Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:26]3[C:31]([F:32])=[C:30]([O:33]C)[CH:29]=[C:28]([O:35][CH3:36])[C:27]=3[F:37])[C:7]2=[O:38])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.O.Cl>CN(C)C=O>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:26]3[C:27]([F:37])=[C:28]([O:35][CH3:36])[CH:29]=[C:30]([OH:33])[C:31]=3[F:32])[C:7]2=[O:38])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(O)cc(OC)c1F)C2
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
To a solution of sodium ethylthiolate [generated from sodium hydride (200 mg, 8.32 mmol) and ethanethiol (616 μL, 8.32 mmol) in dimethylformamide (20 mL)], 1-Cyclopentyl-7-(4-diethylamino-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in dimethylformamide (8 mL) was added. The resulting solution was then stirred at 75° C. for 90 minutes. The solvent was removed under reduced pressure to afford a light brown oil. Dichloromethane (100 mL) and water (20 mL) were added. The bilayer thus afforded was then stirred vigorously while 4 N hydrochloric acid was added. Enough hydrochloric acid was added until the aqueous layer reached pH=5. The layers were separated; the aqueous layer was extracted with dichloromethane (2×80 mL). The organic layers were combined and set aside. Saturated aqueous sodium chloride (20 mL) was to the aqueous layers and was extracted with ethyl acetate (2×80 mL). The organic layers were combined, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. To the yellow oil (794 mg) thus afforded, hexanes were added to remove non-polar impurities. The supernatant was removed, and the remaining residue was placed in vacuo. The oil was purified via reverse phase HPLC to give the title compound (289 mg, 54%) as a clear amber gum: MS (APCI) 519.2, 520.2.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH3:24]I>C1COCC1.C(OCC)(=O)C>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[NH:1][CH3:24])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (4 mL) was added methyl iodide (0.026 ml) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [C:1](=O)([O-:3])N.C1N=C(Cl)C2N=CN([C@@H:15]3[O:19][C@H:18]([CH2:20]O)[C@@H:17](O)[C@H]3O)C=2N=1.N[C@H]1CCCO1>>[CH2-:17][C:18]([CH3:20])=[O:19].[CH3:1][O:3][C:18]([O:19][CH3:15])([CH3:17])[CH3:20]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC(=O)[O-]
Agent: N[C@H]1CCCO1
Product: COC(C)(C)OC
Product: [CH2-]C(C)=O

Procedure:
Preparation of compounds 6 and 7 starting from compound 3 is shown in Scheme 3. Compound 3 was prepared from 6-chloropurineriboside 1 and 3 (R)-aminotetrahydrofuran following the procedure reported earlier (U.S. Pat. No. 5,789,416). Protection of the 2′ and 3′ hydroxy groups as an acetonide with 2,2-dimethoxypropane in the presence of TsOH(cat.) gave 4. Reaction of 4 with CDI in THF followed by treatment with 40% aq.methylamine gave carbamate 5. Deprotection of the 2′,3′ acetonide with 80% AcOH/water at 80-90 C gave carbamate 6. Esterification of 6 with acetic anhydride in pyridine gave diester 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A mixture of methyl 2-methoxy-4-phenoxybenzoate (1.3 g, 5 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (150 mL), methanol (50 mL) and water (50 mL) was stirred at 20° C. for 4 hours. The mixture was adjusted to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 2-methoxy-4-phenoxybenzoic acid (1 g, 82%).
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+:7].[K+].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.CO>O>[C:1]([N:3]=[C:4]([S-:6])[S:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)#[N:2].[K+:7]
Reactant: N#CN=C([S-])[S-]
Reactant: ClCc1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CN=C([S-])SCc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A mixture of 80 g of dipotassium N-cyano-dithioimidocarbonate, 64.9 g of p-chlorobenzyl chloride, 400 ml of methanol and 400 ml of water was stirred for 5 hours and the solvents were evaporated. The residue was crystallized from ethanol to obtain monopotassium S-p-chlorobenzyl N-cyano-dithioimidocarbonate with a melting point of 250° C (dec).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[Cl:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[C:35]=1[S:41](Cl)(=[O:43])=[O:42]>>[Cl:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[C:35]=1[S:41]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32])(=[O:42])=[O:43]
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
5-Chloro-N-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: COC1C=C(C=CC=1OC)C[C@@H](C)N.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.[N+:27]([CH2:30][CH3:31])([O-:29])=[O:28]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:30]([N+:27]([O-:29])=[O:28])[CH3:31])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: COc1ccc(C[C@@H](C)N)cc1OC
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC

