Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])=[CH:8][CH:7]=1.Cl>C(=S)=S>[F:5][C:6]1[CH:11]=[C:10]2[C:9]([CH2:12][CH2:13][CH2:14][C:15]2=[O:16])=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCCc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCCc2ccc(F)cc21
Temperature: 0 °C

Procedure:
To a mixture of aluminum chloride (66 g, 0.50 mol) in carbon disulfide (600 mL) was added dropwise a solution of 4-(4-fluorophenyl)butyryl chloride (75.3 g, 0.37 mole) in carbon disulfide (260 mL) keeping the internal temperature below 10° C. After refluxing for 0.5 h, the reaction mixture was poured into a mixture of concentrated HCl (50 mL) and ice water (800 mL). The mixture was filtered and extracted with diethyl ether. The diethyl ether extracts were dried and concentrated in vacuo to give crude 7-fluoro-1-tetralone. Vacuum distillation gave pure 7-fluoro-1-tetralone b.p., 83° C. at 0.3 mm Hg which solidified to a white solid (94%). m.p., 62-64° C. (lit, J. Am. Chem. Soc., 89, 386, 1967; m.p., 63.5-65.0° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH:9]1([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1cc(OC2CCCC2)ccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(OC2CCCC2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottomed flask 2-bromo-4-cyclopentyloxy-pyridine (339 mg, 1.40 mmol) was dissolved in THF (6 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.1 mL, 1.47 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 min then at room temperature for 2 h. An additional portion of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 0.27 mL, 0.35 mmol) was added and stirring was continued at room temperature for 30 min. Tributyltin chloride (0.42 mL, 1.54 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 4-cyclopentyloxy-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH:10]2[C:12]([CH3:14])([CH3:13])[C:11]2([CH3:16])[CH3:15])=[O:9])=[N:4][C:3]=1[CH3:17].[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Br>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5](=[N:7][C:8]([CH:10]2[C:11]([CH3:16])([CH3:15])[C:12]2([CH3:13])[CH3:14])=[O:9])[N:4]([CH2:23][CH2:22][O:21][CH3:20])[C:3]=1[CH3:17]
Reactant: COCCBr
Reactant: Cc1nc(NC(=O)C2C(C)(C)C2(C)C)sc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1c(C)c(Cl)sc1=NC(=O)C1C(C)(C)C1(C)C

Procedure:
A mixture of the product of Example 118A (150 mg, 0.55 mmol), NaH (60% dispersion in mineral oil, 29.0 mg, 0.71 mmol) and 2-bromoethyl methyl ether (57 μl, 0.61 mmol) in 20 mL of 2:1 THF/DMF was processed according to the method desribed in Example 112B to provide the title compound: 1H NMR (300 MHz, DMSO-d6) δ 1.18 (s, 6H) 1.23 (s, 6H) 1.50 (s, 1H) 2.29 (s, 3H) 3.25 (s, 3H) 3.63 (t, J=5.3 Hz, 2H) 4.27 (t, J=5.3 Hz, 2H); MS (DCI/NH3) m/z 331 (M+H)+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]2[NH:14][C:6](=[O:7])[NH:5][S:2](=[O:4])(=[O:3])[C:12]=2[CH:11]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -40 °C
Yield: 94.8 %

Procedure:
Chlorosulfonyl isocyanate (17 mL, 195 mmol) was dissolved in nitroethane (150 mL) and cooled to −40° C. A solution of 4-methoxyaniline (20 g, 162 mmol) in nitroethane (100 mL) was then added dropwise with stirring. After the addition was completed, the reaction was stirred for an additional 5 min and aluminum chloride (25 g, 195 mmol) was added. The mixture was then quickly heated to 110° C. with stirring for 20 min. The crude material was then poured onto ice and the precipitate was collected by vacuum filtration, washed with cold water, and dried in vacuo to afford the desired product, 7-methoxy-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one (35 g, 153.5 mmol, 79% yield) as a purple powder. 1H NMR (400 MHz, DMSO-d6): δ 3.6 (br, 1H), 3.78 (s, 3H), 7.2 (m, 3H), 11.05 (s, 1H).
Reaction SMILES: O.O.O.O.O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O-:21].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:32]([C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43]Br)[CH:40]=[CH:39][C:37]=2[N:38]=1)#[N:33]>CC(C)=O.CN(C)C=O>[C:32]([C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43][O:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([O:17][CH2:16][C:7]4[CH:8]=[CH:9][C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:6]=4)[CH:19]=3)[CH:40]=[CH:39][C:37]=2[N:38]=1)#[N:33]
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Reactant: [O-]c1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1nc2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1

