Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.C(#N)C.P(Cl)(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:23][C:2]1[CH2:3][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1CC(=O)NN1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC(Cl)=NN1c1cccnc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
A 3-neck round bottomed flask (100 mL) was charged with ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (8.50 g, 36.1 mmol) and acetonitrile (40 mL). Phosphoryl chloride (4.05 mL, 43.4 mmol) was charged and the reaction was heated at 60° C. for 2 h. The reaction was cooled to 20° C. and water (100 mL) was added. Sodium carbonate was added to adjust pH to 8 and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 30-80% ethyl acetate/hexanes as eluent to provide the title compound as a yellow oil (7.30 g, 79%): 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=2.9, 0.8 Hz, 1H), 8.17 (dd, J=4.7, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.79 (dd, J=12.4, 6.9 Hz, 1H), 4.24 (qd, J=7.1, 1.1 Hz, 2H), 3.55 (dd, J=17.7, 12.4 Hz, 1H), 3.33 (dd, J=17.8, 6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.65, 141.90, 141.33, 141.09, 135.13, 123.53, 120.37, 62.89, 62.35, 42.45, 14.03; ESIMS m/z 254 ([M+H]+).
Reaction SMILES: [Li].[C:2]([C:5]1[C:6]([C:12]([OH:14])=[O:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].Cl>O.[Pd]>[C:2]([C:5]1[C:6]([C:12]([OH:14])=[O:13])=[N:7][CH:8]=[N:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1cnc(Cl)nc1C(=O)O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CC(=O)c1cncnc1C(=O)O
Reaction time: 8 h

Procedure:
To a mixture of the lithium salt of 5-acetyl-2-chloro-4-pyrimidinecarboxylic acid (1.1 g, 4.90 mmol) and sodium bicarbonate (0.5 g, 5.95 mmol) in 20 ml of water is added 10% palladium on carbon (0.1 g), and the reaction mixture is kept under H2 overnight. It is then acidified with 1M hydrochloric acid (6 ml) and concentrated. The resulting solid is filtered, rinsed with water and dried to give 5-acetyl-4-pyrimidinecarboxylic acid.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.[CH2:43]([C:50]#[N:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CC[O-].[Na+]>[CH3:42][N:30]([CH3:29])[C:31](=[CH:32][CH:33]=[C:43]([C:50]#[N:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Product: CCOC(=O)C(=CC=C(C#N)c1ccccc1)N(C)C
Yield: 66.9 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (57.2 g), a 2M ethanolic solution of sodium ethylate (105 cc) and benzyl cyanide (23.4 g). Ethyl 2-dimethylamino-5-cyano-5-phenyl-2,4-pentadienoate (36.1 g), m.p. 67° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[NH:3]1.[O:20]=[C:21]1[C:26]2=[CH:27][NH:28][C:29]([CH:30]=O)=[C:25]2[CH2:24][CH2:23][O:22]1>>[O:1]=[C:2]1[C:10](=[CH:30][C:29]2[NH:28][CH:27]=[C:26]3[C:21](=[O:20])[O:22][CH2:23][CH2:24][C:25]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(-c3cccc(C(=O)O)c3)ccc2N1
Product: O=C1Nc2ccc(-c3cccc(C(=O)O)c3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
3-(2-Oxo-2,3-dihydro-1H-indol-5-yl)-benzoic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:33]4[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 89.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (909 mg, 2.2 mmol) in dioxane (7.5 mL) and H2O (2.5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (1.57 g, 6.6 mmol), potassium carbonate (1.82 g, 13.2 mmol), and tetrakis(triphenylphospine)palladium (0) (30 mg, 0.22 mmol). The reaction was heated in the microwave at 150° C. for 20 min. The mixture was then concentrated to dryness. EtOAc (50 mL) was added to the residue and washed with brine. The precipitate which formed between the water and organic layer was filtered and collected as a brown solid to give 874 mg of the title compound (89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[I-:10].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C=O)C.O>[I:10][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [I-]
Reactant: COc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)ccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxyphenol (2.0 ml, 18.2 mmol) was dissolved in dry DMF (50 ml). Sodium iodide (3.3 g, 21.9 mmol) and chloramine-T (5.0 g, 21.9 mmol) was added to the mixture and the reaction was stirred at room temperature for one hour. The reaction mixture was diluted with water (150 ml), acidified with 5% hydrochloric acid solution and extracted with ethyl acetate (2×100 ml). The organic layer was washed with 5% sodium thiosulphate solution (200 ml) and dried over sodium sulphate. The product was purified by flash chromatography on silica gel twice (first with dichloromethane, then with 20% ethyl acetate in petroleum ether). The yield was 0.82 g (18%). 1H NMR (CDCl3, 500 MHz): δ 7.52 (1H, d, J=8.5 Hz), 6.63 (1H, d, J=3.0 Hz), 6.37 (1H, dd, J=8.5 Hz, 3.0 Hz), 5.27 (1H, s), 3.81 (3H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].C([N:36]1[C:44]2[C:39](=[N:40][C:41]([C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)=[CH:48][CH:47]=3)=[C:42]([Cl:45])[CH:43]=2)[N:38]=[C:37]1[O:57][C@@H:58]1[CH2:62][O:61][C@@H:60]2[C@H:63]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH2:64][O:65][C@H:59]12)C=C>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:36][C:37]([O:57][C@@H:58]3[CH2:62][O:61][C@@H:60]4[C@H:63]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:68])[CH3:69])[CH2:64][O:65][C@H:59]34)=[N:38][C:39]2=[N:40][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)=[CH:48][CH:47]=1
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1,4-bis(diphenylphosphino)butane (5.9 mg, 0.014 mmol), palladium(II) acetate (4.0 mg, 0.018 mmol), and ethanol (0.17 ml) were combined in a 4 ml vial. The catalyst mixture was degassed (3×) and placed under nitrogen. The catalyst mixture was an amber suspension that was stirred at room temperature. Sodium borohydride (19.0 mg, 0.502 mmol) was added to a stirred solution of [(3R,3aR,6R,6aS)-3-[1-allyl-6-chloro-5-(4-pyrrolidin-1-ylphenyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (50.3 mg, 0.084 mmol) in ethanol (0.67 ml). The reaction mixture was a yellow suspension that was degassed (3×) and placed under nitrogen. After being stirred at room temperature for 40 minutes, the catalyst mixture was transferred to the reaction mixture via syringe. The reaction mixture was degassed (2×) and placed under nitrogen. After 3.5 hours, the reaction mixture was filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting (20 ml/min) with a 14 minute 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 5 minute 100% acetonitrile+0.05% TFA flush. The product fractions were combined, frozen, and lyophilized to give the title compound as a yellow solid. LC-MS: calculated for C28H37ClN4O4Si 556.23 observed m/e: 557.29 (M+H)+ (Rt 1.24/2 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][O:11][C:12]1[C:13]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH3:9])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: COc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc(Cl)cc1C
Yield: 89.2 %

