extracts on cooling.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl[C:23]1[N:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>C1(C)C=CC=CC=1>[C:29]1([C:26]2[N:25]=[N:24][C:23]([N:12]3[CH2:13][C@@H:8]4[CH2:14][C@H:11]3[CH2:10][N:9]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:28][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ccccc2)nn1
Temperature: 100 °C

Procedure:
Triethylamine (20 mL) was added to a suspension of t-butyl (S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL) and the mixture was heated under nitrogen at 100° C. for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under vacuum to provide the title compound as an off-white solid. The filtrate was concentrated and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate, to provide additional product: MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)=O)n[nH]1

Procedure:
The compound was prepared using the method of Example 34(d). The reaction was conducted in 4 ml of DCM at RT overnight using (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.249 g; 0.91 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.140 g; 0.91 mmol), 0.24 ml of DIPEA, HOBt (0.184 g; 1.36 mmol) and EDCI (0.261 g; 1.36 mmol) as starting materials. Purification was done by EtOH trituration. 1H-NMR (400 MHz; d6-DMSO): δ 0.90 (t, 3H), 1.42-1.67 (m, 2H), 2.51 (s, 3H), 4.19-4.42 (m, 3H), 6.91 (d, 1H), 7.32 (s, 1H), 7.79 (d, 1H), 7.85-8.07 (m, 3H), 8.38 (d, 1H), 14.14 (s, 1H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](OCC)=[O:20]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](=[O:20])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To 20.6 g (166 mmol, 238 mol %) of dimethyl methylphosphonate in 110 mL of THF at −78° C. was added dropwise 65 mL (162 mmol, 232 mol %) of a 2.5M solution of n-BuLi in hexanes. After addition was complete, the mixture was stirred for an additional 1 h, after which 15.0 g (69.9 mmol) of aryloxyester 10 in 40 mL of THF was added dropwise. The reaction was stirred for 1 h and then quenched by the addition of 100 mL of saturated NH4Cl. The mixture was poured into 200 mL of a 1/1 mixture of saturated NaCl/ethyl acetate, layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, and concentrated, to afford 20.5 g (100%) of 11 as a viscous oil. 1H NMR δ 7.22 (t, J=8.1 Hz, 1 H), 7.05-6.90 (m, 2 H), 6.85-6.78 (m, 1 H), 4.72 (s, 2 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.27 (d, J=22.8 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=1.C[O-].[Na+]>CO.[Cu]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13]2[C:14]3[C:15](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[C:11]([CH3:16])[N:12]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(N)nc1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Nc2nc(C)nc3ccccc23)nc1
Temperature: 160 °C
Yield: 31 %

Procedure:
2-Amino-5-methoxy-pyridine. A mixture of 2-amino-5-iodo-pyridine (1 g, 4.54 mmol) in 20 mL of absolute methanol with 400 mg of copper powder and sodium methoxide (6 mmol) was heated at 160° C. overnight in a seal tube. The reaction mixture was cooled to room temperature, diluted with 80 mL of methanol and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography (80% ethyl acetate/hexane) to give the title compound (174 mg, 31%). 1H NMR (CDCl3): 7.78 (d, J=2.7, 1H), 7.09 (dd, J=3.0, 9.0, 1H), 6.48 (d, J=9.0, 1H), 3.78 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A solution of commercial 1-(benzyloxy)-4-bromobenzene (104 g, 395 mmol) and commercial tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (147 g, 474 mmol) in 1100 mL of acetonitrile was purged with nitrogen for 2 min. Water (1100 mL) was added, followed by sodium carbonate (126 g, 1186 mmol) and tetrakis(triphenylphosphine)palladium (27.4 g, 23.7 mmol). The reaction mixture was purged with nitrogen for 5 min, and then heated to 90° C. and stirred for 16 h. The reaction mixture was then allowed to cool to rt and diluted with 1 L of ethyl acetate. The layers were separated, and the aqueous layer was extracted with two additional 250 mL portions of ethyl acetate. The organic layers were combined, washed with 200 mL of brine, dried over sodium sulfate, and evaporated in vacuo to provide an off-white solid. The product was purified by silica gel chromatography eluting with 6% ethyl acetate in petroleum ether to provide 129 g (88%) of the desired product. LC/MS RT (conditions A)=2.732 min, (M−H)+=364.0. 1H NMR (300 MHz, chloroform-d) δ 7.49-7.30 (m, 5H), 7.27 (d, J=10.7 Hz, 2H), 6.99-6.87 (m, 2H), 6.03-5.87 (m, 1H), 5.07 (s, 2H), 4.05 (d, J=2.6 Hz, 2H), 3.62 (t, J=5.7 Hz, 2H), 2.49 (br. s., 2H), 1.49 (s, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2cccc3cnccc23)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(Oc2cccc3c2CCNC3)cc1
Yield: 59.2 %

