Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:5]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:1][OH:2])=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CCC(CO)(CO)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(CC(CO)(CO)CO)(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 57.6 %

Procedure:
Trimethylolpropane (26.84 g, 0.2 mole) was treated with p-nitrobenzoyl chloride (117 g, 0.63 mole), following the general procedure described in Example 1. Part A. The product was worked up in the usual way, except that precipitation occurred during the treatment with saturated aqueous sodium bicarbonate. The mixture was therefore heated to effect solution, the phases separated, the organic phase washed with saturated sodium bicarbonate (3×), and dried over MgSO4. The product crystallized during drying and the mixture was therefore heated to boiling, filtered hot, the solid washed with hot ethyl acetate and hexanes added to the filtrate to induce crystallization. The product, tris-(4-nitrobenzoyl)-trimethylolpropane (67 g) was obtained at a pale yellow solid, m.p. 104°-106° C., which was homogeneous by TLC.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:12][N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Nn1cccc1
Reactant: CCCCN1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN1CCC(Nn2cccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution of 1-butyl-4-piperidone (6.2 g, 40 mmole) and 1-aminopyrrole (3.3 g, 40 mmole) in 100 ml of toluene was stirred at reflux overnight (about 16 hours). The mixture was cooled and then evaporated to an oil, which in turn was dissolved in 75 ml of isopropanol, and 22 ml of ethanol. To the solution was added NaBH4 (3.8 g, 100 mmole). The mixture was stirred at 70° C. for 2 hours and then evaporated, stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated NaCl solution, dried (anhydrous MgSO4), filtered and evaporated to 13 g of an oil. This oil was purified by high pressure liquid chromatography (silica, 1% diethylamine/ethyl acetate) to give 8.2 g of an oil of 1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: COCC(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Product: COCC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Yield: 52 %

Procedure:
Prepared from 5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) and methoxyacetyl chloride (53 mg) following the method of Example 41 to give the title compound (6 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:33]>O1CCOCC1.[Cl-].[Na+].O>[NH2:33][C:13]1[N:14]=[C:15]([CH3:16])[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7](=[O:32])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]=2[N:12]=1
Reactant: [NH4+]
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)nc2c1cc(-c1cnn(CCO)c1)c(=O)n2C1CCCC1
Temperature: 100 °C
Yield: 54 %

Procedure:
To the solution of 8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) in 5 ml 1,4-dioxane was babbled through ammonium gas for 10 minutes. The reaction tube was sealed and heated to 100° C. for 30 minutes. The reaction mixture was poured into brine and the precipitate was collected via filtration. The solid was then re-dissolved in 5 ml methanol and a few drop of concentrated HCl was added and the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (33 mg, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:23][I:24]>[N+](C)([O-])=O.CCOCC>[I-:24].[Cl:1][C:2]1[C:3]([CH2+:16]2[N:20]([CH3:23])[C:19]([CH3:22])([CH3:21])[CH2:18][O:17]2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC1(C)COC(c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)=N1
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CN1[CH2+](c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)OCC1(C)C
Product: [I-]
Yield: 92 %

Procedure:
A solution of 2-(3,5-dichloro-4'-fluoro-2-[1,1'-biphenyl]yl)-4,4-dimethyl-2-oxazoline (4.6 g, 13.6 mmol) and methyl iodide (7 ml) in nitromethane (30 ml) was stirred on a steam bath for sixteen hours. The cooled reaction mixture was diluted with dry ether (200 ml) and, after cooling in an ice-bath, the crystalline product was collected to give 6 g (92%) of the title compound, mp 214°-216° C. (dec.). Crystallization from acetonitrile-ether (1:3, V:V) provided an analytical sample of the title compound, mp 218°-219.5° C. (dec.).
Reaction SMILES: I.CS[C:4](=NC)[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH2:27].C(O)C.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NCCNCCO
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: Cc1ccc(N2CCOCC2)c(N=C2NCCN2CCO)c1

