Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.FC1C=CC=CC=1C([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH3:55])=[CH:48][C:49]3[S:53][CH:52]=[N:51][C:50]=3[CH:54]=2)=[CH:42][N:41]=1)=O.C([O-])(O)=O.[Na+].CC(=O)OCC>C(Cl)Cl>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH3:55])=[CH:48][C:49]3[S:53][CH:52]=[N:51][C:50]=3[CH:54]=2)=[CH:42][N:41]=1)=[O:6]
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2c(F)cncc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A suspension of 3,5-difluoroisonicotinic acid (24 mg, 0.15 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (35 mg, 0.2 mmol) and 45 μl N-methyl morpholine in 2 ml DCM was stirred at r.t. for 1 h before addition of 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (24 mg, 0.1 mmol). The resulting reaction mixture was stirred at r.t. for overnight then at 50° C. for 3 h. The reaction mixture was worked up with aq. NaHCO3/EA. Org. phase was washed with brine, concentrated, subjected to silica flash column chromatography to furnish 8.9 mg (3,5-difluoro(4-pyridyl))-N-[5-(6-methylbenzothiazol-5-yl)(2-pyridyl)]carboxamide (58) as yellow semi-solid. (yield: 23.3%, purity>90%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:7].[ClH:5].[CH3:1][NH:2][C:3](=[SH:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:24][CH:23]=2)[CH2:14][CH2:15]1)[OH:4]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 64.4 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of methyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.75 g (32% of theory) of N-methyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 240°-243° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)Cl)c(OCc2ccccc2)c1)OCc1ccccc1

Procedure:
Thionyl chloride (1.55 ml) and dimethylformamide (2 drops) were added to a solution of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid (7.1 mg) in dichloromethane (50 ml), and the mixture was refluxed under heating for 1.5 hours. After the reaction, the solvent was evaporated under reduced pressure to give 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (50 ml), and the solution was dropwise added to a solution of 4-aminopyridine (1.42 g) and diisopropylethylamine (5.27 ml) in acetonitrile (50 ml) under ice-cooling. The mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give N-(4-pyridyl)-2-benzyloxy-4-benzyloxycarbonylaminomethylbenzamide as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])C#N.CO.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17]>[Ni].O.C(O)=O>[CH3:13][O:14][CH:15]([O:16][CH3:17])[C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: COC(OC)OC
Agent: [Ni]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: COC(OC)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A mixture of 85 g of Raney nickel, which had been washed thoroughly with water, 500 ml of formic acid and 100 g (0.5 mole) of 3-bromo-4-fluoro-benzonitrile was stirred for 24 hours at 90°-100° C. under an atmosphere of a blanketing gas (nitrogen or argon). After cooling to room temperature, 1 liter of water was added and the mixture was extracted twice with 300 ml of toluene. The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water and then dried by incipient distillation. 1.5 g of air-dried ion exchanger SPC 118, 16 g (0.5 mole) of methanol and 58.5 g (0.55 mole) of orthoformic acid trimethyl ester were then added to the solution, the mixture was stirred for a further 1 hour without a bath and was then warmed at 50° C. for 2 hours. The reaction mixture was cooled, filtered to remove the ion exchanger and washed with 200 ml of 5% strength potassium carbonate solution. The solvent was then stripped off and the residue was distilled in vacuo. 93 g (75% of theory) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were obtained in this way, in the form of a colorless liquid with a boiling point of 67°-68° C./0.1 mm Hg.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:25])=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=3[N:16]=2)[CH:10]=1)(=[O:4])=[O:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[OH:25][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)(=[O:4])=[O:3])=[CH:10][C:9]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3O)nc12
Reactant: CN1CCNCC1
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Yield: 97 %

Procedure:
A solution of 5-(5-chlorosulphonyl-2-hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.235 g, 0.0006 mol) and N-methylpiperazine (0.5 ml, 0.0045 mol) in ethanol (40 ml) was stirred at room temperature for 18 hours. The solution was evaporated under vacuum and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). The fine precipitate was filtered off, washed with water then ethyl acetate, and crystallised from ethyl acetate/DMF to give the title compound as an off-white powder (0.260 g, 49%), m.p. 283°-284° C. Found: C,53.53; H,5.89; N,18.40. C20H26N6O4S requires C,53.80; H,5.87; N,18.82%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cc(F)cc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 70.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24)(126 mg, 0.364 mmol) in sodium carbonate (96.3 mg, 0.909 mmol), Pd(PPh3)2Cl2 (10.63 mg, 0.015 mmol), toluene/ethanol/water (3/5/1 ml) to give 160 mg (72.7% yield) of titled compound. MS: m/z=753.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14]O[C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.C1(C)C=CC=C(C2[S:34]C=NC=2C(O)=O)C=1>>[NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][S:34][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Reactant: Cc1cccc(-c2scnc2C(=O)O)c1
Product: Cc1cccc(-c2scnc2C(=O)Nc2cnn(CCN)c2)c1

