Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
The crude 4-(4-Chloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.10 g, 10.0 mmol) was dissolved in methylene chloride (1 mL) and treated with 4 N HCL/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated to yield 1.00 g (48%) of the title compound. 1H-NMR (CDCl3) δ 1.90 (2H, m), 2.23 (1H, brs), 2.83 (2H, m), 3.02 (2H, m), 3.54 (4H, m), 6.58 (2H, d, j=9.3 Hz), 7.13 (2H, d, j=9.3 Hz). ESI-MS m/z: 211 (M+1), FAS method rt: 1.04 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:5]=2)[O:14]1
Reactant: ClCCN1CCCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Product: CC1(C)OB(c2cnn(CCN3CCCCC3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 1-(2-chloroethyl)piperidine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 1-(2-chloroethyl)piperidine hydrochloride, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (69%). LCMS (ES+) 305 (M+H)+, RT 1.91 minutes (Method 1).
Reaction SMILES: CC1C=CC(N)=CC=1N1C2N(N=C(C3C=NC=CC=3)C=2)C=C1.C(OC(NCCOC1C=C(C=C(S(F)(F)(F)(F)F)C=1)C(O)=O)=O)(C)(C)C.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([C:59]2[CH:60]=[C:61]([CH:73]=[C:74]([S:76]([F:81])([F:80])([F:79])([F:78])[F:77])[CH:75]=2)[O:62][CH2:63][CH2:64][NH:65]C(=O)OC(C)(C)C)=[O:58])=[CH:52][C:51]=1[N:82]1[C:89]2[N:85]([N:86]=[C:87]([C:90]3[CH:91]=[N:92][CH:93]=[CH:94][CH:95]=3)[CH:88]=2)[CH:84]=[CH:83]1.FC(F)(F)C(O)=O>ClCCl>[NH2:65][CH2:64][CH2:63][O:62][C:61]1[CH:60]=[C:59]([CH:75]=[C:74]([S:76]([F:79])([F:80])([F:81])([F:78])[F:77])[CH:73]=1)[C:57]([NH:56][C:53]1[CH:54]=[CH:55][C:50]([CH3:49])=[C:51]([N:82]2[C:89]3[N:85]([N:86]=[C:87]([C:90]4[CH:91]=[N:92][CH:93]=[CH:94][CH:95]=4)[CH:88]=3)[CH:84]=[CH:83]2)[CH:52]=1)=[O:58]
Reactant: Cc1ccc(NC(=O)c2cc(OCCNC(=O)OC(C)(C)C)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CC(C)(C)OC(=O)NCCOc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(OCCN)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
40 mg (0.14 mmol) of the compound of Example 6A and 62 mg (0.15 mmol) of the compound of Example 29A were reacted and worked up analogously to the procedure of Example 16. In this manner, 81 mg (86% of theory) of the Boc-protected intermediate tert-butyl {2-[3-({4-methyl-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]phenyl}carbamoyl)-5-(pentafluoro-λ6-sulphanyl)phenoxy]ethyl}carbamate were obtained. This compound was stirred in 1 ml of dichloromethane and 0.5 ml of trifluoroacetic acid at RT for 2 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 18). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 61 mg (76% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:22]([CH:32](P(O)(O)=O)[P:33]([OH:36])([OH:35])=[O:34])[CH:23](P(O)(O)=O)[P:24]([OH:27])([OH:26])=[O:25])[CH2:2][N:3]([CH:13](P(O)(O)=O)[P:14]([OH:17])([OH:16])=[O:15])[CH:4](P(O)(O)=O)[P:5]([OH:8])([OH:7])=[O:6].[OH-].[Na+]>S([O-])([O-])(=O)=O.[Zn+2].O>[CH2:1]([N:22]([CH2:23][P:24]([OH:26])([OH:27])=[O:25])[CH2:32][P:33]([OH:36])([OH:35])=[O:34])[CH2:2][N:3]([CH2:4][P:5]([OH:8])([OH:7])=[O:6])[CH2:13][P:14]([OH:16])([OH:17])=[O:15]
Reactant: O=P(O)(O)C(N(CCN(C(P(=O)(O)O)P(=O)(O)O)C(P(=O)(O)O)P(=O)(O)O)C(P(=O)(O)O)P(=O)(O)O)P(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P(O)(O)CN(CCN(CP(=O)(O)O)CP(=O)(O)O)CP(=O)(O)O

