Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-].[CH:11]1[CH:16]=CC=C[CH:12]=1>C(OCC)C.C1(C=CC[Ti])C=CC=C1>[C:2]1([C@H:1]([OH:8])[CH2:16][CH:11]=[CH2:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Ti]CC=CC1C=CC=C1
Agent: [F-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC[C@@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution in 100 ml of diethyl ether of 9.8 mmol of cyclopentadienylallyltitanium bis-(1,2:5,6-di-O-isopropylidene-α-glucofuranose) complex according to Example 1 is cooled to -74° C. by means of a CO2 /acetone bath, and 0.89 ml (8.8 mmol) of freshly distilled benzaldehyde is added. The clear yellow solution is stirred for a further 2 hours at -74° C., and 50 ml of NH4F solution (45% in water) are added. The beige emulsion is warmed to RT and separated in a separating funnel. The ether phase is extracted once with 50 ml and then with twice 30 ml of 2N HCl and is diluted with 300 ml of ether and is then washed with twice 300 ml of water and once with 300 ml of saturated NaCl solution, dried by means of MgSO4, filtered and evaporated to dryness on a rotary evaporator. The crude product is flash chromatographed (45 g of silica gel, 25 cm length, diameter 2 cm, 10 ml/fraction, 0.3 bar, 1:5 ether/n-hexane) and distilled (boiling point 150° C./14 mbar); 1.02 g (79% yield) of a clear, colourless oil are obtained: [α]D =+44.1° (c 6.5, benzene), 91% ee (methods A and B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>N1C=CC=CC=1>[C:9]([CH:8]([CH3:11])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:14])[CH3:12])=[CH:7][CH:6]=1)#[N:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C#N)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(C)C#N)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Amino-phenyl)-propionitrile (10.2 g, 69.8 mmol) in pyridine (40 mL) was added Ac2O (7.49 g, 73.4 mmol) at room temperature. The reaction mixture was refluxed for 1 hrs then cooled to room temperature, and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]([F:30])([F:29])[CH2:24][CH2:25][C:26](O)=[O:27].C(N(CC)CC)C.C(OCC)(=O)C>C(OCC)C.CCCCCC>[F:22][C:23]([F:30])([F:29])[CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:27]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(CCC(F)(F)F)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 31.5 %

Procedure:
Preparation of example 15 from the title compound of Example 7 (15 mg, 0.054 mmol), 4,4,4-trifluorobutyric acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylfomamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:25][CH2:26]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCC3)CC2)c1

Procedure:
Example 137 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 546.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[CH3:8][O:9][C:10]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:44]([O:45][CH3:46])=[CH:43][C:42]([O:47][CH3:48])=[CH:41][C:40]=1[O:49][CH3:50])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH2:36])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1>>[CH3:58][O:57][C:51]1[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=[C:10]([O:9][CH3:8])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:40]([O:49][CH3:50])=[CH:41][C:42]([O:47][CH3:48])=[CH:43][C:44]=1[O:45][CH3:46])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][CH:4]([C:3]([OH:7])=[O:2])[CH3:5])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][CH:4]([C:3]([OH:2])=[O:7])[CH3:5])[CH:16]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: COC(=O)C(C)Br
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(C)C(=O)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(C)C(=O)O)c2)c(OC)c1

Procedure:
A solution of methyl-2-bromopropionate (40 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method B. The product obtained was purified by recrystallization from acetone. (m.p. 176-180° C.)
Reaction SMILES: CN(C)C=O.[N+](C1C=CC(O[C:16](=[O:28])/[C:17](/[CH3:27])=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[NH2:26])=CC=1)([O-])=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>C(Cl)Cl.CO.C(OCC)(=O)C.O>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:16](=[O:28])[C:17]([CH3:27])=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[NH2:26])=[CH:33][CH:32]=1
Reactant: COc1ccc(CCN)cc1
Reactant: C/C(=C\c1ccc(Cl)cc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(C)=Cc2ccc(Cl)cc2N)cc1
Yield: 91.8 %

