Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28](NCC(O)=O)=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C[N:46]([C:48]([O:52]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:10][N:9]2[CH2:28][C:48]([NH2:46])=[O:52])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1CN(CC(N)=O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.37 h
Yield: 70.7 %

Procedure:
To a mixture rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (25.4 mg, 0.048 mmol, example 17) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (30.3 mg, 0.080 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.6 mg, 0.12 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetamide (16.3 mg, 64.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[CH:6]=[CH:5]2.ClC1C(Cl)=CC(C(O)=O)=C(C=O)C=1.C([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH2:55])[CH:41]([OH:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([NH:55][C@H:40]([C:41](=[O:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])[CH2:39][C:38]([OH:56])=[O:37])=[O:17])[CH:6]=[CH:5]2
Reactant: CC[C@@H](C(=O)O)n1ccc2cc(Cl)c(Cl)cc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2cc(Cl)c(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(6,7-dichloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (synthesized from 4,5-dichloro-2-formyl-benzoic acid [prepared as described in methods Q-S] using procedures similar to those described in methods A-E) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The title compound was isolated as a white solid (94% last step). IR (solid) 1784.5, 1734.7, 1650.1, 1610.2, 1585.4, 1515.7, 1490.8, 1426.0, 1216.9, 1172.1, 1092.5, 933.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.80 (3H, t), 1.90-1.98 (1H, m), 2.04-2.12 (1H, m), 2.55-2.79 (2H, m), 4.56-4.71 (1H, m), 5.08-5.41 (3H, m), 6.67 (1H, d), 7.56-7.59 (2H, m), 8.07 (1H, brd s), 8.25 (1H, d) 8.85-8.95 (1H, 2×d), 12.73 (1H, brd s) ppm; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.93, −140.95, −140.99, −141.01, −141.04, −141.07, −141.10, −156.76, −156.79, −156.82, −156.85, −156.89, −156.91; MS ES (+) 577.14 (M+H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Add 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (16.8 g.) to a solution of sodium borohydride (6 g.) in methanol (500 cc.), swirl the mixture which boils spontaneously. When all the material has been added and the reaction has subsided, add acetic acid (15 cc.). Reduce the mixture in volume by evaporation of most of the solvent, add water and extract the product with ether. Evapoate the washed and dried extracts to obtain crude crystalline product (16.8 g.), m.p. 102°-5° on recrystallization from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CCCC1N=CNC=1Br)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[Br:1])([O-:23])=[O:22]
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br
Reactant: NCCCCc1nc[nH]c1Br
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br

Procedure:
When 5-bromo-4-(4-aminobutyl)imidazole is reacted with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[4-(5-bromo-4-imidazolyl)butylamino]ethylene, m.p. 157°-158° treated with methylamine by the procedure of Example 8(ii) , the title compound, m.p. 145°-148° is produced.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=O)[C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[N:10]1.C(=O)(O)O.[NH2:45][C:46]([NH2:48])=[NH:47]>COCCO>[NH2:48][C:46]1[N:47]=[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH:24]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=4)[CH:15]=3)[NH:20][CH:21]=2)[N:45]=1
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C#CCCCN4C(=O)c5ccccc5C4=O)c3c2)cn1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCN(CC)CC
Solvent: COCCO
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN5C(=O)c6ccccc6C5=O)nc(N)n4)c3c2)cn1

Procedure:
8.5 0.92 ml (6.7 mmol) of triethylamine is added to a solution of 116 mg (0.265 mmol) of 2-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-6-oxohex-4-ynyl}isoindole-1,3-dione and 70 mg (0.39 mmol) of guanidine carbonate in 4 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 6 hours. After cooling, the mixture is evaporated, and the residue is purified by preparative HPLC, giving 2-(3-{2-amino-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrimidin-4-yl}propyl)isoindole-1,3-dione as brown solid; ESI 479, EMD 1183586.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: Cl
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-aminophenol (32 mg, 0.290 mmol) similar to Example 97 and isolated as a yellow solid (37 mg, 52%). 1H NMR (DMSO-d6): 10.51 (s, 1H), 8.98 (d, J=6.0 Hz, 2H), 8.54 (d, J=6.6 Hz, 2H), 7.32-7.21 (m, 5H), 6.61-6.57 (m, 1H).