Procedure:
To 3.35 kg of water in a stirred crutcher were added 3.0 kg of ethylene diamine tetra (methylene phosphonic acid), followed by 1.7 kg of caustic soda flakes. When all the ethylene diamine tetra (methylene phosphonic acid) was dissolved, 3.95 kg of a zinc sulphate solution (made from 1.975 kg ZnSO4.7H2O in 1.975 kg water) were added slowly. The slurry obtained was drum-dried to obtain a particulate dry product.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+]>[C:1]1([S:7]([NH:11][CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([OH:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 151 mmol (26.6 g) of benzenesulphonyl chloride and 50 ml of 4M aqueous sodium hydroxide is added to a solution of 37.8 mmol (6.25 g) of phenylalanine in 50 ml of 4M aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours. The solution is then rendered acidic to pH=2 with dilute hydrochloric acid and extracted with ether. The organic phase is dried over magnesium sulphate and concentrated. The resulting residue is recrystallised from ethanol to yield the expected compound.
Reaction SMILES: [C:1]1([C:7]2([C:19]([NH2:21])=O)[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([C:7]2([CH2:19][NH2:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 3.1 g (0.011 mol) of 3-phenyl-1-(phenylmethyl)-3-pyrrolidinecarboxamide in 150 ml of dry tetrahydrofuran was added 0.84 g (0.022 mol) of lithium aluminum hydride in portions under argon. The suspension was stirred overnight at room temperature. To the mixture was added 0.7 ml of water, 0.9 ml of 40% sodium hydroxide, and 3.0 ml of water. The grainy precipitate was filtered, and the filtrate was concentrated to give 2.9 g of 3-phenyl-1-(phenylmethyl)-3-pyrrolidinemethanamine. A solution of the residue from the above reaction, 0.5 g of 20% palladium on carbon, and 100 ml of methanol was shaken in an atmosphere of hydrogen at 50 psi for 18 hours. The catalyst was filtered and the filtrate concentrated to give 1.8 g of the title compound.
Reaction SMILES: Br[C:2]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:11]3[CH:10]=[CH:9][C:8]([Br:19])=[CH:7][C:6]=3[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=2[CH:3]=1.C([Li])CCC.C(O[B:45]1[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]1)(C)C.Cl>O1CCCC1.CO.CCCCCC.C(OCC)C>[Br:19][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:2]([B:45]4[O:46][C:47]([CH3:52])([CH3:53])[C:48]([CH3:50])([CH3:51])[O:49]4)=[CH:3][C:4]=3[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:7]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2c1cc(Br)c1ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2c1cc(B1OC(C)(C)C(C)(C)O1)c1ccccc21
Temperature: -70 °C
Reaction time: 0.83 h

Procedure:
Under an inert atmosphere, 70.00 g (0.117 mol) of 5,9-Dibromo-7,7-dioctyl-7H-benzo[c]fluorene (M-15) was dissolved in dehydrated tetrahydrofuran (1170 mL) and dehydrated diethylether (1170 mL). To the obtained solution, 73 mL (1.6 mol/L) of a hexane solution of n-butyllithium was added dropwise at −70° C. for 30 minutes and further stirred at −70° C. for 50 minutes. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added dropwise at −78° C. for 10 minutes and further stirred at −78° C. for one hour. To this solution, an aqueous hydrochloric acid solution was added dropwise at room temperature for 15 minutes and the water layer was removed from the organic layer. To the organic layer, 1170 mL of distilled water was added and stirred. Thereafter, the water layer was removed and a 5% aqueous sodium hydrogen carbonate solution (1170 mL) was added and stirred. Thereafter, the water layer was removed. After distilled water (1170 mL) was added and stirred, the water layer was removed. Concentration and dehydration were performed to obtain an oily substance. The oily product was dissolved in tetrahydrofuran. To this, methanol was added to obtain a solid substance as a precipitate, which was filtrated and dried. Further, the solid substance was recrystallized from tetrahydrofuran and methanol, twice to obtain a desired compound 2-(9-Bromo-7,7-dioctyl-7H-benzo[c]fluoren-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (M-14) (57.7 g) in a yield of 76%.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)(=[O:4])=[O:3].[ClH:16].O1CCOCC1.C(OCC)(=O)C>C(OCC)C>[ClH:16].[ClH:16].[NH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)NCCN
Yield: 100 %