Procedure:
Treatment of 2-bromo-5-chlorotoluene (5.0 g, 24.33 mmol) with 2-methoxybenzeneboronic acid (4.8 g, 31.63 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.478 g, 0.608 mmol), and potassium carbonate (8.41 g, 60.83 mmol) generally according to the procedure described for Intermediate 37 provided 5.05 g (89%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether. Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether (5.05 g, 21.48 mmol) with boron tribromide (5.37 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 4.58 g (97%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol as a yellow oil. Anal. calcd. for C13H11ClO: C, 71.4; H, 5.07. Found: C, 71.03; H, 4.84.
Reaction SMILES: F[B-](F)(F)F.[N:6]1([O:15]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Br:32][C:33]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[CH:60]=[CH:59][C:44]([C:45]([NH:47][CH2:48][C@H:49]([N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:50](O)=[O:51])=[O:46])=[CH:43][CH:42]=2)[CH:36]=[CH:35][N:34]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[Br:32][C:33]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]([NH:47][CH2:48][C@@H:49]([C:50](=[O:51])[NH:6][OH:15])[N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[O:46])=[CH:59][CH:60]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NC[C@@H](C(=O)O)N1CCCCC1)c1ccc(OCc2ccnc(Br)c2)cc1
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H](C(=O)NO)N1CCCCC1)c1ccc(OCc2ccnc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.5 %