Procedure:
Into 2 ml of dimethylformamide, 0.20 g (0.60 mmol) of (E)3-(2-amino-4-chlorophenyl)-2-methyl-2-propenoic acid p-nitrophenyl ester and 0.11 g (0.72 mmol) of 2-( 4-methoxyphenyl)ethylamine (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved, and the mixture was reacted for 20 hours at room temperature. After the completion of the reaction was verified by TLC, ethyl acetate and water were added thereto. The resulting ethyl acetate layer was fractionated, and was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. The washed solution was dried with magnesium sulfate anhydride, and the solvent was evaporated under a reduced pressure. The crude product obtained here was refined by a silica gel column chromatography (developing solvent: methylene chloride/methanol=95/5), whereby 0.19 g of the aimed compound was obtained (yield: quantitative).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].S.[OH-].[Na+]>C(=O)=O.C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:29][C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:9][C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(CC(=O)CC(C(=O)c2ccccc2)c2ccccc2)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C=O
Agent: S
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1cccc(Cc2cc(-c3ccccc3)c(-c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 3.92 h
Yield: 82.3 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 51.6 g (0.150 mole) of 1,2-diphenyl-4-m-anisylbutane-1,4-dione, 100 ml of xylene and 30 g (0.0675 mole) of phosphorus pentasulfide. The autoclave was cooled in Dry Ice and charged with 130 g (3.81 moles) of hydrogen sulfide. The mixture was then heated and stirred 235 minutes at 154°-177° C. (1120-1320 psig). The vessel was cooled to room temperature. The hydrogen sulfide was vented into a sodium hydroxide solution. The residue was treated with 150 ml of absolute ethanol to destroy excess phosphorus sulfides. Washing the product with another 330 ml of ethanol gave 32 g (62.3%) of crude product. Recrystallization from 50 ml of toluene and 150 ml of ethanol gave 19.8 g (38.5%) of pure 2,3-diphenyl-5-m-anisylthiophene, m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][N:39]([CH3:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([N:39]([CH3:47])[CH2:38][CH2:37][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][C:20]=2[O:25][CH3:26])=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc(Cl)cc2)cc1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccc(Cl)cc1
Temperature: 75 °C
Yield: 98 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added 2-[4-chloro(methyl)anilino]ethyl p-toluenesulfonate (170 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (136 mg, 98%). 1H NMR (DMSO-D6) δ 3.00 (3H, s), 3.77 (5H, m), 4.21 (2H, m), 6.81 (2H, d, J=9.0 Hz), 7.02-7.20 (5H, m), 7.58 (2H, d, J=8.6 Hz), 7.95 (3H, m), 8.39 (1H, s). Calcd. for C28H23Cl2N3O3S×3HCl: C, 50.81; H, 3.96; N; 6.35. Found: C, 50.91; H, 3.95; N, 6.23.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5])=[C:2]=[O:3].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:2]([NH:1][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)[CH3:5])=[O:3])[CH:26]=[CH:25][CH:24]=2
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Reactant: CC(N=C=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(NC(=O)Nc1cccc2cnc(N)cc12)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(1-Isocyanatoethyl)-4-(trifluoromethyl)benzene (1.64 mmol) in toluene (8 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (220 mg, 1.09 mmol) and DIEA (1.4 mL). The mixture was heated at 80° C. for 6 hours, cooled to room temperature, and the precipitate was collected by filtration. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 4 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL) and filtered. The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.64 (s, 1H), 7.91 (d, 1H), 7.58-7.74 (m, 4H), 7.22-7.36 (m, 3H), 7.14-7.18 (m, 2H), 6.97 (s, 1H), 4.94 (m, 1H), 1.44 (d, 3H, J=6.8 Hz); MS (ESI+) m/z 375 (M+H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24](/[C@H:29]1[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]1)=[CH:25]\[CH2:26][CH2:27][CH3:28]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:35][C@H:32]1[CH2:31][CH2:30][C@H:29](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH3:28])[CH2:34][CH2:33]1
Reactant: CCC/C=C/[C@H]1CC[C@H](C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Product: CCC/C=C/[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 21 g of anhydrous (methoxymethyl)triphenylphosphonium chloride in 100 ml of abs. diethyl ether is treated with 6.86 g of potassium tert.-butylate at 0° C. in a nitrogen atmosphere. The red suspension is stirred at 0° C. for 15 minutes and then treated dropwise at 5°-10° C. with a solution of 7.9 g of trans-4-(1E-pentenyl)cyclohexanecarboxaldehyde in 30 ml of diethyl ether. The mixture is stirred at room temperature for 4 hours, washed with 40 ml of ice-cold saturated sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over sodium sulphate, filtered and concentrated. The residue is dissolved in 100 ml of hexane and 40 ml of 80 percent aqueous methanol. The hexane phase is washed with 10 ml of 80 percent aqueous methanol and 20 ml of water, dried over sodium sulphate and concentrated. Distillation of the residue in a vacuum yields trans-1-(2-methoxy-vinyl)-4-(1E-pentenyl)cyclohexane as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:37][CH3:38])=[C:19]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:26][CH2:25]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:37][CH3:38])=[C:19]([CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:28][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CC2CCN(CCC(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 90 °C
Yield: 13.9 %