Procedure:
To a stirred solution of sodium 3-(2-quinolinylmethyloxy)phenoxide pentahydrate (3.63 g, 10 mmol) in acetone (85 ml) and dimethylformamide (10 ml) at room temperature are added successively potassium carbonate (2.07 g, 15 mmol) and 2-cyano-6-bromomethylbenzoxazole (1.90 g, 8.02 mmol). The resulting solution-suspension is refluxed for 16 hours and concentrated. Water (100 ml) and ethyl acetate (200 ml are added. Extraction with ethyl acetate is followed by washing with water and brine, drying (MgSO4) and evaporation under reduced pressure. The residue is subjected to flash chromatography over silica gel. Elution with 33% ethyl acetate in hexane and concentration of the appropriate fractions provides 2-cyano-6-[3-(2-quinolinylmethyloxy)phenoxymethyl]benzoxazole which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH:7]=[O:8].[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:6]=1[CH2:7][OH:8]
Reactant: COCOc1ccc(C(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
The solution of 2-methoxymethoxy-5-(trifluoromethyl)benzaldehyde (3.3 g) from Example 59 in anhydrous methanol (20 ml) was cooled in an ice bath, followed by gradual addition of NaBH4 (0.53 g). After stirring at room temperature for 15 minutes, the solvent was removed under reduced pressure. To the residue was added water, and the aqueous layer was extracted with ether. The ether layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give an colorless oil compound as the title compound (3.15 g; 95%).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:11][C:12]([F:25])([F:24])[C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15].P(Cl)(Cl)Cl.ClC1C=CC=CC=1>C(OCC)(=O)C>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[C:12]([F:11])([F:24])[F:25])=[O:10]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=C(O)c1ccccc1O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1ccccc1O
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of salicylic acid (6.90 g, 50 mmol), 2,5-bis(trifluoromethyl)-aniline (11.46 g, 50 mmol), phosphorus trichloride(2.18 ml, 25 mmol) and chlorobenzene(150 mL) was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane to give the title compound(8.4 g, 47.8%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+]>CO.O1CCCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([S:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH2:9][CH2:10]2)(=[O:15])=[O:16])[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (2.2 g, 5.8 mmol) in methanol (6 ml) and tetrahydrofuran (6 ml) was treated with 3N KOH (6 ml, 3 equiv.) and stirred at room temperature for 24 hours. The organic solvents were evaporated and the aqueous slurry treated with HCl 3N so as to reach pH 3. The white precipitate was filtered washing with methanol and water and dried under high vacuum to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid as an off-white solid, 1.9 g (88%). This was used as such in the following reaction.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[C:9]3[C:12](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][S:14](=[O:17])(=[O:16])[CH2:15][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:11]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:15][S:14](=[O:16])(=[O:17])[CH2:13][C:12](=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]2=[N:10]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=S1(=O)CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 1.6g of 2,3,3a,4,6,7-hexahydro-3-phenyl-7-(phenylmethylene)thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 30ml of acetic acid is heated on a steam bath for 15 minutes. Hot water (50ml) is added with stirring and the solution is allowed to cool to room temperature. The solids are collected and washed well with water and dried in vacuo over phosphorus pentoxide at 50°C to yield 1.65g of the title compound, melting point 218°-219.5°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)Cl
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 36.9 %