Procedure:
130 mg (0.4 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 0.2 ml (1.2 mmol) of diisopropylethylamine are added to a solution of 185 mg (0.4 mmol) of (S)-3-[4-(2-bromopyridin-4-ylmethoxy)benzoylamino]-2-piperidin-1-ylpropanoic acid in 10 ml of dimethylformamide. After stirring for 20 minutes at ambient temperature, 65 mg (0.4 mmol) of O-tert-butyldimethysilylhydroxylamine diluted in 3 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 18 h, then hydrolysed with 1 ml of an aqueous solution of 5% citric acid and 2 ml of water. After stirring at ambient temperature for 1 h, the mixture is brought to pH=8 with a saturated aqueous solution of sodium hydrogen carbonate then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is precipitated in an 8/2 heptane/ethyl acetate mixture then filtered. The residue obtained is recrystallized in ethyl acetate. 20 mg (10%) of 4-(2-bromopyridin-4-ylmethoxy)-N—((S)-2-hydroxycarbamoyl-2-piperidin-1-ylethyl)benzamide are obtained in the form of a pale-yellow solid having a melting point of 150° C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH2:4]O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)CC.[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:4][C:3]2[CH:6]=[C:7]([Br:11])[CH:8]=[C:9]([Br:10])[C:2]=2[NH2:1])[CH2:15][CH2:14]1
Reactant: Nc1c(Br)cc(Br)cc1CO
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: CN1CCN(Cc2cc(Br)cc(Br)c2N)CC1
Temperature: 140 °C

Procedure:
A mixture of 0.56 part of 2-amino-3,5-dibromobenzylalcohol, 1.0 part of N-methyl piperazine and 2 parts of propionic acid is heated at 140° C for 8 hours under stirring. Then, the propionic acid is distilled off under reduced pressure. The residue is extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent gives oily residue. The residue is chromotographed over silica gel. Ethyl acetate eluates are treated with ethanolic hydrochloric acid. This procedure gives N1 -methyl-N4 -(2-amino-3,5-dibromobenzyl)piperazine hydrochloride melting at 182° to 185° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([F:18])[CH:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Temperature: 0 °C
Yield: 89.5 %

Procedure:
To a mixed solvent solution of benzyl 4-bromo-2-fluorobenzoate (67.0 g) and 2-hydroxyphenylboronic acid (31.3 g) in 1,2-dimethoxyethane (750 ml) and water (250 ml) were added sodium carbonate (68.7 g) and tetrakis(triphenylphosphine)palladium (12.5 g), followed by stirring under heating at reflux for 5 hours. The reaction solution was brought back to room temperature, and then poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and further washed with hexane to afford benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (62.5 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1.[Se:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[Se:20][C:21]([C:24]2[Se:25]C=CC=2)=[CH:22][CH:23]=1.CN(C=O)C>C(OCC)(=O)C>[CH:11]([C:10]1[Se:25][C:24]([C:21]2[Se:20][C:19]([C:15]3[Se:14][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:22]=2)=[CH:13][CH:9]=1)=[O:12]
Reactant: C1CCOC1
Reactant: c1c[se]c(-c2ccc(-c3ccc[se]3)[se]2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(-c3ccc[se]3)[se]2)[se]1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
LDA (1.0 M solution in THF, 310 mL) was added to an anhydrous THF solution (4 mL) containing 2,2′:5′,2″-terselenophene (100 mg) under N2 at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (1 mL) was added, stirred at −78° C. for 1 h, and slowly warmed to room temperature. The reaction solution was diluted with ethyl acetate (100 mL) and washed with H2O (4×100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was chromatographed over silica gel using CH2Cl2 to afford 2-formyl-5,2′:5′,2″-terselenophene in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O:11]C)=O)[CH2:4][CH2:3]1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:14][NH2:15])=[O:11])[CH2:6][CH2:7]1
Reactant: COC(=O)CN1CCN(C)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(CC(=O)NN)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, methyl ester (16.3 g., 0.0946 mole) and hydrazine monohydrate (7.0 ml., 0.142 mole) in ethanol (100 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ether with cooling at -78° and the resulting solid was filtered. The product was triturated again with ether-ethyl acetate to give 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide as a solid melting at 87°-89° C. (8.94 g., 55%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (1 g; 6.58 mmol), BrCH2CO2Et (0.806 ml; 7.24 mmol) and K2CO3 (1 g, 7.24 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and H2O (100 ml). The organic layer was separated and dried over MgSO4, and filtrate evaporated, to give the product (1.29 g; 97%), as colourless solid. 1H-NMR (CDCl3) 1.28 (tr, 3H, J=7.11 Hz); 3.84 (s, 3H); 4.25 (q, 2H, J=7.14, 14.28 Hz); 4.69 (s, 2H); 6.30 (d, 1H, J=2.16 Hz); 6.58 (dd, 1H, J=1.77, 8.73 Hz); 7.83 (d, 1H, J=8.7 Hz); 10.36 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([C:23]#[N:24])[CH:3]=1.[Br-].[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[Zn+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:27]4[S:26][CH:30]=[CH:29][N:28]=4)=[CH:3][C:4]=3[C:23]#[N:24])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C#N)c(C)nc12
Reactant: [Zn+]c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nccs4)cc3C#N)c(C)nc12
Temperature: 65 °C
Yield: 62.9 %