Procedure:
The title compound was synthesized according to above mentioned procedure for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide, starting from 5-(m-tolyl)thiazole-4-carboxylic acid. LC-MS conditions B: tR=0.54 min, [M+H]+=328.10.
Reaction SMILES: [CH3:1][C:2]1([CH:15]([NH:17][C:18](=O)[CH3:19])[CH3:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3>P(Cl)(Cl)(Cl)=O>[CH3:19][C:18]1[N:8]2[C:7]3[C:2]([CH3:1])([O:3][CH2:4][CH2:5][C:6]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:15]([CH3:16])[N:17]=1
Reactant: CC(=O)NC(C)C1(C)OCCc2c1[nH]c1ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NC(C)C2(C)OCCc3c2n1c1ccccc31

Procedure:
A mixture of N-[1-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)ethyl]-acetamide (2.0 g, described in Example 2) and phosphorus oxychloride (10 ml) is heated at 100°-110° C. for 3 hours and evaporated. The residue is partioned between chloroform and 10% sodium carbonate. The organic layer is collected, washed with water, saturated brine solution and dried over magnesium sulfate. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a less polar isomer, isomer A(0.40 g), of the title compound, nmr(CDCl3) δ0.86(d) and 3.74(q) and a more polar isomer, isomer B(0.40 g), of the title compound nmr(CDCl3) δ0.78(d) and 4.07(q).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: OCCCCCc1ccc(-c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
[1,1′-biphenyl]-4-pentanol (3.34 g, 13.90 mmol) and carbon tetrabromide (5.99 g, 18.07 mmol) were dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Triphenyl phosphine (4.98 g, 18.07 mmol) in methylene chloride (10 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The mixture was poured into hexanes (100 mL) and then filtered through a short silica gel column, washed with ethylacetate/hexanes (1/4). The combined organic solvents were evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (hexanes:ethylacetate 30:1) to afford 4.18 g of the title compound. Yield: 99%. 1H NMR (300 MHz, CDCl3) δ 1.52 (m, 2H), 1.67 (m, 2H), 1.91 (m, 2H), 2.67 (t, J=7.5 Hz, 2H), 3.41 (t, J=6.9 Hz, 2H), 7.21-7.60 (m, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 28.2, 30.9, 33.0, 34.1, 35.6, 127.1, 127.2, 128.8, 128.9, 138.8, 141.2, 141.5 ppm.
Reaction SMILES: [S:1]([O-:9])([O:4][CH2:5][CH2:6][O:7][CH3:8])(=[O:3])=[O:2].[Na+:10].[CH2:11]([OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC.S(=O)(=O)(O)O>>[S:1]([O-:9])([O:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:3])=[O:2].[Na+:10].[CH3:8][O:7][CH:6]([OH:29])[CH3:5]
Reactant: COCCOS(=O)(=O)[O-]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)[O-]
Product: COC(C)O

Procedure:
In the most preferred embodiment of the present invention, equimolar quantities of sodium methoxyethyl sulfate and oleyl alcohol are reacted in the presence of catalytic quantities of sulfuric acid at ambient temperature to form sodium oleyl sulfate and methoxyethanol. This reaction proceeds as follows: ##STR2##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].BrC1C=CC=CC=1[O:17]C.IC1C=CC=CC=1OC.[Mg].[NH:29]1[C:37](=[O:38])[C:35](=O)[C:33](=[O:34])[NH:32][C:30]1=[O:31]>C(OC(C)C)(C)C>[OH:17][N:29]1[C:37](=[O:38])[CH:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[C:33](=[O:34])[NH:32][C:30]1=[O:31]
Reactant: COc1ccccc1Br
Reactant: COc1ccccc1Cl
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: COc1ccccc1I
Agent: [Mg]
Solvent: CC(C)OC(C)C
Product: COc1ccccc1C1C(=O)NC(=O)N(O)C1=O

