Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Cl)[N:7]=1.[NH4+].[Cl-].[CH2:15](OCC)[CH3:16]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][CH3:2])[N:7]=1)[CH3:16]
Reactant: CC[Mg]Br
Reactant: Clc1cccc(Cl)n1
Reactant: CCOCC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CCc1cccc(CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of ethylmagnesium bromide in ethyl ether [prepared from Mg (16.5 g, 0.68 mol) and ethyl bromide (50 mL, 0.68 mol) in 500 mL of ether] was added dropwise to a mixture of 2,6-dichloropyridine (50 g, 0.34 mol) and NiCl2(dppp) (1.0 g, 2 mol) in anhydrous ethyl ether (500 mL) at 0° C. under N2 atmosphere. After addition, the resulting mixture was stirred at ambient temperature overnight, was then heated to reflux for about 3 hours. The suspension was poured into cushed ice (200 g) and the mixture was saturated with NH4Cl. The organic layer was separated and the aqueous phase was extracted with ether (200 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the product (41.1 g, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>CN(C)C=O>[Br-:9].[Br-:9].[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([CH2:10][CH2:11][CH2:12][CH2:13][N+:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccncc1
Reactant: BrCCCCBr
Solvent: CN(C)C=O
Product: N#Cc1cc[n+](CCCC[n+]2ccc(C#N)cc2)cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 226.3 %

Procedure:
A mixture of 4-cyanopyridine (12.5 g; 0.12 mol) and 1,4-dibromobutane (13 g; 0.06 mol) in dimethylformamide (50 ml) was stirred at 60° C. for 24 hours, and yellow precipitate was collected by filtration and washed with acetine to give tetramethylenebis(4-cyanopyridinium)dibromide (28.8 g). m.p., 296°-300° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.[H-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C=O)n2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1H-pyrazole-3-carbaldehyde (3.00 g, 31.22 mmol) in THF was added 60% NaH (1.64 g, 41.00 mmol) in mineral oil. After 20 minutes, p-toluenesulfonyl chloride (7.82 g, 41.00 mmol) was added. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10-50% EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford (1-(toluene-4-sulfonyl)-1H-pyrazole-3-carbaldehyde) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(O)(=O)C>O1CCOCC1.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(N2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(N2CCCCC2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
The compound of Example 38 (540 mg, 2.466 mmol) was dissolved in dioxan (12 ml) and water (8 ml). Lithium hydroxide hydrate (300 mg, 7.143 mmol) was added and the mixture stirred at 40° C. for 1 h. The mixture was acidified with acetic acid, evaporated, azeotroped with toluene and chromatographed on silica (eluant 60/40/2, v/v/v, EtOAc/hexanes/AcOH) to provide a colourless solid (450 mg, 90%).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3](=O)[CH2:2]1.N1(C(OCC)=O)CCC(=O)C(=O)CC1.Br.Br.[NH2:31][CH2:32][C:33]([NH2:35])=[NH:34]>>[NH2:35][C:33]1[CH:32]=[N:31][C:5]2[CH2:6][CH2:7][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][C:4]=2[N:34]=1
Reactant: N=C(N)CN
Reactant: CCOC(=O)N1CCCC(=O)C(=O)C1
Agent: Br
Agent: CCOC(=O)N1CCC(=O)C(=O)CC1
Product: CCOC(=O)N1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 13 by reacting a mixture of ethyl hexahydroazepine-3,4-dione-1-carboxylate and ethyl hexahydroazepine-4,5-dione-1-carboxylate (prepared from ethyl hexahydroazepine-4-one-1-carboxylate by selenium dioxide oxidation) with 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[N:6][CH:7]=1.[ClH:17].CCOCC>CO>[ClH:17].[ClH:17].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101 %

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide (500 mg, 1.64 mmol) in 5 mL of MeOH was added HCl (4.10 mL, 16.4 mmol, 4M in dioxane). The reaction mixture was stirred at room temperature for 2.5 h, during which time a white precipitate was formed. 20 mL of Et2O was added. After stirring for an additional 20 min, the reaction mixture was filtered, washing with 10 mL of Et2O. 454 mg (99%) of the title compound was isolated as a white solid after drying under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloronicotinic acid (2.0 g, 13 mmol) and HBTU (4.8 g, 13 mmol) in DMF (20 mL, 200 mmol) at 0° C. were added N,N-diisopropylethylamine (6.6 mL, 38 mmol) and 4-(trifluoromethyl)benzylamine (2.2 mL, 15 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform). The product was not thoroughly dried proceeding to the next reaction. Assumed 100% conversion.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][S:59]([CH3:58])(=[O:61])=[O:60])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 187b (250 mg, 0.38 mmol) in DCM (4 mL) was added DIPEA (267 μL, 1.53 mmol) followed by methanesulfonyl chloride (60 μL, 0.77 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.25 min, m/z 732 [MH+].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[N:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cncc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (132 mg) and a solution of 5-fluoropyridine-3-sulfonyl chloride (127 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as a colorless oil (yield 224 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]([Cl:22])=O)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[C:20](/[CH:19]=[CH:18]/[C:17]3[CH:23]=[CH:24][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(/C=C/c2nc3cc(C)ccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-nitroaniline and (E)-4-methoxycinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[N:17]=[C:7]2[CH:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[OH:13])[NH:9][CH2:10][CH2:11][N:6]2[N:5]=1.[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([C:3]([F:18])([F:2])[F:19])[N:17]=[C:7]2[CH:8]1[CH:12]([CH:14]1[CH2:15][CH2:16]1)[OH:13])=[O:31])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: OC(C1CC1)C1NCCn2nc(C(F)(F)F)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1)Cc1cc(F)c(F)cc1F