Procedure:
tert-Butyl {2-[(methylsulfonyl)amino]ethyl}carbamate (21 g, 88 mmol) was stirred in a solution of 4 N hydrogen chloride in 1,4-dioxane (97 mL, 388 mmol) for 30 minutes. Trituration with ethyl acetate and hexanes followed by diethyl ether and hexanes gave the desired compound as a gum (19 g, 100%). LCMS calculated for C3H11N2O2S (M+H)+: m/z=139.0.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([C:15](OCC)=[O:16])([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>>[C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([F:13])([F:14])[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1[C@@](C)(N[S@](=O)C(C)(C)C)C(F)(F)CO
Yield: 80 %

Procedure:
Starting from (1S,2S)-2-[(R)-2-ethoxycarbonyl-2,2-difluoro-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-cyclopropanecarboxylic acid tert-butylester (intermediate J3.3) the reduction with lithium borohydride yielded the (1S,2S)-2-[(R)-2,2-difluoro-3-hydroxy-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-propyl]-cyclopropanecarboxylic acid tert-butyl ester (80% yield) as a white solid. MS (ISP): m/z=370.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: COc1cc(C(C)=O)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(C(C)=NOCc2ccc3nonc3c2)ccc1F
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 4-fluoro-3-methoxyacetophenone (0.056 g, 0.332 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.072 g, 0.359 mmol) and pyridine (0.10 ml, 1.24 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a 4′-fluoro-3′-methoxyacetophenone-O-[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-129) as a white solid (0.078 g, 74%), m.p. 65°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CC(=O)O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A stirred suspension of 3-hydroxyphenylacetic acid (10.2 g, 67 mmol) in acetic anhydride (100 mL, 1.06 mol) under anhydrous conditions was treated with pyridine (0.5 mL). In the mildly exothermic reaction, the solids dissolved within several minutes and the mixture was maintained at 40° C. for 5 h. The reaction was concentrated in vacuo to about half volume, then water (30 g) in the form of ice chips was added at such a rate that the temperature remained <45° C. When the exotherm had subsided, a second portion of water (200 mL) was added slowly and the mixture was stirred for another 30 min. The precipitated solid was filtered, washed with water and dried to constant weight in vacuo over P2O5 to give 3-acetoxyphenylacetic acid (11.7 g, 90%). This material was used without further purification. In an inert atmosphere, a solution of the above 3-acetoxyphenylacetic acid (1.942 g, 10 mmol), diphenylphosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) was stirred at room temperature for 1 h, then the reaction temperature was slowly raised to 70° C. Evolution of gas began to be evident as the reaction temperature reached approximately 55° C. and became much more vigorous as the reaction temperature approached 70° C. Within 30 minutes at that temperature gas evolution had stopped and the reaction solution containing 3-acetoxybenzylisocyanate was cooled to 40° C. Another portion of diisopropylethylamine (3.84 mL, 22 mmol) was added, followed by 4-amino-2-chlorobenzoic acid methyl ester hydrochloride salt (2.95 g, 13.3 mmol) and the brownish purple solution was stirred and heated at reflux under argon overnight. The reaction mixture was cooled, diluted with benzene (50 mL) and washed in turn with 1N hydrochloric acid (50 mL) and dilute brine. The aqueous layers were re-extracted with benzene and the combined extracts were dried (MgSO4), evaporated and purified by HPLC (silica gel; 40% ethyl acetate/hexane). Evaporation of the appropriate fractions provided 3.24 g of the solid urea which was then crystallized from dichloromethane-ethyl acetate to afford 4-[[(3-acetoxybenzyl)amino]carbonyl]amino-2-chlorobenzoic acid, methyl ester (2.71 g, 72%) as a colorless solid, mp 113-114° C.
Reaction SMILES: S(Cl)(Cl)=O.Cl.C(OC([N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:15][CH2:14]1)=O)(C)(C)C.[CH3:28]O>>[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([O:24][CH3:28])=[O:23])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C(=O)O)c2)CC1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (2.39 mL, 32.7 mmol) was added dropwise to 15 mL of anhydrous methanol. The resulting anhydrous methanolic HCl solution was added to 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzoic acid (3.31 g, 10.9 mmol) and the reaction mixture was stirred at rt for 6 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 5-10% stepwise gradient in 1% increments of 10% NH4OH (28% solution)/methanol in DCM) to give methyl 3-(1,2,3,6-tetrahydropyridin-4-yl)benzoate. ESI-MS calc. for C13H15NO2: 217; Found: 218 (M+H).
Reaction SMILES: C(OC(N1CCNC[C@@H]1C)=O)(C)(C)C.FC(F)(F)CCI.C(N(CC)CC)C.C(=O)([O-])O.[Na+].C(OC([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][C:49]([F:52])([F:51])[F:50])[CH2:43][C@@H:42]1[CH3:53])=O)(C)(C)C.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>C(#N)C.ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[CH3:53][C@@H:42]1[NH:41][CH2:46][CH2:45][N:44]([CH2:47][CH2:48][C:49]([F:52])([F:50])[F:51])[CH2:43]1
Reactant: C[C@H]1CN(CCC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: FC(F)(F)CCI
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(CCC(F)(F)F)CCN1

