Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:15]1[CH2:17][CH:16]1[CH2:18]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH:16]3[CH2:17][O:15]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: Clc1ccc(N2CCN(CC3CO3)CC2)cc1Cl
Yield: 97 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3,4-dichloro-phenyl)-piperazine) and 3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after Biotage chromatography the title compound as a yellow oil in a 97% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]Br>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([Br:31])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrBr
Reactant: CC(O)c1ccc(F)c(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(Br)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 412A (1.5 g, 6.8 mmol) and triphenyl phosphine (1.9 g, 7.2 mmol) in dimethylformamide (20 ml) was added bromine (1.1 g, 6.8 mmol) through a syringe. After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water (100 ml) and ethyl acetate (200 ml). The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (2.6% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH4) m/z 282 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][O:8][CH:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12]=O>[Pd].CO>[CH3:12][N:5]([CH2:6][CH2:7][O:8][CH:9]([OH:11])[CH3:10])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(O)OCCNC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(O)OCCN(C)C(C)(C)C
Temperature: 80 °C
Yield: 81.2 %

Procedure:
A total of 145 g of tertiarybutylaminoethoxyethanol, 108 g of 37% aqueous formaldehyde, 10 g of 10% Pd/C, and 1 l of methanol were charged to an autoclave, pressured up to 1000 psi with H2 and heated at 80° C. for 8 hours. Filtration and distillation of the reaction mixture yielded 128 g of N-methyl-N-tertiarybutylaminoethoxyethanol with b.p. of 128° C. at 23 mm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][CH2:39][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][N:33]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1cnccn1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cnccn4)cc3)oc2C)cc1
Yield: 69.2 %

Procedure:
Method E. Reaction of oxalyl chloride (74 λL, 0.8 mmol) and benzoic acid 4 (209 mg, 0.6 mmol) with subsequent coupling to 2-pyrazinylmethylamine (90 mg, 0.6 mmol) gave benzamide 13 (192 mg, 74%) as a white powder: mp (EtOAc) 204-206° C.; 1H NMR δ 9.30 (t, J=5.8Hz, 1 H, CONH), 8.66 (d, J=1.5Hz, 1 H, H-3′), 8.59 (dd, J=2.6, 1.5Hz, 1 H, H-5′), 8.54 (d, J=2.6Hz, 1 H, H-6′), 8.02 (d, J=8.6Hz, 2 H, H-2, H-6), 7.90 (d, J=8.6Hz, 2 H, H-3, H-5), 7.67 (d, J=8.3Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 4.62-4.66 (m, 4 H, CH2SO2, CH2N), 2.41 (s, 3 H, CH3), 2.14 (s, 3H, CH3); 13C NMR δ 165.7, 158.0, 154.1, 149.9, 144.5, 143.9, 143.5, 143.2, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 53.0, 42.9, 21.0, 9.7; MS m/z 433.6 (MH+, 100%). Anal. calcd for C24H22N4O4S: C, 62.32; H, 4.79; N, 12.11. Found: C, 62.36; H, 4.67; N, 12.09%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3ccc4[nH]ccc4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
5-bromo-1H-indole (31.4 mg, 0.160 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (114 mg, 0.301 mmol), Fibercat palladium catalyst (Johnson-Matthey, 31 mg), and K2CO3 (2 M in water, 0.45 ml, 0.90 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (5:1->4:1->2:1 hexanes/EtOAc) to afford crude product. This crude material was then purified two times via HPLC (10%->95% MeCN/water with 0.1% TFA) afford title compound (12.2 mg, 21%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH:12]C(=O)C)([O-:5])=[O:4].C(O)C>O>[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH2:12])([O-:5])=[O:4]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of potassium hydroxide (2.5 g), 3-nitro-4-acetamido-1,1′-biphenyl (23.5 g), prepared in (A) above, water (6 mL) and ethanol (12 mL) is heated at reflux for one hour. The reaction mixture is cooled to room temperature and then poured into 300 mL of a mixture of water and ice. The solid is collected by filtration and the crude product is recrystallized from methanol (800 mL) to give 14.1 g of the title compound as an orange solid melting at 170–172° C.
Reaction SMILES: C[Si](I)(C)C.C1(C[O:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:28]=[C:27]4[C:23]([C:24]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:25][NH:26]4)=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)C=CC=CC=1>CO>[OH:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:28]=[C:27]3[C:23]([C:24]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3cccc(OCc4ccccc4)c3)ccc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cccc(O)c3)ccc12
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 0.4 g of N-[6-[3-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, and the mixture is refluxed for 3 hours. 50 cm3 of methanol are then added and refluxing is continued for 15 minutes. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 50° C.), 50 cm3 of ethyl acetate are added and the organic phase is washed with 3×50 cm3 of 10% sodium thiosulphate solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 0.18 g of N-[6-(3-hydroxyphenyl)-1H-indazol-3-yl]butanamide is obtained in the form of a grey powder melting at 188° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:20]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:33]([CH2:32][CH2:31][N:22]2[C:21](=[O:20])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:30])(=[O:34])=[O:35])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.00 g (7.032 mmol) 1-Isopropyl-piperidin-4-ylamine (commercially available, or obtainable as described in EP 1479676) was dissolved in 100 ml dichloromethane. Subsequently 1.38 ml (1.1 equiv.) diisopropylethylamine (DIPEA) and 2.12 g (1.1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (commercially available) were added. The resulting mixture was stirred for 5 h at room temperature. After complete conversion the mixture was diluted with 100 ml dichloromethane and washed with 150 ml water. The organic phase was then washed with 100 ml of a half saturated NaHCO3-solution and finally with brine. Drying over anhydrous MgSO4 and removal of the solvent by evaporation under reduced pressure gave crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide as a light yellow foam. Yield: 2.48 g MS (ES+): m/e=380.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:59][N:60]1[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH3:59])[N:61]=2)=[N:3][CH:4]=1
Reactant: COCCOc1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ccn(C)n2)nc1
Yield: 35 %