Procedure:
According to the present invention, (R)-3,4-dimethoxyamphetamine (3) is prepared according to the synthesis depicted in following Scheme I whereby the starting material 3,4-dimethoxy-benzaldehyde (veratric aidehyde) (10), which is a cheap raw material available from the market, is condensed with nitroethane (Henry's reaction), to form 3,4-dimethoxy-phenyl-2-nitropropene (11), which is then suitably reduced to an intermediate, i.e., 3,4-dimethoxy-phenyl-acetone (12) by means of a catalytic hydrogenation. The intermediate (12) is then reacted with an optically active amine, (R)-α-methyl-benzyl-amine (13) to form the corresponding chiral imine (14). In a key step of the present synthesis, the chiral amine (14) is diastereo-selectively reduced to the intermediate product, (R,R)-N-phenylethyl-3,4-dimethoxy-amphetamine (15) hydrochloride by catalytic hydrogenation with Raney-Nickel. The intermediate (15) is finally debenzylated by hydrogenation, to form (R)-3,4-dimethoxyamphetamine (3) hydrochloride. ##STR12##
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.O.O.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O-:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].[Na+].[CH3:25]C(C)=O>>[CH3:25][C:17]1([N+:14]([O-:16])=[O:15])[CH:22]=[CH:21][C:20]([O:23][CH2:7][C:6]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][CH:10]=2)=[O:9])=[CH:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: O
Product: CC1([N+](=O)[O-])C=CC(OCC(=O)c2ccccc2)=CC1
Yield: 78.9 %