Procedure:
To a solution of ethyl 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoate (D141) (0.63 g, 1.133 mmol) in Isopropanol (5 mL) and Water (5.00 mL) was added NaOH (2.266 mL, 1.133 mmol). The reaction solution was heated to 90° C. for 1 hour. The solvent was evaporated in vacuo and the residue was acidified to pH=2-3, extracted with ethyl acetate, washed with water, dried and purified by Mass Directed AutoPrep to afford 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoic acid (E106) (83 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.00 (3H, t), 1.28 (6H, d), 1.44 (2H, m), 1.72 (3H, m), 2.63 (4H, m), 2.83 (4H, m), 3.17 (4H, m), 4.79 (1H, m), 7.24 (2H, m), 7.32 (1H, d), 7.59 (1H, dd), 7.94 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H34ClN3O3S requires 527.2. found 528.1 (M+H+)
Reaction SMILES: [CH2:1]([OH:22])[CH2:2][CH:3]([OH:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([C:29](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:22][CH2:1][CH2:2][CH:3]([OH:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCCCCCCCC(O)CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(O)CCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Icosane-1,3-diol (3.7 g, 11.8 mmoles) is co-evaporated twice with anhydrous pyridine (50 mL each) and then is dissolved in anhydrous pyridine (60 mL). The solution is chilled in an ice bath, and 4,4′-dimethoxytritylchloride (4.2 g, 12.4 mmoles) is added. The reaction is allowed to warm to ambient temperature and is stirred for 16 hours. The remaining 4,4′-dimethoxytritylchloride is quenched with methanol (10 mL), and the yellow solution is then evaporated to near dryness. The residue is co-evaporated twice to dryness with toluene (50 mL each). The crude product is purified on silica gel (150 mL bed volume) eluting with hexanes:acetone:triethylamine (95.5:5:0:5 [v/v/v], 500 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow syrup. The syrup is dried well in vacuo. The yield is 6.8 g (93%).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([OH:9])=[CH:7][CH:8]=1)#[N:2].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:9][C:6]1[N:5]=[C:4]([OH:10])[C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:15]
Reactant: N#Cc1ccc(O)nc1O
Reactant: O=C(Cl)c1ccccc1Cl
Product: N#Cc1ccc(OC(=O)c2ccccc2Cl)nc1O
Yield: 54.8 %