Procedure:
2-Bromo-5-(2-methoxy-ethoxy)-pyridine (0.42 mmol), sodium-tert.-butylate (1.4 eq.), tris-(dibenzylidene-aceton)-dipalladium (0.1 eq.), BINAP [=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] (0.1 eq.) and 1-methyl-1H-pyrazole-3-amine (1.4 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) is added. The reaction suspension is heated for 100 min to 120° C. and for 30 min to 150° C. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. [5-(2-Methoxy-ethoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine (“A22”) is obtained after reversed phase column chromatography (Water/acetonitrile+0.1% TFA) as yellow oil in a yield of 35%: HPLC (method C): 1.16 min; LC-MS (method A): 0.43 min, 249.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 10.803 (s, 1H), 7.900 (d, 1H, J=2.8 Hz), 7.802 (dd, 1H, J=2.8 Hz, J=9.4 Hz), 7.739 (d, 1H, J=2.3 Hz), 7.314 (d, 1H, J=9.4 Hz), 6.103 (d, 1H, J=2.3 Hz), 4.149-4.131 (m, 2H), 3.861 (s, 3H), 3.688-3.670 (m, 2H), 3.323 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1.C1COCC1>[NH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[C:20]([OH:25])([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)[C:21]([F:22])([F:23])[F:24]
Reactant: Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5 M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5 M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of THF over 2 min. The solution was stirred an additional 10 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5 N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131-135° C. 1H NMR (300 MHz, CDCl3) δ7.34-7.36(m, 1H); 7.04(dd, 1H, J=10.4, 2.4 Hz); 4.58(br. s, 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). 19F NMR (282 MHz, CDCl3) δ−131.5(s, 1F), −80.5(s, 3F). High resolution mass spec: calculated for C13H11NOClF4(M+H)+: 308.0470, found: 308.0465.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:28]([CH:29]([F:40])[C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[C:27]([CH:41]4[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]4)[C:26]4[CH:25]([O:49][CH2:50][C:51]5[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=5)[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=4[N:20]=3)[CH2:15][CH2:14]2)=[N:11][CH:12]=1>>[F:48][C:44]1([F:47])[CH2:43][CH2:42][CH:41]([C:27]2[C:26]3[CH:25]([O:49][CH2:50][C:51]4[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=4)[CH2:24][C:23]([CH3:59])([CH3:60])[CH2:22][C:21]=3[N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:10]4[N:11]=[CH:12][C:7]([N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:8][N:9]=4)[CH2:14][CH2:15]3)[C:28]=2[CH:29]([F:40])[C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:46][CH2:45]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CNCCO
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N(C)CCO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Yield: 26 %

Procedure:
Reactions similar to those of Reference Example 13 were performed except for using 2-(methylamino)ethanol instead of isonipecotic acid ethyl ester, and from 100 mg (0.120 mmol) of 2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 25 mg of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(2-hydroxyethyl)(methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline was obtained (yield: 26%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:25]1[N:29]2CCCNC2=C[CH:26]=1>>[N:25]1[N:29]2[CH2:4][CH2:3][CH2:2][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)[C:6]2=[CH:5][CH:26]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: c1cc2n(n1)CCCN2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCn4nccc43)n2)c1

Procedure:
B47 was prepared following the procedure reported for B1 using Al and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.11-2.22 (m, 2H), 4.10-4.20 (m, 4H), 4.22 (s, 2H), 6.85 (bs, 3H), 7.06 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.34 (s, 1H), 7.54-7.82 (bm, 2H), 8.47 (s, 1H), 10.00 (bs, 1H). MS (ES) C16H18N8O2S requires: 386. found: 387 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[C:17]1([CH2:23][C:24](=O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:25]([C:24]([CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CC(=C(Cc2ccccc2)Cc2ccccc2)C=C1