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxyethyl)ethylenediamine (6.8 ml) and ethanol (80 ml)) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give 4-{2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4-methylphenyl}morpholine sesquifumarate (m.p. 135°-136° C.).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([N:15]([CH2:20]OC)[Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1(=O)OC[CH:25]=[CH:24]1>C(=O)(O)[O-].[Na+]>[CH2:8]([N:15]1[CH2:20][C@H:2]2[C@H:24]([CH2:25][O:5][C:3]2=[O:4])[CH2:23]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CCO1
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1OC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (0.136 mL) was added to a solution of N-benzyl-N-(methoxymethyl)-N-trimethylsilylamine (43.9 g, 185 mmol) and γ-crotonolactone (12.5 g, 176 mmol) in 1,2-dichloromethane (176 mL), and the mixture was stirred in a nitrogen atmosphere at room temperature for four hours. A saturated sodium bicarbonate solution (250 mL) was added to the reaction solution, followed by extraction with chloroform (200 mL×2). The organic layer was washed with brine (400 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25→66:34→50:50) to give 37.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([OH:10])=[N:8][S:7][N:6]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([O:10][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:8][S:7][N:6]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3O)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nsnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
200 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg of methyl bromoacetate were dissolved in 10 ml of N,N-dimethylformamide, to this was added 100 mg of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. This reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was washed with hexane to obtain 0.18 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-1,2,5-thiadiazole [present compound 10-7].
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1cc(CN2CCCC2)cc(OCCCNc2nc3ccccc3s2)c1

Procedure:
3-[3-(Pyrrolidinomethyl)phenoxy]propylamine (2.0 g) and 2-chlorobenzthiazole (1.45 g) were fused at 130° C. for 21/2 hours. The cooled reaction mixture was subjected to column chromatography on silica using chloroform and then chloroform:methanol (10:1) as eluants to give the title compound as a yellow oil. This was treated with maleic acid in ethanol to give 2-[3-[3-(pyrrolidinomethyl)phenoxy]propylamino]benzthiazole dimaleate (0.35 g), m.p. 91°-92° C. (recrystallised from isopropanol/ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O-])=O.O.NN>CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phenyl)carbamate (1.6 g, 4.99 mmol, 1 eq.) in methanol (20 mL) was added hydrazine hydrate (14 mL) and ferric chloride (0.05 g, 0.3 mmol, 0.06 eq.). The resulting mixture was warmed to 60° C. and stirred for 2 h. The reaction was then filtered through Celite, the solids were washed with MeOH. The filtrate was concentrated under reduced pressure. Water was added to the residue and the suspension was stirred for 1 h. The obtained solid was filtered, washed with hexanes then dried to yield tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (1.2 g, 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CCN=C=N[CH2:16][CH2:17][CH2:18]N(C)C.Cl.[CH:23](Cl)(Cl)Cl>C(O)(C)(C)C.CN(C1C=CN=CC=1)C>[C:17]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1)([CH3:18])([CH3:23])[CH3:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cncc(Br)c1
Reactant: ClC(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
5-Bromo-nicotinic acid (20.2 g, 100 mmol) was dissolved in CHCl3 (200 mL) and tert-BuOH (40 mL); and WSC-HCl (21.1 g, 110 mmol) and DMAP (21.1 g, 110 mmol) was added thereto in order, and stirred at room temperature over night. The reaction mixture was diluted with chloroform, washed with 0.5N HCl aq. (220 mL), 0.5N NaOH aq. (100 mL), brine and dried over MgSO4 and silica gel. After filtration, the solvents were removed in vacuo to afford 5-Bromo-nicotinic acid tert-butyl ester as a colorless solid. This solid was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.CN(C=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:8]3[CH:9]=[CH:10][C:11]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1
Reactant: C=CCOC(=O)c1c(CCCC(=O)O)ccc2ccccc12
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOC(=O)c1c(CCCC(=O)c2ccc(-c3ccc(OC)cc3)cc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A solution of Example 11E (282 mg, 0.946 mmol) in benzene (5 mL) was treated with thionyl chloride (0.138 mL, 1.89 mmol) and DMF (1 drop), stirred at room temperature for 30 minutes, concentrated to dryness and redissolved in dichloromethane (5 mL). The resulting solution was treated with 4-methoxybiphenyl (348 mg, 1.89 mmol) and aluminum chloride (377 mg, 2.84 mmol) at 0° C., stirred at room temperature for 40 minutes, quenched with ice-water, extracted with dichloromethane, dried (Na2SO4), filtered, concentrated and purified on silica gel with a gradient of 5% to 20% ethyl acetate/hexanes to provide 200 mg (45%) of the desired compound contaminated with 30% of the ortho substituted isomer.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.CN1CCOCC1.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.00 g, 22.8 mmol) in methylene chloride (100 mL) and 4-methylmorpholine (16 mL) at 0° C. was added methanesulfonyl chloride (2.1 mL, 28 mmol). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide as a white solid (6.32 g, 93% yield). MS m/z 298 (M+1).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][CH2:11][C:12]1([CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17](OC)=[O:18])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O1CCCC1>[CH2:3]([O:10][CH2:11][C:12]1([CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][OH:18])[CH2:13][CH2:14]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CC1(COCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1(COCc2ccccc2)CC1