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC(=O)[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[C:41]3[O:40]C(C(C)(C)C)=[N:38][C:37]=3[CH:36]=[CH:35][C:34]=2[Cl:46])(=[O:32])=[O:31])[CH2:26][CH2:25]1)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:38][C:37]1[C:41]([OH:40])=[C:33]([S:30]([N:27]2[CH2:26][CH2:25][CH:24]([NH2:23])[CH2:29][CH2:28]2)(=[O:32])=[O:31])[C:34]([Cl:46])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: C1COCCO1
Solvent: Nc1ccccc1
Solvent: O
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCC(N)CC2)c1O
Yield: 74.9 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, [1-(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-piperidin4-yl]-carbamic acid tert-butyl ester (4.18 g, 8.86 mmol), water (5.5 mL), and H2SO4 (5.5 mL) in 1,4-dioxane (55mL) were reacted to afford the title compound (2.03 g, 75%). LCMS m/z 306(M−H)+.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(NS(C)(=O)=O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(NS(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
A mixture of N-[1-(7-acetyl-5-chloroquinolin-8-yl)piperidin-4-yl]methanesulfonamide (0.027 g, 0.071 mmol) and ammonium acetate (0.0545 g, 0.707 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.17 mL, 0.17 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H24ClN4O2S (M+H)+: m/z=383.1; Found: 383.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>C(N(CC)CC)C>[O:15]=[C:14]1[CH2:13][CH2:12][N:11]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:10][CH:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1CCN(Cc2ccccc2)CC1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Reaction time: 6.3 h
Yield: 86.5 %

Procedure:
To a stirred mixture of 10 parts of 3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinone and 65 parts of dichloromethane were added dropwise 5 parts of ethyl carbonochloridate at room temperature. After stirring for 6.30 hours at reflux, there were added 5 parts of N,N-diethylethanamine. Upon completion, stirring at reflux was continued for 24 hours. The reaction mixture was washed successively with water, a diluted hydrochloric acid solution and again with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.1 parts (86.5%) of ethyl 4-oxo-3-(phenylmethoxy)-1-piperidinecarboxylate as an oily residue (intermediate 47).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH:29]1N=CN(C(N2C=NC=C2)=S)C=1.[F:41][C:42]([F:51])([F:50])[CH2:43][NH:44][CH2:45][CH:46]([OH:49])[CH2:47][OH:48].CCN=C=NCCCN(C)C.NC(N)=S>CN(C1C=CN=CC=1)C.O.ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]=[C:29]4[N:44]([CH2:43][C:42]([F:50])([F:51])[F:41])[CH2:45][CH:46]([CH2:47][OH:48])[O:49]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OCC(O)CNCC(F)(F)F
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: NC(N)=S
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: OCC1CN(CC(F)(F)F)C(=Nc2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)O1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
[2-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylimino}-3-(2,2,2-trifluoro-ethyl)-oxazolidin-5-yl]-methanol is prepared from N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine. 1,1-Thiocarbonyldiimidazole (55 mg, 0.28 mmol) is added to a solution of N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (100 mg, 0.253 mmol) in 1:1 THF:DCE (1 ml). After 30 min, a 1:1 THF:DCE (1 ml) solution of 3-(2,2,2-trifluoro-ethylamino)-propane-1,2-diol (88 mg, 0.51 mmol) is added. After 16 h, the reaction mixture is concentrated and the resulting solid is suspended in Et2O and filtered. EDCI (110 mg, 0.560 mmol) and catalytic DMAP is added to a suspension of the solid thiourea in 1:1 THF:DCE (4 ml), After 6 h, an additional 200 mg EDCI is added and the reaction mixture is heated to 70° C. After 16 h, the reaction mixture is cooled to room temperature and diluted with water. The aqueous