Procedure:
A solution of 5-phenoxyisoquinoline (1 g, 4.5 mmol) in methanol (50 ml) was shaken on a Parr hydrogenator at 55 psi hydrogen in the presence of platinum oxide (0.2 g) for 3 h. The catalyst was then removed by filtration and the solvent evaporated. The residue was triturated with hexane to give the title compound as a colourless solid (0.6 g, 60%); δH (CDCl3) 2.65-2.75 (2H, m, ArCH2CH2N), 3.1-3.2 (2H, m, ArCH2CH2N), 4.05 (2H, br s, ArCH2N), 6.75 (1H, d, J 8 Hz, ArH), 6.83 (1H, d, J 8 Hz, ArH), and 6.9-7.35 (6H, m, ArH); m/z (CI+, NH3) 226 (M+1)+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[NH3:6]>>[N:6]([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:3][CH2:2][C:1]([NH2:5])=[O:4]
Reactant: N
Reactant: C=CC(N)=O
Product: NC(=O)CCN(CCC(N)=O)CCC(N)=O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A Parr autoclave was charged with an aqueous solution of acrylamide and a 10% molar excess of aqueous ammonia. The resulting mixture was warmed to 65° C. and autogenous pressure (<50 psi) and stirred at these conditions for three hours. At the end of this period, the reaction mass was allowed to cool to room temperature and white, crystalline nitrilotripropionamide (melting range 184°-186° C.) was recovered. NMR spectroscopy confirmed the structure.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH:11]3O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCc2c(-c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C1=Cc2cccc(-c3ccccc3)c2C1
Yield: 96.2 %

Procedure:
A stirred solution of 16.7 g (0.08 mole) of 4-phenyl-1-indanol and 0.1 g of p-toluenesulfonic acid in 180 ml of benzene was heated under reflux for one hour as by-product water was collected in a Dean-Stark trap. The reaction mixture was washed with two portions of 50 ml of a 5% aqueous solution of sodium bicarbonate, then with one portion of 50 ml of water. The organic phase was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure, keeping the temperature under 50° C., to give 14.8 g of 7-phenyl-1H-indene. The nmr specturm was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH2:22])=[S:21])[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[NH:22])[S:21][CH3:24])[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCCC1
Reactant: CI
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCCC2)c1
Yield: 94 %

Procedure:
Using the compound obtained in Example 149 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 82 mg of the titled compound (yield, 94%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[CH:12])[CH2:4][CH2:5][CH3:6].[I:14]I.ClCl>CO.O>[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[C:12][I:14])[CH2:4][CH2:5][CH3:6]
Reactant: II
Reactant: C#CCOC(=O)NCCCC
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)OCC#CI
Reaction time: 1 h
Yield: 166.2 %