Procedure:
Alternatively, 2-chloroanisole, 2-bromoanisole or 2-iodoanisole is converted to the corresponding Grignard reagent by reaction with magnesium turnings in diisopropyl ether. The reagent is chilled and reacted with anhydrous alloxan according to Example 5 to yield 5-(hydroxy-5-(2-methoxyphenyl)-2,4,6(1H,3H,5H)pyrimidintrione.
Reaction SMILES: [Br-].[C:2]([C:6]1[C:19]2[NH2+:18][C:17]3[C:12](=[CH:13][C:14]([Br:20])=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8](Br)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br-:20].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:8]2[CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]3[C:10]([CH:9]=2)=[S+:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[CH:13]=2)[N:18]=3)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3nc4c(C(C)(C)C)cc(N5CCN(C)CC5)cc4[s+]c3c2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1-t-butyl-3,7-dibromophenothiazinium bromide (400 mg, 0.8 mmol) in chloroform (15 mL) kept under argon, 1-methylpiperazine (400 mg, 4.0 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system: dichloromethane-methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: FC(F)(F)c1nccc(Cl)n1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccnc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=364.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-chloro-2-trifluoromethyl-pyrimidine.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C@:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]2)([OH:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A 250 mL three-necked flask was charged with magnesium turnings (2.88 g, 0.12 mol) and a small crystal of iodine in THF (20 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture. After heating under reflux for 1 h, most of magnesium was consumed, the reaction mixture cooled to rt. Another 250 mL three-necked flask was charged with (R)-3-(3-chloro-benzoyl)piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent derived from 1-chloro-4-methoxybutane (20 mL) was added dropwise. After addition, the mixture was allowed to warm slowly to rt and stirred for 2 h. The mixture was quenched with sat'd aq NH4Cl (100 mL), extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE 10:90) to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (3.0 g, 73%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.52-1.58 (m, 3H), 1.75 (m, 1H), 1.92 (m, 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H), 3.95 (m, 1H), 4.35 (m, 1H), 7.20-7.26 (m, 3H), 7.36 (m, 1H). MS (E/Z): 412 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:4]1.[C:18](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](=[O:29])[NH:27][CH3:28])[CH:22]=1.C(N(CC)C(C)C)(C)C>>[CH3:28][NH:27][C:26]([C:23]1[CH:22]=[C:21]([CH2:20][O:19][C:18]([NH:1][CH2:2][CH:3]2[CH2:4][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)[CH2:6]2)=[O:30])[O:25][N:24]=1)=[O:29]
Reactant: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(CN)C2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCC2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 1, step 1.1. Starting with 0.24 g (1.00 mmol) of tert-butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-carboxylate (isomer 2b), described in Example 9 (step 9.1.), 0.321 g (1.00 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained in step 4.1., 0.258 g (2.00 mmol) of N,N-diisopropylethylamine and 0.012 g (0.10 mmol) of N,N-dimethylaminopyridine, and after purification by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.320 g of pure product is thus obtained in the form of an amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (3 g, 19 mmol), L-proline (2.19 g, 19.0 mmol) and triethylamine (10.6 ml, 76 mmol) were dissolved in DMSO (15 ml) then heated at 90° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue treated with water and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to a residue. Purification by column chromatography using dichloromethane/methanol (97:3) gave 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.9 g, 20%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][N:14]1[C:21]2[N:17]([N:18]=[CH:19][CH:20]=2)[CH:16]=[CH:15]1)=[O:6])[CH:2]=[CH2:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9][C@H:8]1[CH2:13][N:14]1[C:21]2[N:17]([N:18]=[CH:19][CH:20]=2)[CH:16]=[CH:15]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cn1ccn2nccc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccn2nccc12

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (3.16 g) in a mixture of ethyl acetate (60 ml) and triethylamine (2.27 ml) was dropwise added a solution of methanesulfonyl chloride (1.18 ml) in ethyl acetate (5 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water (50 ml) with stirring and the organic layer was separated. The organic layer was washed in turn with saturated aqueous sodium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl -2-(imidazo[1,2-b]pyrazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (3.06 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:23]([O:21][C:20](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Finely divided t-butoxycarbonyl-D-tryptophan (3 g, 10 mmol) was suspended in methylene chloride and benzyl alcohol (1.08 mL, 10 mmol) and 4-dimethylaminopyridine (0.12 g, 1 mmol) were added and stirred at room temperature. Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) was then added in three roughly equal portions over 5 minutes. The reaction mixture was stirred for 3 hours at room temperature during which time the reaction mixture became a homogeneous solution. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (2×50 mL). The combined methylene chloride layers were washed with 5% aqueous citric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL). The resulting methylene chloride layer was dried over magnesium sulfate, filtered and evaporated under vaccum to give an off-white solid. This solid material was chromatographed on silica gel using ethyl acetate/hexanes (2:3 v/v) as eluant. This afforded 3.56 g (91%) of the desired benzyl ester as a white amorphous powder.