layer is extracted with EtOAc. The combined organic extracts are dried (Na2SO4) and concentrated. Purification on a silica gel column (EtOAc) yields the desired product as a yellow solid (10 mg, 7%0). MS ESI (+) m/z 576.2, 578.2 (M+1) detected; 1H NMR (400 MHz, DMSO-d4) δ 9.56 (s, 1 H), 8.47 (s, 1 H), 8.08 (d, 1 H), 7.94 (s, 1 H), 7.77 (m, 1 H), 7.62 (m, 2 H), 7.47 (m, 1 H), 7.32 (m, 2 H), 7.24 (d, 1 H) 7.19 (m, 1 H), 5.25 (s, 2 H), 5.19 (t, 1 H), 4.77 (br, I1 H), 3.77 (m, 1 H), 3.66 (m, 1 H), 3.55 (m, 2 H), 2.97 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][N:16]=1)[CH3:2]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(C)c1OCCCCOc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.6 g of 3-ethyl-5methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]phenol and 0.23 g of potassium carbonate, to which a solution of 0.28 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.50 g of 3-ethyl-5-methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (64% yield), nD23.0 1.5170.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C[C@H](C(O)=O)C1C=CC2C=C(OC)C=CC=2C=1.O[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([O:16][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: ON1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)ON3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To 1.15 g (0.005 mol) of (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, i.e., naproxen, in 50 ml of ethyl acetate was added 0.53 g (0.005 mol) of N-hydroxypiperidine in 20 ml of ethyl acetate and 1.1 g (0.005 mol) of dicyclohexylcarbodiimide. A suspension formed immediately. After 0.5 hour, the suspension was filtered and the residue of dicyclohexylurea (0.6 g) was discarded. The filtrate was concentrated and that residue was suspended in 200 ml of ether and filtered. The ether filtrate was concentrated and that residue was crystallized from 20 ml of cyclohexane. The crystals from cyclohexane were filtered and identified as the acylurea by-product. The cyclohexane solution was concentrated to 5 ml and diluted with 5 ml of heptane to give 0.84 g (mp 95°-97° C., 54% yield) of the desired acylated hydroxylamine (C). The crude product was recrystallized from heptane to give analytically pure product: TLC (silica gel, ether) Rf 0.51; IR (KBr) 1735 cm-1 (s) (C=O), NMR (CDCl3)δ7.8-7.0 (m, 6, aromatic-H), 3.9 (s, 3, CH3 --O), 3.8 (q, 1, J=7 Hz, CH--CH3), 3.5-2.3 (m, 4, CH2N), 1.57 (d, 3, J=7 Hz, CH3 --CH) and 2.0=0.9 (m, 6, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:4].[CH3:15][NH:16][C:17](=[O:29])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH2:19]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C:7]([C:8]([NH:19][CH:18]([C:17]([NH:16][CH3:15])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:10])=[CH:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: COC(=O)CC=C(CC(C)C)C(=O)O
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(=CCC(=O)OC)CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
N,N-Dicyclohexylcarbodiimide (515 mg, 2.5 mmol) was added to an ice-cooled solution of 4-methoxycarbonyl-2-(2-methylpropyl)but-2-enoic acid (500 mg, 2.5 mmol) and O-methyl-L-tyrosine N-methylamide (520 mg, 2.5 mmol) in dry dichloromethane (30 ml), and the mixture was stirred at room temperature for 18 h. The precipitated solid was filtered off and washed with a little dichloromethane, then the organic solution was washed successively with 1N hydrochloric acid (20 ml), 1N sodium bicarbonate (20 ml), and water. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography (30 g silica) of the residual solid, eluting with 5% methanol/dichloromethane gave the title compound (520 mg, 53%), m.p. 142°-144° C. (dichloromethane/pentane).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].O1CCOCC1>O>[CH2:26]([N:29]([CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: CCCNCCC
Solvent: C1COCCO1
Solvent: O
