Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[O:18][CH:17]2[CH:6]([CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16]2)[O:5]1)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:4]([O:5][CH:6]1[CH:17]([OH:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C1OC2CCC=CCCC=CCCC2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)COC1CCC=CCCC=CCCC1O
Yield: 78.9 %

Procedure:
The same procedure as that described in example 2(b) was followed but using 5.92 g of 14-isopropyl-13,15-dioxabicyclo[10.3.0]pentadeca-4,8-diene and 39.5 ml of a 1.2M solution of DIBAH in toluene. 4.71 g of 12-isobutoxy-4,8-cyclododecadien-1-ol were obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>ClCCl>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)=[O:23]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (5.75 g, 0.05 moles) in dry dichloromethane (-50 ml) was added dropwise with stirring to N-[2-(3-amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (13.1 g, 0.05 moles) and triethylamine (10.1 g, 7.5 ml, 0.1 mole) in dry dichloromethane (250 ml). Stirring was continued at 20° for 18 hr and the solution was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried and evaporated. The residue on recrystallisation from benzene gave the sub-title compound (15.9 g) as ivory-coloured plates mp 129°-130°.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30](Cl)=[O:31].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30]([NH:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: O=C(Cl)COc1cccc(Cl)c1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)COc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cis/trans mixture of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (800 mg) was initially introduced into the reaction vessel with 540 μl triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (approx. 15 mg) in 20 ml methylene chloride, 790 mg (3-chlorophenoxy)acetyl chloride (1.05 molar equivalents) were added dropwise at −20° C. and the mixture was stirred overnight, while warming to room temperature. For working up, the mixture was rendered alkaline (pH>10) with one molar sodium hydroxide solution and extracted with diethyl ether (3×20 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated to dryness. The crude product obtained (1.53 g) was chromatographed on silica gel (3.0×17 cm) with 100 ml diethyl ether followed by 500 ml diethyl ether/methanol (v:v=2:1). 346 mg of the more polar diastereoisomer of 2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide were obtained and, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate, were converted into the corresponding hydrochloride by addition of 16 μl water and 110 μl chlorotrimethylsilane (322 mg of a white solid, m.p. 220° C.).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25](Cl)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:36]5[O:37][C:33]([CH:29]6[O:30][CH2:31][CH2:32][O:28]6)=[CH:34][CH:35]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(-c4ccc(C5OCCO5)o4)cc23)cc1
Yield: 56 %

Procedure:
(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g) were reacted together in dioxan (100 ml) as in Procedure B. Purification by column chromatography gave a cream solid (2.59 g); δH [2H6]DMSO 10.6 (1H, s) 9.26 (1H, s) 8.82 (1H, s) 8.78 (1H, s) 8.25 (2H, d) 8.0-8.3 (4H, d+m) 7.65-7.8 (3H, m) 7.21 (1H, d) 6.82 (1H, d) 6.09 (1H, s) 4.0-4.2 (4H, m); m/z 501 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](O)=[O:32])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C.CCCP(=O)=O>C1COCC1>[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:14]5[CH:15]=[N:16][CH:17]=[CH:18][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:32])[N:29]=2)[CH2:24][CH2:23]1
Reactant: Cc1oc(C2CC2)nc1CC(=O)O
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1oc(C2CC2)nc1CC(=O)Nc1cncc(C(=O)c2cn(C(C)C)c3ccncc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 19, 80 mg, 0.285 mmol) and (2-cyclopropyl-5-methyl-1,3-oxazol-4-yl)acetic acid (Preparation 87, 52 mg, 0.285 mmol) in THF (5 mL) was added triethylamine (138 uL, 0.997 mmol) and propylphosphonic anhydride (429 uL, 0.712 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness and purified using preparative HPLC to afford the title compound as a white solid (50 mg, 39%).
Reaction SMILES: [C:1]([NH:11][CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>P(Cl)(Cl)(Cl)=O>[CH3:20][C:18]1[O:19][C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(NC(=O)C=Cc1ccccc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C=Cc2ccccc2)oc1C