Procedure:
At 8° C., 10.1 g of sodium hydroxide (0.244 mol) and 19.0 g of propargyl butylcarbamate (0.122 mol) are introduced as initial charge in 48 g of methanol and 50 g of water. At this temperature, 15.5 g of iodine (0.061 mol) are added in portions. Chlorine (5.6 g, 0.079 mol) is then slowly introduced into the reaction mixture so that the temperature still remains below 8° C. When the metered addition is complete, the mixture is stirred for 1 h at this temperature and then 105 g of water are added. The precipitated solid is isolated by filtration, washed with water and dried in vacuo. This gives 28.5 g of 3-iodo-2-propynyl N-butylcarbamate (purity: 95.0% (HPLC), polyiodized compounds: 0.3% (HPLC), yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.C([O-])(O)=O.[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:9][C:4]1[N:3]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-Amino-2,6-dichloropyrimidine (500 mg, 3.05 mmol) was refluxed in acetic anhydride (10 ml) for 3 h. Upon cooling to room temperature, the reaction mixture was cooled in an ice bath and basified to pH 8 with 10% aqueous NaHCO3. The phases were separated, and the aqueous portion was extracted twice with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated to give an off-white solid (503.7 mg, 2.44 mmol, 80% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](#N)C.CI>C1COCC1>[CH2:5]([C@H:4]([NH2:3])[CH2:9][O:10][CH3:11])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](N)CC(C)C
Temperature: 55 °C

Procedure:
Sodium hydride (60% dispersion in oil: 9.39 g, 0.24 mol) was added to a stirred solution of L-leucinol (25 ml, 0.20 mol) in a mixture of dry acetonitrile (12 ml) and dry THF (60 ml) at room temperature under argon. The mixture was heated at reflux for 2 h, cooled to 55° C. and methyl iodide (12.8 ml, 2.1 mol) carefully added. The reaction mixture was heated at reflux overnight and allowed to cool to room temperature. Ice cold brine (100 ml) was added carefully and the mixture extracted with ethyl acetate (3×100 ml) The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was distilled under reduced pressure to give (S)-1-isobutyl-2-methoxyethylamine as a colourless oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CO.O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]3[N:29]=[N:30][N:31]=[C:2]3[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c3nnnn23)cc1OC
Yield: 78.9 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in a mixture of methanol (9 ml) and water (1.5 ml) was added sodium azide (0.163 g). The mixture was stirred at 50° to 55° C. for an hour. After removal of the solvent, the residue was washed with water and collected by filtration to give 4,5-dihydro-7-(3,4-dimethoxyphenyl)-4-methyl-5-(2,4,6-trimethylphenylimino)tetrazolo[1,5-a]pyrimidine (0.80 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([Cl:25])([Cl:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:2].[OH:27]O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([Cl:25])([Cl:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:27])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCSc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCS(=O)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
2.0 g (4.55 mmol) 104 and 6 ml 30% hydrogen peroxide in 20 ml glacial acetic acid were oxidized to form 2.08 g (99%) 106 as a colourless oil analogously to 78 (example 26).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:8]2[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]=2[OH:23])[S:13][N:14]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2snc(-c3ccccc3F)c2c1O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccccc3F)nsc12

Procedure:
The title compound was synthesized in analogy Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 333.2 (M+1).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/N=C/c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A quantity of 16 ml (295.41 mmol) of nitromethane was admixed with 436 μl (2.50 mmol) of N,N-diisopropylethylamine and the yellow solution was stirred at RT for 1 h. Then 2.0 g (8.34 mmol) of the compound from Example 111A were added and the mixture was stirred overnight at RT. All of the volatile constituents were removed on a rotary evaporator. The residue was dissolved in 9 ml of isopropanol in the heat of boiling, and the solution was then cooled to 0° C. The white solid precipitated was filtered off with suction and washed with a little cold isopropanol. Drying in an HV gave 1.18 g (47% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([CH3:14])[CH3:13])[CH2:11][O:10]1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([S:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:14])[CH3:13])[CH2:11][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC(C)(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Temperature: 105 °C
Reaction time: 17 h
Yield: 94.3 %

Procedure:
A mixture of 64.0 g (182 mmol) of (-)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane, 25.1 g (364 mmol) of 1,2,4-triazole, 50.3 g (364 mmol) of potassium carbonate, and 910 ml of DMF was stirred at 105° C. for 17 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and to the residue were added dichloromethane and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of chloroform and methanol (30:1) as an eluent. The solvent was removed by distillation under reduced pressure to obtain 72.0 g (94%) of (+)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a pale yellow oily substance.