Procedure:
4-Methylphenacyl chloride (XVI: X=Cl) (37.8 g, 0.224 mole) and sodium 4-nitrophenolate (XI) (38.6 g, 0.24 mole) were added to acetone (300 ml), and the mixture was heated under reflux for 10 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 29 to obtain 47.9 g of 4-methyl-α-(4-nitrophenoxy)acetophenone (XII) (yield, 78.9 %).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:18]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:19][N:20]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[CH:23]=[CH:22][C:21]=34)[CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl>[CH:5]1([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:18]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:19][N:20]4[C:25]([CH3:26])=[C:24]([C:27]([NH:40][CH:37]5[CH2:39][CH2:38]5)=[O:28])[CH:23]=[CH:22][C:21]=34)[CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1c(C(=O)O)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Reactant: NC1CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(C(=O)NC2CC2)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Thionyl chloride (200 μL, 2.7 mmol) was added to 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylic acid (31 mg, 0.072 mmol) which had been pre-cooled to 0° C. The reaction mixture was stirred at room temperature for 1 hour. The excess thionyl chloride was removed in vacuo. To a solution of the residue in dichloromethane (300 μL) was added cyclopropylamine (50 uL 0.72 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was quenched with water and diluted with ethyl acetate. Saturated aqueous sodium bicarbonate solution was added to the biphasic mixture. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:2 hexanes:ethyl acetate to 2:3 hexanes:ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxamide (15 mg, 44%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (d. 1H), 8.05 (d, 1H), 7.62 (m, 2H), 7.30 (d, 1H), 7.13 (t, 2H), 6.29 (d, 1H), 5.10 (d1 1H), 4.30 (m, 1H), 2.96 (s, 3H), 2.94 (m, 1H), 2.05 (m, 2H), 1.76–1.50 (m, 6H), 0.92 (m, 2H), 0.66 (m, 2H); MS m/z 471 (M+1).
Reaction SMILES: [Cl-].CO[C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O-].[Na+].N1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O>CO>[C:34]1(/[CH:39]=[CH:8]/[C:7]2[CH:6]=[CH:5][CH:4]=[CH:29][CH:28]=2)[CH:30]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccn1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C(=C/c1ccccc1)\c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
(4-Methoxybenzyl)triphenylphosphonium chloride (4.79 g, 11.4 mmol) was suspended in 50 mL of dry methanol. Sodium methoxide (4.94 g of 25% solution in methanol, 22.8 mmol) was added in one portion to the above suspension and the resulting mixture was stirred at room temperature under nitrogen for 30 minutes. Pyridinecarbaldehyde (1.57 g, 11.4 mmol) was then added and the stirring was continued at room temperature overnight. Excess of sodium methoxide was quenched by addition of water and pH of the reaction mixture was adjusted to pH=4.5 with 1 N HCl, and then to pH=7.5-8.0 by addition of saturated sodium bicarbonate. Products were then extracted with ethyl acetate (500 mL). Combined extracts were washed with water and brine, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate in hexane (5%-10%) to give 1.27 g (46%) of trans-stilbene.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reactant: C1COC(CN2CCNCC2)C1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CCCO3)CC2)cc1
Yield: 12 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 12%. White crystals, m.p. 220-221° C.; IR (KBr): ν 1708 (ester C═O), 1660 (amide C═O) cm−1.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=C.[C:13]([O:21]CC)(=[O:20])[CH2:14][C:15](OCC)=O.[OH-].[K+]>C1COCC1.CCOCC.CCO>[CH:1]1(/[CH:7]=[CH:9]/[CH2:15][CH2:14][C:13]([OH:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=CC1CCCCC1
Reactant: C=C[Mg]Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CC/C=C/C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of cyclohexane carboxaldehyde (11.22 g, 100 mmol, 1 equiv) in THF (100 mL) was added dropwise via addition funnel to a solution of vinylmagnesium bromide (100 mL of a 1.0 M solution in THF, 100 mmol, 1.0 equiv) in Et2O (100 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 1 h at 0° C. and then partitioned between 0.5 M HCl (150 mL) and a 1:1 mixture of EtOAc and hexanes (2×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford a yellow oil. This material was combined (neat) with diethyl malonate (16.7 mL, 110 mmol, 1.1 equiv) and Ti(OEt)4 (2.10 mL, 10.0 mmol, 0.10 equiv) and was heated to 160° C. for 1 h (distilling out EtOH as it was formed). The reaction mixture was then maintained at 190° C. for 4 h and then cooled to 60° C. EtOH (50 mL) and 6.0 M KOH (50 mL) were added sequentially, and the brown reaction mixture was refluxed for 3 h. After cooling to 23° C., the reaction mixture was filtered through a medium frit, and the filtrate was partitioned between water (150 mL) and Et2O (2×100 mL). The aqueous layer was then acidified to pH=2 (as indicated by pH paper) with concentrated HCl and extracted with a 1:1 mixture of EtOAc and hexanes (2×150 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was distilled at reduced pressure to afford trans-5-cyclohexyl-pent-4-enoic acid (5.68 g, 31%) as a colorless liquid: bp: 150-156° C. (1 torr); IR (cm-1) 3001 (br), 2923, 1711; 1H NMR (CDCl3) δ 0.96-1.32 (m, 5H), 1.60-1.76 (m, 5H), 1.85-1.94 (m, 1H), 2.27-2.44 (m, 4H), 5.31-5.48 (m, 2H); Anal. (C11H18O2) C, H.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[N:7](C)[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].P(OC)(OC)(O[CH3:18])=O.CS(O)(=O)=O>>[F:1][CH:2]([F:14])[C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:6]([CH3:18])[N:7]=1
Reactant: CCOC(=O)c1cnn(C)c1C(F)F
Reactant: COP(=O)(OC)OC
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 170 °C
Reaction time: 7 h
Yield: 79.4 %

Procedure:
To 20.4 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) was added 14.4 g of trimethyl phosphate and 0.82 g of methane sulfonic acid. The mixture was heated to 170° C. and stirred for 7 hours. The solution was cooled and distilled to recover recycled trimethyl phosphate and 2.0 g of starting ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. The remaining solution was added to 50 g of cold water. The solution was allowed to stir for 30 min. The precipitating solid was filtered and dried to give 16.2 g of product.
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]([CH:10]=[O:11])=[C:6]([O:8]C)[N:7]=1.ClCCl.P(Br)(Br)Br>CCOCC>[CH:10]([CH:5]1[S:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])=[O:11]
Reactant: COc1nc(OC)c(C=O)s1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1SC(=O)NC1=O