Procedure:
A 160 mg portion of [2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazin-8-yl](cyclopropyl)methanol hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by preparative TCL (silica gel, 10% methanol/dichloromethane) gave 176 mg of the product as a mixture of diastereomers. HPLC (OD chiralcel column, 6% ethanol/hexane) separated the first and last eluting diastereomers. The middle fractions containing two diastereomers were further subjected to HPLC (OD chiralcel column, 3% ethanol/hexane) to provide the second and the third eluting diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Cl:12]N1C(=O)CCC1=O>C(O)(C)C>[Cl:12][C:11]1[C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc2cc(N)ccc2s1
Solvent: CC(C)O
Product: Cc1nc2c(Cl)c(N)ccc2s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-methylbenzothiazole (818 mg, 4.99 mmol) in isopropanol (12 mL) was added N-chlorosuccinimide (732 mg, 5.48 mmol). The mixture was stirred at 60° C. for 15 min., partitioned between DCM and 5% sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to give a residue that was purified with flash chromatography (EtOAc/DCM gradient elution). 4-Chloro-2-methylbenzothiazol-5-ylamine was obtained as off-white crystalline solid (510 mg, 51%). mp 121-122° C. (lit. 124° C.); TLC single spot at Rf 0.51 (20% EtOAc/DCM); 1H NMR (270 MHz, DMSO): δ 7.61 (1H, d, J=8.6 Hz, ArH), 6.91 (1H, d, J=8.6 Hz, ArH), 5.49 (2H, s, NH2), 2.75 (3H, s, CH3); APCI-MS 199 (MH)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1.O[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:37]=[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35](=[O:36])[N:27]1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.6 %

Procedure:
Diethyl azodicarboxylate (17.4 g, 100 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypyrrolidin-1-carboxylate (9.40 g, 50.0 mmol), 2-hydroxyisoindoline-1,3-dione (8.16 g, 50.0 mmol) and triphenylphosphine (26.2 g, 100 mmol) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 5/95 to 12.5/87.5) to give (S)-tert-butyl 3-(1,3-dioxoisoindoline-2-yloxy)pyrrolidin-1-carboxylate (6.74 g, 41%) as a white solid: LCMS: 277 [M−55]+.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+].[CH3:21][C:22]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(#N)C>[O:10]=[C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2]([O:3][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[N:30][C:22]=2[CH3:21])=[CH:1]1
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 20 °C

Procedure:
2.07 g (0.015 mol) of distilled 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 3.34 g (0.033 mol) of triethylamine are stirred for 2.5 hours at a temperature of 60° C. in 50 ml of acetonitrile in the presence of 98 mg (1.5 mmol) of potassium cyanide. Cooling to a temperature of 20° C. is then carried out and 2.35 g (0.11 mol) of 2-methyl-6-trifluoromethyl-nicotinoyl chloride, freshly prepared according to WO 00/15615, dissolved in a small amount of acetonitrile are added. The 2-methyl-6-trifluoromethylnicotinic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (known from WO 00/15615) obtained in situ as intermediate is fully converted within a period of 3.5 hours (monitoring by thin-layer chromatography). The reaction mixture is then acidified with dilute hydrochloric acid and extracted with ethyl acetate against water at a pH value of 2, dried over Na2SO4 and concentrated by evaporation. The product is purified by means of column chromatography (eluant: ethyl acetate/hexane 4:1) to yield 3.16 g of 90% 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one (58.3% based on the 4-methylene-3-oxabicyclo[3.2.1]octan-2-one used or 83.3% based on the 2-methyl-6-trifluoromethylnicotinoyl chloride used).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[CH3:10][N:11]=[C:12]=[S:13]>C(O)C>[CH3:10][NH:11][C:12]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[S:13]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)Nc1c(Cl)cccc1Cl