Procedure:
4.3 g of lithium borohydride are added in portions to a solution of 30.9 g of 1-benzyloxymethyl-1-[2(S)-tert-butoxycarbonylamino-2-methoxycarbonyleth-1-yl]cyclopropane in 300 ml of tetrahydrofuran, while stirring. The mixture is stirred at room temperature for a further 2 h, 500 ml of methanol are then slowly added dropwise, the mixture is concentrated almost to dryness and the residue is taken up in methylene chloride. The organic phase is washed with 1N hydrochloric acid. Further customary working up gives the pure title compound: Rf (B)=0.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[O:17][C:16]([CH3:18])=[N:15][CH:14]=1)[C:6]([NH:8][NH2:9])=[O:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:12]([C:13]3[O:17][C:16]([CH3:18])=[N:15][CH:14]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NNC(=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A mixture of 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.10 g), 3,4-difluorophenylacetic acid (3.15 g), HATU (7.57 g) and triethylamine (2.77 mL) in DMF (77 mL,) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the resultant precipitate was collected by filtration and washed with hexane and acetone to give the title compound (4.69 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])=[CH:5][CH2:6]OC(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:33]([N:35]([CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])[CH2:36][CH3:37])[CH3:34]
Reactant: COC(OC)C(C)=CCOC(C)=O
Reactant: CCNCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN(CC)CC=C(C)C(OC)OC

Procedure:
A mixture of 56.4 g (0.30 mol) of 4-acetoxy-2-methyl-2-butenal dimethyl acetal, 150 ml of diethylamine, 675 mg (3 mmol) of palladium (II) acetate and 3.9 g (15 mmol) of triphenylphosphine was boiled under reflux for 15 hours under argon. After concentrating the mixture, the residue was suspended in 170 ml of ether/pentane (1:1), the solution was treated with active carbon, filtered over Hyflo and concentrated. The residual oil was firstly distilled at 40°-55°/0.3 mmHg over a 5 cm Vigreux column, there being obtained 57.1 g of N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine as a 90:10 (E/Z) mixture. This mixture was then fractionated over a 30 cm packed column. There were firstly obtained a total of 34.8 g (58%) of mixed fractions [(E/Z)=86:14] and then 14.5 g (24%) of pure (E)-N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine of boiling point 30°-32°/0.06 mmHg.
Reaction SMILES: BrCC1CC1(F)F.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][C:18]1[N:19]=[C:20]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:31]2[C:32](=[O:33])[N:28]([C:20]3[S:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]([CH3:17])[N:19]=3)[CH:29]=[N:30]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Preparation 13, making variation as required to replace bromomethyl-2,2-difluorocyclopropane with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.47-7.30 (m, 2H), 7.11-6.97 (m, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:9][C:5]1[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:2]([O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: [O-]c1ccccc1
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1Oc1ccccc1
Temperature: 165 °C

Procedure:
A mixture of 1 mol of 2,4,5-trichloro-1-nitrobenzene, 2 mols of potassium phenolate and phenol was heated for 1 hour at 165° C., and the reaction product was isolated as described in Example A(a), yielding the title compound, m.p. 95° C. (recrystallized from ethanol).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[C:6]([CH2:14][CH3:15])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:16].ClCCl>CCC(O)CC.CN(C=O)C>[CH2:14]([C:6]1[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=[C:4]([O:16][CH:6]([CH2:14][CH3:15])[CH2:5][CH3:4])[CH:5]=1)[CH3:15]
Reactant: CCc1cc(Cl)nn2c(N)nnc12
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(O)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(OC(CC)CC)nn2c(N)nnc12
Reaction time: 8 h

Procedure:
3-Pentanol (1.2 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (77 mg) was added while cooling with ice. After stirring at 55° C. for 2.5 h, 6-chloro-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.003, 60 mg), dissolved in 3-pentanol (1.5 ml) and 4 ml of DMF (4 ml), was added dropwise. After stirring for 2 h, the reaction mixture was left to stand at RT overnight, admixed with water and dichloromethane and then extracted three times more with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 70 mg of the title compound were obtained.