Procedure:
A mixture of 4'-[(6-hydroxyhexyl)methylamino]-4-methylsulfonylstilbene (5.00 g, 12.9 mmol) was treated with triethylamine (1.63 g, 16.2 mmol) and acryloyl chloride (1.46 g, 16.2 mmol) as above. The product was purified by chromatography on silica gel (CH2CL2 eluent) and recrystallization from acetone/hexanes to yield 2.10 g (37%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=CC=CC=3)=[C:9]3[N:32]=[C:12]([C:13](Br)=[C:14]4[NH:30][C:17](=[C:18](C5C=CC=CC=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C[C@@]12C(=O)CC[C@H]1[C@@H]1CCC3C=C(O)C=CC=3[C@H]1CC2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:30][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:32][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc([nH]3)c(Br)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Agent: [Pd]
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-diphenylporphyrin (31.0 mg, 0.05 mmol) with (+)-estrone (108 mg, 0.2 mmol), using Pd2(dba)3 (4.6 mg, 0.005 mmol) and DPEphos (10.7 mg, 0.02 mmol) in the presence of Cs2CO3 (65.2 mg, 0.2 mmol). The reaction was conducted in toluene at 100° C. for 40 h. The title compound was isolated by flash chromatography (silica gel, methylene choloride:ethyl acetate (v/v)=9:1) as a purple solid (49.1 mg, 98%). 1H NMR (300 MHz, CDCl3): δ 9.30 (d, J=4.5 Hz, 4H), 8.78 (d, J=4.8 Hz, 4H), 8.16 (m, 4H), 7.74 (m, 6H), 7.16 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4, 2.7 Hz, 1H), 6.86 (d, J=8.4, 3.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 2H), 1.20-2.8 (m, 30H), 0.88 (s, 3H), 0.86 (s, 3H), −2.47 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 141.1, 138.1, 134.6, 133.1, 132.0, 131.3, 131.0, 127.8, 126.9, 120.2, 116.3, 114.0, 50.3, 47.9, 44.0, 38.3, 38.1, 35.9, 31.5, 29.4, 26.3, 25.8, 21.5, 13.8. UV-vis (CH2Cl2, λmax, nm): 420, 517, 555, 598, 655. HRMS-EI ([M]+): calcd for C68H62N4O4, 998.4771, found 998.4773 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[NH:16][C:15]1=[O:21]>>[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=2)[C:15]1=[O:21]
Reactant: CC1NC(=O)N(C)C1=O
Reactant: COC(=O)c1ccc(Br)nc1C
Product: COC(=O)c1ccc(N2C(=O)N(C)C(=O)C2C)nc1C
Yield: 16.4 %

Procedure:
Using methyl 6-bromo-2-methylnicotinate (96 mg) and 3,5-dimethylimidazolidine-2,4-dione (107 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Preparation Example 48, the title compound (19 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]>Cl.O>[OH:3][C:2]1[N:1]=[C:4]([CH3:11])[CH:5]=[C:6]([OH:10])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(=O)c(C#N)c(N)o1
Agent: Cl
Solvent: O
Product: Cc1cc(O)c(C#N)c(O)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile from above was dissolved in 4 N HCl/H2O (2500 ml) and refluxed for 5 h with stirring strongly. After cooled to r.t., the precipitate was filtered, washed with H2O (500 ml), ethanol (500 ml) and MTBE (200 ml) and dried under high vacuum. 2,4-dihydroxy-6-methylnicotinonitrile was obtained as a yellow powder. (165 g, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH2:11](I)[CH3:12]>>[Cl:1][C:2]1[N:7]([CH2:11][CH3:12])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CCI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Product: CCn1c(Cl)cc(=O)n(C)c1=O

Procedure:
The sub-title compound was prepared by the method of example 9, part a) using 6-chloro-3-methyl uracil and ethyl iodide.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[C:22](=[N:24]S(Cl)(=O)=O)=[O:23].O>CCOCC>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][C:22]([NH2:24])=[O:23])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1cc(-c2nnc(NC(N)=O)s2)cc(C(C)(C)C)c1O
Yield: 53.8 %