Procedure:
To a flask containing 5-bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.25 g, 0.62 mmol) and PdCl2(dppf) (0.023 g, 0.031 mmol) is added a solution of 0.5 M 2-thiazolylzinc bromide (6.0 mL, 3.10 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×25 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.16 g, 0.39 mmol, 64%). 1H NMR (CDCl3) δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.58 (s, 3H), 2.66 (s, 3H), 3.25-3.35 (m, 1H), 6.78 (s, 1H), 7.38 (d, J=3.5 Hz, 1H), 7.70 (s, 1H), 7.84 (d, J=3.5 Hz, 1H). LC/MS (m/z): calcd. for C21H21N5S2 (M+H)+: 408.6; found: 408.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([CH2:22][O:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[O:44]1CCCC1.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>>[CH2:1]([N:8]1[CH2:9][CH:10]([CH2:22][O:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:12]([OH:44])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Agent: B
Agent: O=C([O-])[O-]
Agent: OO
Product: COc1ccc(C2C(O)CN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 62(d), by hydroboration of (RS)-1-benzyl-4-(4-methoxy-phenyl)-3-trityloxymethyl-1,2,3,6-tetrahydro-pyridine with borane-tetrahydrofuran and subsequent oxidation by means of sodium percarbonate there was obtained (3RS,4RS,5SR)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol as a colourless foam; MS: 570 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH2:2][CH3:3].[S:13](Cl)[Cl:14].Cl.C(N(CC)CC)C>CCCCCC.C(N(CC)CC)C>[Cl:14][S:13][N:4]([CH2:1][CH2:2][CH3:3])[P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: CCCNP(=S)(OCC)OCC
Reactant: ClSCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCN(SCl)P(=S)(OCC)OCC
Reaction time: 0.5 h

Procedure:
A solution of 2.98 gm. (0.014 mole) O,O-diethyl n-propylphosphoramidothioate in 10 ml. hexane and 2 ml. triethylamine is added to a cold (0° C.) solution of 1.0 ml. (0.016 mole) sulfur dichloride in 10 ml. hexane slowly and with stirring. There is vigorous reaction and heavy precipitation of triethylamine hydrochloride. An additional 20 ml. hexane is added. The reaction mixture is kept at 0° to 5° C. and stirred for 30 minutes, then it is filtered. The filtrate is concentrated to a pale yellow oil by evaporating the hexane under reduced pressure. The oil comprises the desired O,O-diethyl N-(chlorothio)-n-propylphosphoramidothioate which can be used for further reactions with N-methylcarbamates.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[OH:19].[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[O:19][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]1)=[O:29])=[O:20]
Reactant: COC(=O)c1cc(Oc2ccccc2)ccc1O
Reactant: CC1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cc(Oc2ccccc2)ccc1OC(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Sodium hydride (0.38 g, 9.93 mmol of a 60% oil dispersion) was added in portions under a nitrogen atmosphere to a solution of 2-hydroxy-5-phenoxybenzoic acid methyl ester (2.0 g, 8.19 mmol) in 30 ml of benzene. The reaction was stirred at room temperature for 30 minutes. 4-Methyl-1-piperidinecarbonyl chloride (1.46 g, 9.03 mmol) was then added and the reaction refluxed for 3.5 hours. The reaction mixture was washed with 1N HCl, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 3.38 g of a clear oil. Purification of this oil on 300 g of silica gel (230-400 mesh) using hexane-methylene chloride as the eluent gave 2.71 g of a white crystalline solid. Recrystallization of this solid from diisopropyl ether-hexane then gave the title compound as a white crystalline solid (2.02 g, 67%), mp 67°-69C.