Procedure:
A solution of (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol), 1,1,1-trifluoro-3-iodo-propane (268 mg, 1.2 mmol) and triethylamine (200 mg, 2 mmol) in acetonitrile (10 ml) was stirred at 80° C. for 3 days. After standard work-up (aqueous sodium hydrogencarbonate, dichloromethane), (S)-2-methyl-4-(3,3,3-trifluoro-propyl)piperazine-1-carboxylic acid tert-butyl ester was deprotected under standard conditions with trifluoroacetic acid (1 h) to give (S)-3-methyl-1-(3,3,3-trifluoro-propyl)-piperazine trifluoroacetic acid salt which was used without purification in the next step. LC/MS (method 7): Rt=0.07 min; m/z=197.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNc1nc(Cl)ncc1[N+](=O)[O-]

Procedure:
To a solution of 5 g of 2,4-dichloro-5-nitro-pyrimidine in 150 ml of dichloromethan 3.1 g of neopentylamine and 10.5 ml of diisopropylethylamine were added in succession at 0° C. After 2 hours the mixture was washed with saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness yielding (2-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as yellow cristals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[CH:8]3[CH2:18][CH2:17][C:12]4(OCC[O:13]4)[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:21])[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[CH:8]3[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc2c(c1F)OC1CC3(CCC21)OCCO3
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCOc1ccc2c(c1F)OC1CC(=O)CCC21
Reaction time: 18 h

Procedure:
135.0 g (459 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-spiro[dibenzo[b,d]furan-3,2′-1,3-dioxolane] are dissolved in 1800 ml of toluene and stirred vigorously together with 550 ml (14.6 mol) of formic acid with addition of 10.0 ml (0.56 mol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one as colourless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.OP(O)(O)=O>O.CS(C)=O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
A solution of 1-fluoro-4-(methylsulfonyl)benzene (2.2 kg), KOH (906.3 g), 4-(trifluoromethoxy)phenol (2.364 kg) and DMSO (4.4 L) was heated to 90° C. and stirred until HPLC showed <0.5% starting material remained (about 10 hours). HPLC conditions: Zorbax SB-C8 4.6 mm×25 cm; mobile phase was a gradient of 70% water with 0.1% H3PO4/30% acetonitrile to 10% water with 0.1% H3PO4/90% acetonitrile over 15 minutes at a flow rate of 1.5 mL/min, followed by a five minute hold at 10/90; UV detection at 220 nM. Retention times: starting sulfone, 4.5 min; desired product, 7.8 min.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([NH:13][C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10]1)(=[O:8])C1C=CC=CC=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=C=O>>[O:24]=[C:18]1[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[C:15]2[C:20](=[N:21][CH:22]=[CH:23][C:14]=2[NH:13][CH:11]2[CH2:10][N:9]([C:1]([NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:8])[CH2:12]2)[NH:19]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(c1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Product: O=C(Nc1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 359 using the amine intermediate from example 366 and isocyanato benzene to provide 367. LC-MS (M+H=386, obsd.=386).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl.Cl[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.C(OCC)C>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil, 6 mmol) of sodium hydride are added slowly to a solution of 1.67 g (12 mmol) of 3-nitrophenol in 10 ml of dimethylformamide and the mixture is stirred at room temperature for 1 hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalyst) are added and the mixture is stirred at 80° C. for 3 days. The reaction mixture is cooled and 150 ml of diethyl ether are added. The precipitate is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue which is purified by preparative high performance chromatography. The title compound is converted to the oxalate and crystallized from ethanol, M.p.: 174°-178° C.