Procedure:
To a stirred solution of 2,4-dimethoxythiazole-5-carboxaldehyde (0.01 mol), which may be prepared as described in Step (b) above, in a solvent such as dichloromethane is added phosphorous tribromide or another suitable ether cleaving reagent, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the corresponding 2,4-thiazolidindione-5-carboxaldehyde is formed, the reaction is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated. The residue is dissolved in THF, and 1 mol equivalent of a suitable non-nucleophilic base as described above in Example 17 is added, followed by 1 mol equivalent of methyl iodide. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the corresponding 2-methoxy-4,5-dihydro-thiazolin-4-one-5-carboxaldehyde is formed, the mixture is partitioned and worked up as described above. The resulting residue is dissolved in THF, and 1 mol equivalent of a suitable non-nucleophilic base as described above in Example 17 is added, followed by 1 mol equivalent of 2,2-difluoro-hex-5-ynoyl chloride, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the reaction is partitioned and worked up as described above to give (E)-5-(2,2-difluoro-hex-5-ynoyloxymethylene)-2-methoxy-4,5-dihydro-thiazolin-4-one, which may be purified, if needed or desired, by chromatography on silica gel or crystallization. Also formed is (Z)-5-(2,2-difluoro-hex-5-ynoyloxymethylene)-2-methoxy-4,5-dihydro-thiazolin-4-one, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: O.[CH2:2]([N:9]1[C:14]([CH3:15])=[CH:13][C:12](=O)[N:11]=[C:10]1[NH:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)([Cl:21])=O>>[Cl-:21].[Cl:21][C:12]1[CH:13]=[C:14]([CH3:15])[N+:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:10]([NH:17][CH3:18])[N:11]=1
Reactant: CCCCCCCn1c(C)cc(=O)nc1NC
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCC[n+]1c(C)cc(Cl)nc1NC
Product: [Cl-]
Temperature: 130 °C

Procedure:
A mixture of 1,4-dihydro-1-heptyl-6-methyl-2-methylamino-4-pyrimidinone monohydrate (0.75 g, 2.9 mM) and phosphorus oxychloride (3.5 ml, an excess) was heated at a bath temperature of 130° C. for 2.5 hours. Excess phosphorus oxychloride was removed by evaporation. The residue was mixed with toluene (20 ml) and the volatile material evaporated. The procedure was repeated with a further portion of toluene (20 ml) to give 4-chloro-1-heptyl-6-methyl-2-methylaminopyrimidinium chloride as a crude solid. This material was mixed with ethanol (5 ml) and N-methylaniline (0.8 g, 7.5 mM). The solution obtained was heated at reflux for 2.5 hours. The ethanol was removed by evaporation and water (10 ml) was added to the residue. The aqueous mixture was extracted with ether (4×10 ml) and the extracts were discarded. The aqueous phase was extracted with methylene chloride (4×10 ml). Water was removed from these extracts by filtration through phase-separating filter paper and the solvent was evaporated. The brown, oily residue obtained crystallised on trituration with ether to give a white solid (0.742 g). This solid was recrystallised from acetone-ether to give 1-heptyl-6-methyl-2-methylamino-4-N-methylanilinopyrimidinium chloride as a crystalline solid (0.49 g, 46% yield), m.p. 154°-155° C.; microanalysis, found: C,65.7; H,8.6; N,14.9%; C20H31N4Cl.0.25 H2O requires C,65.3; H,8.6; N,15.2%; NMR: 0.9(3H,t,CH3), 1.3[10H,complex,(CH2)5 ], 2.36(3H,s,CH3), 2.9(3H,br,NCH3), 3.5(3H,s,N-CH3), 4.0(2H,t,NCH2), 5.8(1H,br,aromatic), 7.4-7.6(5H,complex,aromatic), 8.65(1H,br,NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1C=C(COS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:19]2[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:50])[CH3:51])[N:47]=[C:42]([C:36]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=3[F:34])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O

Procedure:
Following the procedure of Example 1 (10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](Cl)=[N:29][CH:28]=1>>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and methyl-6-chloronicotinate [CAS Reg. No. 73781-91-6]. MS (m/e)=501.0 [MH+].