Procedure:
A mixture of ethyl 2-cinnamoylaminoacetoacetate (5.7 g) and phosphorus oxychloride (40 ml) was heated on an oil bath at 100°-110° C. for 30 minutes and the phosphorus oxychloride was distilled off under reduced pressure. The residue was neutralized with aqueous sodium hydrogen carbonate and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was treated with hexane to give ethyl 5-methyl-2-styryl-4-oxazolecarboxylate as crystals; yield 4.3 g (80.7%). Recrystallization from ethanol gave light-yellow prisms melting at 98°-99° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].O.Cl>CN(C)C=O.C(OCC)(=O)C>[O:15]1[C:14]2[CH:18]=[CH:19][C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[CH:12][C:13]=2[O:17][CH2:16]1
Reactant: CS(=O)(=O)OCCOCCc1ccc2c(c1)OCO2
Reactant: CCNCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In 3 mL of N,N-dimethylformamide is dissolved 1.00 g of 2-[2-(1,3-benzodioxol-5-yl)ethoxy]ethyl methanesulfonate. To the solution is added 2.54 g of diethylamine. The resulting mixture is stirred at 100° C. for 2 hours in an ampoule. After cooling, the reaction mixture is introduced into a mixture of water and ethyl acetate, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and the aqueous layer is separated. Ethyl acetate is added to the aqueous layer, pH is adjusted to 9.5 with sodium carbonate, and the organic layer is separated. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=20:1 to 10:1) to obtain 0.75 g of N-{2-[2-(1,3-benzodioxol-5-yl)ethoxy]ethyl}-N,N-diethylamine as an oily product.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.CS(O)(=O)=O>>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: CS(=O)(=O)O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
In the present example, 2,9-dimethylquinacridone is used as a pigment. A total of 10 parts by weight of 2,9-dimethylquinacridone is placed in a pear-shaped flask with a capacity of 300 mL, and 80 parts by weight of methanesulfonic acid is added thereto under normal temperature. The pear-shaped flask is immersed in oil bath heated to 80° C., and heating and stirring are performed for 10 min under an argon gas atmosphere. The 2,9-dimethylquinacridone is dissolved and a quinacridone pigment solution of a blue-violet color is prepared.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7](O)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23].[CH3:24][NH:25][CH3:26]>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([N:25]([CH3:26])[CH3:24])[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23]
Reactant: CNC
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(N(C)C)C(C)(C)O2
Yield: 89 %

Procedure:
Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 236 and dimethylamine, the title compound was synthesized in the same manner as in Example 297. Yield: 89%. Melting point: 111-112° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[C:8](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:5]=2[CH:6]=1.[Na].C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C>O.C(O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:12][CH2:13]3)[C:8](/[CH:14]=[CH:15]/[C@H:16]([CH2:17][C@H:18]([CH2:19][C:20]([O-:22])=[O:21])[OH:23])[OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:5]=2[CH:6]=1.[CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:12][CH2:13]3)[C:8](/[CH:14]=[CH:15]/[C@H:16]([CH2:17][C@H:18]([CH2:19][C:20]([O-:22])=[O:21])[OH:23])[OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:5]=2[CH:6]=1.[Ca+2:37]
Reactant: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C([O-])C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pitavastatin sodium (5.22 g) prepared according to U.S. Pat. Nos. 5,011,930 A, 5,856,336 A and 5,872,130 A is dissolved in a mixture of 75 ml of water and 15 ml of ethanol and stirred at room temperature under a nitrogen atmosphere. Successively 12 ml of 1 mol/L calcium acetate in water is added drop wise thereto over 20 minutes. The reaction mixture is stirred at the ambient temperature for 3 hours, and the resulting precipitate is collected, washed with water and dried to give 4.5 g of crude pitavastatin calcium salt material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:24]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][CH:16]=3)=[O:25])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(Oc2cccnc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2cccnc2)nc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The 6-(pyridine-3-yloxy)pyridine-3-amine (200 mg, 1.24 mmol) and indole-3-carboxylic acid (200 mg, 1.24 mmol) were dissolved in DMF (5 ml), DCC (280 mg, 1.37 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (250 mg, 61%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26](I)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:26][CH3:27])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(C(=O)OC)c1ccc(C(C)(C)C)cc1
Yield: 115.2 %