Procedure:
In an atmosphere of nitrogen, 8.0 g (121.0 mmol) of cyclopentadiene and 100 ml of dehydrated THF were placed in a 500 ml three-necked flask, and they were stirred. This mixed solution was cooled in an ice bath, and to the mixed solution was added 80 ml (125.6 mmol) of a hexane solution of n-butyllithium having a concentration of 15.7 mol/liter. Thereafter, the mixture was stirred at room temperature for 3 hours, and the resulting white slurry was cooled in an ice bath, followed by adding a solution obtained by dissolving 25.0 g (118.0 mmol) of 1,3-diphenyl-2-propanone in 50 ml of dehydrated THF. Thereafter, the mixture was stirred at room temperature for 12 hours, and the resulting yellow solution was quenched with a saturated NH4Cl aqueous solution. Then, 100 ml of hexane was added to extract a soluble matter, and this organic phase was washed with water and a saturated saline solution, followed by drying using magnesium sulfate. Then, the solvent was distilled off, and the residue was purified by column chromatography to obtain a desired product of a yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11]>CO.O>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1
Yield: 86.2 %

Procedure:
10.0 mmol of Benzaldehyde was dissolved in 30 ml of 30% solution of CH3OH and H2O, and added into a triangular flask equipped with magnetic stirrer. 10.0 mmol of hydroxylamine hydrochloride was added under stirring. After hydroxylamine hydrochloride was dissolved, 5.0 mmol of dry and porphyrized sodium carbonate was slowly added. The reaction was carried out at room temperature. After the completion of the reaction monitored by TLC, methanol was removed from the system under reduced pressure. 30 ml H2O and dichloromethane (3×30 ml) were added to extract the mixture. The organic layers were combined, and then dried over anhydrous sodium sulfate. The solvent was removed to afford a crude product of benzaldehyde oxime in 86.2% yield. The crude material was directly used in the next reaction without separation and purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[NH:24][N:23]=[N:22][N:19]=3)=[CH:20][CH:21]=2)=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCCOc1ccc(C=Cc2ccncc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=Cc1ccc(OCCCCc2nnn[nH]2)cc1)c1ccncc1
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of 5.3 g (19 mmol) of compound of Example 1, 3.7 g (57 mmol) sodium azide, 3.0 g (57 mmol) ammonium chloride and 40 ml N,N-dimethylformamide is stirred for 3 days at 125° C. One adds thereto a further 2.5 g sodium azide and 2.0 g ammonium chloride, stirs for a further 6 h at 125° C., evaporates, takes up the residue in water, extracts with dichloromethane, dries, evaporates and triturates with 2-propanol. There remain 2.7 g of title compound (44% of theory) of the m.p. 158°-159° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(CCc2ccc(F)cc2)CCN1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene (2.45 g, 12.1 mmol) and i-Pr2NEt (3.25 g, 4.5 ml, 25 mmol) were combined in acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture was concentrated and partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.30 g, 48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H), 2.78-2.62 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:22].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][I:22])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)C(CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 2 (392 g) in acetone (3.14 L), sodium iodide (542 g) was added. The reaction temperature went up to 29° C. from 17° C. The reaction mixture was maintained at room temperature over weekend. The mixture was filtrated and washed with MTBE. The filtrate and washings were combined and concentrated. The residue was treated with MTBE and water with a small amount of sodium thiosulfate. The organic layer was washed with water and concentrated to an oil. The oil was charged slowly into a mixture of water (2 L) and DMF (300 ml) with a small amount of seed at 5° C. The crystals were filtered and dried to give 3 (400 g, 93% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:5].[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22]>>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:5]
Reactant: COc1cccc(CNC(=O)C(C)(C)CO)c1
Reactant: N#Cc1c(N)cccc1F
Product: COc1cccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)c1

Procedure:
Prepared as in Example 22b from 3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46c) and 2-amino-6-fluorobenzonitrile as a white solid (41%). MS 354 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:2]([O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(O)c(C)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(C)cc1C

Procedure:
The product was generated via general protocol A using 1-bromotetradecane (44 mL, 0.149 mol), 2,4-dimethylphenol (19.5 mL, 0.164 mol), K2CO3 (82.4 g, 0.596 mol) and CH3CN (200 mL). Yielded 43.13 g (90.8%). 1H NMR (CDCl3, 600 MHz) δ: 7.00 (s, 1H, Ar—H), 6.94 (d, 3J=8.41 Hz, 1H, Ar—H), 6.75 (d, 3J=8.15 Hz, 1H, Ar—H), 3.97 (t, 3J=6.46 Hz, 2H, OCH2), 2.31 (s, 3H, Ar—CH3), 2.26 (s, 3H, Ar—CH3), 1.83 (p, 3J=7.3 Hz, 2H, O—CH2—CH2), 1.52 (p, 3J=7.6 Hz, 2H, O—CH2—CH2—CH2), 1.44-1.28 (m, 22H), 0.95 (t, 3J=7.05, 3H, CH2—CH3). 13C NMR (150 MHz) δ: 155.24, 131.45, 129.20, 126.88, 126.66, 111.08, 68.17, 53.41, 32.02, 31.90, 29.97, 29.79, 29.78, 29.76, 29.52, 29.50, 29.46, 26.24, 22.78, 20.47, 16.19, 14.19.