Product: CCCN(CCC)CC1CCn2c(nc3ccccc32)S1
Yield: 14.3 %

Procedure:
To 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole were added 4 ml of di-n-propylamine and 20 ml of dioxane. The mixture was reacted in a sealed tube, at 120° C. and for 67 hours. After cooling down the temperature of the reaction mixture, it was condensed under reduced pressure. Water was added to the condensed reaction mixture,followed by an extraction with chloroform and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 0.13 g (yield: 14.3%) of the intended product, m.p. 82°-84° C.; IR νmaxKBr cm-1 : 3100-2700, 1420; Anal. Calcd. for C17H25N3S: C, 67.29; N, 8.30; N, 13.85; S, 10.56; Found: C, 67.52; H, 8.41; N, 13.98; S, 10.09.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(C=C(Br)Br)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred, cooled (ice/salt, 0°) solution of carbon tetrabromide (48.82 g) in anhydrous DCM (200 ml) was added, portionwise over 3 minutes, triphenylphosphine (77.1 g), maintaining the temperature below 10°. The resulting orange suspension was stirred at 0° for 1 hour before adding to it 3-fluorobenzaldehyde (7.8 ml). After the addition was complete, the suspension was stirred at 0° for 1 hour then quenched by the addition of water (75 ml). The organic phase was separated and washed with brine (75 ml), dried (Na2SO4) and evaporated to dryness. The residue was poured into cyclohexane (1 L) and stirred for 30 minutes. The organic phase was decanted and the residue taken up into DCM and poured into cyclohexane (1 L). This procedure was repeated twice more and the combined organic phases concentrated to ˜100 ml and passed through silica gel. The filtrate was concentrated to give the title compound as a mobile yellow oil (24 g, 100%). MH+ 280, MH− 279
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH:30]([CH:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([CH3:42])(O)[CH3:40])[CH2:34][CH2:33]4)[CH2:29][C:28]=3[CH:43]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C1(C)C=CC=CC=1.ClCCl.CO>[F:11][C:39]([CH3:42])([CH3:40])[CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([CH:30]2[CH2:29][C:28]3[CH:43]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:19][CH:20]=4)[CH:25]=[CH:26][C:27]=3[O:31]2)[CH2:33][CH2:34]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(O)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(F)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of [bis(2-methoxyethyl)amino]sulfur trifluoride in toluene (50%; 162 μL) is added to an ice-cooled solution of 1-{4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol (100 mg) in dichloromethane (2 mL) and the resulting mixture is stirred for 16 h. The reaction mixture is diluted with methanol and concentrated in vacuo. The residue is purified by HPLC to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8](=[S:10])=[S:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>C1C=CC=CC=1.CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:9][C:8](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1
Reactant: N#CCC#N
Reactant: COc1ccc(CCl)cc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc(CSC(SCc2ccc(OC)cc2)=C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DMF (40 mL) was slowly added to a rapidly stirred mixture of malononitrile (13.2 g, 0.2 mol) and NaH (9.6 g, 0.4 mol) and CS2 (22.8 g, 0.3 mol) in benzene (200 mL). The reaction mixture was stirred at room temperature for 30 min and 4-methoxybenzyl chloride (93.6 g, 0.6 mol) was added. The resulting mixture was stirred for 12 h, and benzene (50 mL) and ice-water (200 mL) were added. The organic layer was separated, dried, and concentrated in vacuum. The product was purified by flash chromatography on silica gel, eluting with ethyl acetate:hexanes (15:85). Yield: 45.8 g (0.12 mol, 60%). NMR (δ, CDCl3): 7.22 (4H, d, J=8.6 Hz); 6.85 (4H, d, J=8.6 Hz); 4.33 (4H, s); 3.79 (6H, s).