Procedure:
4 g (19 mmol) of methyl 4-tert-butylphenylacetate, 19.5 mL (1.0 M, 19 mmol) of lithium bis(trimethylsilyl)amide and 3.12 g (20 mmol) of ethyl iodide were reacted as described in Preparation 11 to yield 5.13 g of a brown oil. Chromatography, eluting with a gradient solvent of hexane to hexane/ethyl acetate 19:1 gave the title compound 2.35 g (53%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=1)=[O:5].[CH2:22]([Mg]Cl)[CH2:23][CH3:24]>C1COCC1>[C:13]1([C:11]2[O:12][C:8]3[CH:7]=[C:6]([C:4](=[O:5])[CH2:22][CH2:23][CH3:24])[CH:20]=[CH:19][C:9]=3[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CON(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of N-methoxy-N-methyl-2-phenylbenzo[d]oxazole-6-carboxamide (1.57 g, 5.6 mmol) in THF (20 mL) was added n-PrMgCl (2.0M in ether, 4.2 mL, 8.4 mmol, 1.5 eq) at 0° C. The mixture was warmed up to room temperature then stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl then extracted with EtOAc (3×40 mL). Solvent was removed then crude product was purified by flash column chromatography (0-20% EtOAc in hexanes) to afford the title compound (1.07 g, 4.0 mmol, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 16 h

Procedure:
5-Hydroxybenzo[1,3]dioxole (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine, The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:22]=1.C1CCN2C(=NCCC2)CC1.Cl>O1CCOCC1.O>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:30])[N:22]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
By the procedure of Example 4, 0.62 g of the sulfonamide of Example 3 was reacted with 0.57 g of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.33 g of DBU in 10 ml of p-dioxane. After stirring two hours at room temperature the solution was diluted with about 75 ml of water and acidified with concentrated hydrochloric acid (red to litmus). Following filtration, the residue was washed with 1×5 ml of warm ethyl acetate to give 0.28 g of the subject compound; m.p. 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[C:20]=[S:21]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:20]([NH:19][C:22]1[CH:23]=[CH:24][C:25]([S:28](=[O:30])(=[O:29])[NH2:31])=[CH:26][CH:27]=1)=[S:21]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(S(N)(=O)=O)cc1
Yield: 47 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.974 g, 4.01 mmol) and 4-isothiocyanatobenzenesulfonamide (0.858 g, 4.00 mmol) to afford the product (0.858 g); m.p. 193-195° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 78 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol. Methyl α-aminoisobutyrate HCl was added (2.4 eq) followed by triethylamine (2.4 eq). The reaction mixture was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was concentrated to dryness and triturated with H2O, Silica gel chromatography of the resulting brown solid afforded the title compound as a bright yellow crystalline solid (78% yield based on recovered starting material). M.p. 121-122° C., 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67 (s, 3H), 8.53 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CCO>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CCO
Product: CC(=O)c1ccc(N2CCOCC2)nc1
Yield: 101.9 %

Procedure:
A solution of 32 (1.25 g, 7.9 mmol) and morpholine (2.20 mL, 25.2 mmol) in EtOH (22 mL) was refluxed for 12 h and then evaporated to dryness. The residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO3 (50 mL×2) and brine (50 mL), dried over Na2SO4, filtered and evaporated to afford the title compound 33a (1.66 g, quantitative yield) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C(=O)CC.C1COCC1.C(=O)CC.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: CC(=O)OCC(F)Br
Reactant: C1CCOC1
Solvent: CCC=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionaldehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionaldehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using anhydrous magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=CC=CC=1S.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Fc1ccccc1S
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol), piperazine (1.4 g, 16.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) were mixed in DMF (10 mL) in a sealed tube. The mixture was heated at 100° C. overnight. The reaction mixture was concentrated and chromatographed on silica gel (ethyl acetate to EA/MeOH/Bt3N=9:1:0.5) to give 1.05g of the desired product. MS calculated for C10H12F3N3:(M+H) 232.1; found 232.1.