Procedure:
130 g of 2,6-dichloro-aniline, 100 g of methyl isothiocyanate and 300 ml of 95% ethanol are refluxed during 14 hours, with stirring. The resulting solution is cooled in the freezer: the white solid formed is filtered and washed with isopropyl oxide. After recrystallization from isopropanol, 65 g of product (III : R = CH3), m.p. = 184° C, are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21]Cl)=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][NH:10][CH3:11].N1C=CC=CC=1.O.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CN1CCCC1=O>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][CH2:21][N:10]([CH3:11])[CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCCl
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 9.9 g of 2-[5-chloro-2-[(2-chloroethyl)phenoxy]phenoxy]-N-methyl-ethylamine dissolved in 500 ml of N-methyl-2-pyrrolidone was slowly added to a mixture of 1 1 of N-methyl-2-pyrrolidone and 500 ml of pyridine at 85° C. and stirred overnight at this temperature. Water was added, the mixture was extracted with diethyl ether and the ether layer was washed with water and dried over sodium sulphate. The organic solution was evaporated to dryness and the residue was crystallized from dichloromethane-diethyl ether after addition of 1 eq of maleic acid to obtain 2.3 g (28%) of 3-chloro-7,8,9,10-tetrahydro-8-methyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine (Z)-2-butenedioate (1:1). Mp 145-157° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:8]([N:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO>CCO.C(Cl)Cl.[Pd]>[C:1]([C:5]1[NH:6][C:7]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[C:8]([NH2:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N=O)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A suspension of Intermediate 51b (150 mg, 0.617 mmol) and Pd/C (10%, 15 mg) in EtOH (10 mL) was stirred at RT under H2 for 2 h. The flask was evacuated and purged with N2 thrice, then the mixture filtered through Celite, and the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to leave a red-brown gum. FCC, using 1-6% MeOH in DCM, gave the title compound as a yellow-orange gum (96.3 mg, 68%). LCMS (Method 3): Rt 2.26 min, ink 230 [MH+].
Reaction SMILES: B.CSC.[CH2:5]1[O:17][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])[O:7][CH2:6]1.[OH-:18].[Na+].OO>C1COCC1.O>[CH2:6]1[O:7][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][OH:18])[O:17][CH2:5]1
Reactant: [OH-]
Reactant: C=Cc1ccccc1C1OCCO1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1ccccc1C1OCCO1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Borane-dimethyl sulphide complex (2.0M in THF, 7.67 ml, 15.3 mmol) was added dropwise to 2-vinylbenzaldehyde ethylene acetal (2.7 g, 15.3 mmol) in THF (80 ml) at 0° C. Stirring was continued at room temperature for 4 h, cooled to 0° C. and 10% aqueous sodium hydroxide (3 ml) added dropwise, followed by hydrogen peroxide (30% by volume, 1.8 ml). After 1 h at room temperature, the mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated to give a colourless viscous gum (2.2 g), MS (+EI) 194 (M+), 1H NMR (CDCl3) 7.48 (1H, d, J6 Hz), 7.3-7.1 (3H, m), 5.91 (1H, s), 4.1-3.9 (4H, m), 3.78 (2H, t, J6.5 Hz), 2.93 (2H, t, J6.5 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][P:4](Cl)(Cl)=[O:5].[CH2:8]([S:10][CH2:11][CH2:12][OH:13])[CH3:9].N1[CH:19]=[CH:18]C=CC=1>CCOCC>[CH2:8]([S:10][CH2:11][CH2:12][O:13][P:4]([CH2:3][CH2:2][Cl:1])(=[O:5])[O:13][CH2:12][CH2:11][S:10][CH2:18][CH3:19])[CH3:9]
Reactant: c1ccncc1
Reactant: O=P(Cl)(Cl)CCCl
Reactant: CCSCCO
Solvent: CCOCC
Product: CCSCCOP(=O)(CCCl)OCCSCC
Reaction time: 14 h

Procedure:
To a solution of 18.1 g (0.1 mol) of 2-chloroethane phosphonic acid dichloride in 150 ml of absolute ether is added dropwise with stirring a solution of 21.2 g (0.2 mol) of hydroxyethyl ethyl sulphide and 15.8 g of absolute pyridine in 100 ml of absolute ether at room temperature, during which the temperature increases to 35° and crystallisation occurs. Stirring is continued for a further 14 hours at 25° after which the crystals are removed by filtration and the ethereal filtrate is washed to neutrality with 5% hydrogen carbonate solution and water. It is dried and evaporated and further dried by rotation under high vacuum for 2 hours. A yellow oil is obtained having the following characterisation data:
Reaction SMILES: CC(O)C.Cl.C(OC([NH:13][CH:14]([CH2:27][O:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:15][O:16][C:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[O:19][N:18]=1)=O)(C)(C)C>CO>[ClH:26].[NH2:13][CH:14]([CH2:27][O:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:15][O:16][C:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[O:19][N:18]=1
Reactant: CNC(=O)OCC(COc1noc2ccc(Cl)cc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CNC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
In 10 ml of methanol is dissolved 3-(2-tert-butoxycarbonylamino-3-methylaminocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole, and to this solution is added 9.6 ml of a 2-propanol solution (7.5N) of hydrogen chloride, and they are subjected to reaction at 20°-25° C. for 4.5 hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, and to the residue obtained is added 5 ml of 2-propanol, after which the crystals precipitated are collected by filtration, to obtain 0.30 g of colorless, crystalline 3-(2-amino-3-methylaminocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 206°-209° C.