Procedure:
A suspension of 4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol (1.0 g, 0.0032 mole) in ether (5 ml) is added to a 0° C. solution of N-carbonylsulfamyl chloride (0.46 g, 0.0032 mole) in ether (5 ml). The resulting mixture is stirred 15 minutes before water (10 ml) is added. The mixture is diluted with ether and washed with 2M HCl and saturated aqueous NaCl. Extract with aqueous 1M NaOH (3×). The combined aqueous layers are made acidic with aqueous 2M HCl. The resulting precipitate is filtered and washed with water to provide 0.6 g (1.2 g theor., 53%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-urea after drying in vacuo at 50° C.; mp >270° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[Li]C.[Li]CCCC.CN([CH:27]=[O:28])C.[NH4+].[Cl-]>C1COCC1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[C:2]([CH:27]=[O:28])=[CH:3][C:4]2[CH2:5][CH2:6][CH2:7][NH:8][C:9]=2[N:10]=1
Reactant: CN(C)C=O
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C=O)CCCN2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 15.0 g, 52.2 mmol) in THF (400 ml) at −78° C. under argon, was added MeLi (1.6 M in Et2O, 32.6 ml, 52.2 mmol), the solution was stirred for 5 min, then n-BuLi (1.6 M in hexane, 35.9 ml, 57.5 mmol) was added slowly and the solution was stirred for 20 min. THF (100 ml) was added to the reaction at −78° C. Subsequently, n-BuLi (1.6 M in hexane, 49.0 ml, 78 mmol) was added and the reaction mixture was stirred for 20 min, then again n-BuLi (1.6 M in hexane, 6.53 ml, 10.45 mmol) was added and the mixture was stirred for 10 min at −78° C. DMF (2.10 ml, 27.2 mmol) was added and the reaction mixture was stirred at −78° C. for 45 min, then it was allowed to warm to room temperature, poured into sat. aq. NH4Cl and extracted twice with DCM. The combined organic phases were dried over Na2SO4, filtered and evaporated to give the title compound as an orange oil. (UPLC-MS 3) tR 0.63 min; ESI-MS 237.2 [M+H]+.
Reaction SMILES: C(C1C=C(C)C(I)=CC=1C(O)=O)C.[Cl:14][C:15]1[C:24]([I:25])=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH2:26][CH3:27])[CH:16]=1.C(C1C=C(C)C(I)=CC=1C([O-])=O)C>>[Cl:14][C:15]1[C:24]([I:25])=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH2:26][CH3:27])[CH:16]=1
Reactant: CCc1cc(Cl)c(I)cc1C(=O)OC
Agent: CCc1cc(C)c(I)cc1C(=O)O
Agent: CCc1cc(C)c(I)cc1C(=O)[O-]
Product: CCc1cc(Cl)c(I)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 211.3, except methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was used in place of 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[C-:32]#[N:33].[Na+].O>CN(C=O)C>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[C:32]#[N:33])=[N:14][N:15]=1
Reactant: [C-]#N
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C#N)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a suspension of 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (145 mg, 0.33 mmol) in DMF (2 mL) was added sodium cyanide (18 mg, 0.36 mmol) and the mixture was stirred for 18 h at ambient temperature. The resulting yellow-green suspension was treated with water (15 ml) and cooled to 0° C. After stirring for 15 min at 0° C. the suspension was filtered off and washed twice with ice cold water (5 ml) affording the title compound (119 mg, 84%) which was obtained as a yellow solid. MS: m/e=430.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:34][CH2:35]2)[S:28][CH:29]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(Cl)cc4Cl)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (201 mg, 0.700 mmol), 1-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.636 mmol) and diisopropylethylamine (0.222 ml, 1.27 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 116 mg (40.3%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[N:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:28]([C:26]2[CH:27]=[N:23][NH:24][CH:25]=2)=[O:29])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2cn[nH]c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75 mg) in DMF (3 mL) was ice-cooled, and 1H-pyrazole-4-carboxylic acid (33.4 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg), 1-hydroxybenzotriazole (49.4 mg) and diisopropylethylamine (80 mg) were added. The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (72 mg).