Procedure:
The general procedure of Example 81 was followed using 2.00 g of 3-cyano-2,6-dihydroxypyridine and 2.57 g of 2-chlorobenzoyl chloride, thereby producing 2.21 g of the title compound in a yield of 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH2:10]([C:14]1[S:18][C:17]([S:19]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])=[O:20])=[C:16](B(O)O)[CH:15]=1)[CH:11]([CH3:13])[CH3:12].[OH-].[Na+].CCO>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.O.C1(C)C=CC=CC=1>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[C:14]([CH2:10][CH:11]([CH3:12])[CH3:13])[S:18][C:17]=2[S:19]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])(=[O:21])=[O:20])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Cc1cc(-c2cccc(CO)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A mixture of m-bromobenzyl alcohol (1.05 g, 5.80 mmol), 5-iso-butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (2.41 g, 7.55 mmol; see step (c)), Pd(PPh3)4 (270 mg, 0.235 mmol), NaOH (19.1 mL, 1.5 M aq, 28.6 mmol), EtOH (5.0 mL) and toluene (30 mL) was stirred under N2 at 90° C. for about 4 h. After cooling, water (10 mL) was added to the reaction mixture and this was then extracted with ethyl acetate. The combined organic phase was dried and concentrated in vacuo. The crude product was purified on column chromatography (EtOAc/hexane, 30:70) to give sub-title compound as a colourless syrup in 57% yield (1.26 g, 3.31 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1/[CH:4]=[N:5]/[NH2:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[N:19]=1.O>C1(C)C=CC=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1/[CH:4]=[N:5]/[NH:6][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[N:19]=1
Reactant: N/N=C/c1ccccc1Cl
Reactant: Cc1cc(Cl)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Cl)cc(N/N=C/c2ccccc2Cl)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
(E)-1-(2-chlorobenzylidene)hydrazine (0.351 g, 2.27 mmol), dichloro[1,1′bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.0185 g, 0.0227 mmol) and potassium carbonate (0.471 g, 3.41 mmol) was added to a 50-mL RBF. Toluene (2 mL) was added and 2,4-dichloro-6-methylpyridine (0.368 g, 2.27 mmol) in 3 mL of toluene was added. The red mixture was heated to 100° C. After 18 h, the reaction was allowed to cool to RT and water (20 mL) was added. The mixture was filtered and 190 mg of (E)-1-(2-chlorobenzylidene)-2-(4-chloro-6-methylpyridin-2-yl) hydrazine was collected as a tan solid. The filtrate was absorbed on silica gel and purified by silica gel chromatography (8/2 hexanes/DCM to 7/2/1 hexans/DCM/EtOAc) to afford an additional 200 mg of (E)-1-(2-chlorobenzylidene)-2-(4-chloro-6-methylpyridin-2-yl) hydrazine as a tan solid. MS (ESI, pos. ion) m/z: 280.0 (M+1).
Reaction SMILES: C(OCC1C=CC=CC=1)C1C=CC=CC=1.[Li].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li]CCCC.[O:30]=[C:31](N1[C@@H](C(C)C)COC1=O)[C@@H:32]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:33][CH3:34]>C1COCC1>[C:38]1([CH2:37][S:36][CH2:35][C@@H:32]([CH2:33][CH3:34])[C:31]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:30])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@H](CSCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: OCc1ccccc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](CSCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 161.2 %

Procedure:
To a magnetically stirred, cooled (-10° C.) solution of lithium benzyloxide in anhydrous THF (400 mL), prepared from freshly distilled benzyl alcohol (28.7 mL, 30.0 g, 277 mmol) and 127.5 mL (1.6M in hexane, 204 mmol) of n-BuLi, was added a solution of the product of step 7 (48.9 g, approx. 146 mmol) in anhydrous THF (170 mL) over a 0.5 h period. After 15 min. at -10° C., the reaction mixture was warmed to 0° C., stirred for 2 h and then quenched by the addition of half-saturated aq NH4Cl (300 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with H2O (3×) and brine, dried over MgSO4 and concentrated in vacuo to give 74 g of a pale yellow oil. This crude material was purified in two portions by flash chromatography on silica with toluene giving the title compound as a colorless liquid (32.8 g), containing a small amount of butanoic acid benzyl ester and an unidentified impurity. This product was used as such for the next step.