Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and methanamine hydrochloride (8.45 mg, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid. 1H NMR (CHLOROFORM-d) δ: 8.37 (br. s., 1H), 7.58-7.89 (m, 3H), 7.15 (br. s., 1H), 6.87 (d, J=8.8 Hz, 2H), 6.07 (d, J=4.5 Hz, 1H), 5.06 (dt, J=13.6, 2.5 Hz, 1H), 4.42 (dd, J=10.1, 3.8 Hz, 1H), 3.55 (br. s., 2H), 3.36 (br. s., 4H), 3.08-3.24 (m, 1H), 2.56-3.08 (m, 8H), 2.40 (dd, J=13.5, 1.1 Hz, 1H), 1.74 (br. s., 2H). [M+H] calc'd for C, 23; H, 28; N, 6; O, 2; S, 453; found, 453.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=O)[O:19]N1C(=O)CCC1=O.C(N(CC)CC)C>C(#N)C>[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=[O:19])[O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COC(=O)ON2C(=O)CCC2=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 122 %

Procedure:
To a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (0.4 g, 3.0 mmol) in acetonitrile (10 mL) was added carbonic acid bis-(2,5-dioxo-pyrrolidin-1-yl) ester (1.15 g, 4.5 mmol) and triethylamine (0.84 mL, 6.0 mmol). After stirring at ambient temperature for 10 min, the mixture was concentrated at reduced pressure, sat. NaHCO3 (50 mL)was added, and the solution was extracted with ethyl acetate and organic phase was separated and concentrated to obtain 1.0 g of crude product that was used without further purification in the next step. MS (APCI) m/z: 273 [M+H]+ 1H NMR (DMSO-d6) δ: 4.50 (m, 1H), 4.40-4.29 (m, 2H), 4.04 (m, 1H), 3.73 (dd, J=6.0 and 9.0 Hz, 1H), 2.80 (s, 4H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25]CCN1CCCC1C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:25][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22]#[N:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: CC1CCCN1CCCCl
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCN1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 88.4 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (315 mg, 1.55 mmol), 1-(3-chloro-propyl)-2-methyl-pyrrolidine (400 mg, 2.48 mmol), DMF (6 ml) and K2CO3 (833 mg, 6.03 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (450 mg, 88%) as an orange oil. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-3.99 (m, 4H), 3.89 (td, 2H), 2.35-1.62 (m, 14H), 1.42 (m, 1H), 1.09 (d, 3H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15](=[O:19])[NH:16]2)=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1Cc2ccc(NC(=O)c3ccncc3)cc2N1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1Cc2cc([N+](=O)[O-])c(NC(=O)c3ccncc3)cc2N1
Reaction time: 2 h

Procedure:
5.5 g. (21.7 mMol) 6-isonicotinoylaminoindolin-2-one are dissolved portionwise in 20 ml. concentrated sulphuric acid, cooled with ice and 2.19 g. (21.7 mMol) potassium nitrate dissolved in concentrated sulphuric acid slowly added dropwise thereto. After 2 hours, the solution is poured on to ice, neutralised and filtered with suction. The residue is substantially dissolved in 2N hydrochloric acid, filtered, treated with Floridin (fullers' earth), filtered with suction and neutralised. There are obtained 4.5 g. (70% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCNC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCN(C(=O)COC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-3-ylamide (example A180) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[C:9]1([C:15]2[CH2:16][CH:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18](=[O:21])[NH:19][N:20]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccccc2)CC1c1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
135 ml (135 mmole) of a solution of phenylmagnesium bromide (1M) in THF was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 250.1 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[NH:4][C:3](=[O:15])[CH2:2]1.[OH-].[Na+].CO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3](=[O:15])[CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
In a 250 ml round-bottomed flask were place the preceding methyl 1,4-benzoxazine-3-one-6-carboxylate (5.8 g, 28 mmole), 50% aqueous sodium hydroxide (9.0 g, 112 mmole), methanol (125 ml), and water (19 ml). The resulting mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and the solvent eliminated in the rotary evaporator. The crude reaction product was taken up in water and the resulting aqueous solution was washed with hexane (2×50 ml) and acidified to pH=1 with concentrated aqueous hydrochloric acid. The solid which formed was separated by suction filtration, and dried in a vacuum oven yielding 5.1 g of the expected 1,4-benzoxazine-3-one-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:9]
Reactant: Cc1cc(C(=O)O)no1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)on1

Procedure:
2,5-Hexanedione, 9 is the starting material for the process. 2,5-Hexanedione 9 is nitrated and oxidized with nitric acid to form 5-methyl-3-isoxazolecarboxlic acid 8, (isoxazole acid). Isoxazole acid 8 is esterified by treating it with methyl alcohol and sulfuric acid to give 5-methyl-3-isoxazolecarboxylic acid methyl ester, isoxazole ester 7. Isoxazole ester 7 is reacted with Benzylhydrazine 5 which itself is prepared from the reaction of benzaldehyde 6 with hydrazine and then reduced with hydrogen to form Benzylhydrazine 5.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc2cccnc2c2ncccc12
Yield: 62 %

Procedure:
A magnetically stirred solution of 5nitro-1, 10-phenanthroline (2,.01 g, 8.93 mmol) and tin(II) chloride dihydrate (6.05 g, 26.81 mmol) was heated to reflux for 3 h in ethanol (100 mL) and then concentrated in vacuo to give a viscous residue. The residue was treated with concentrated NaOH and then extracted with CHCl3 (3×50 mL). The organic layer was separated, washed with water (2×50 mL) and brine (1×50 mL), dried over anhydrous sodium sulfate, and then concentrated in vacuo to afford 1.08 g (62%) of the amine as a tan solid: m.p. 255-258 C; MS(fab):m/e 196 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(OCC)C.[H-].[Na+].CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:12][CH2:13][CH2:14][O:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: ClCCCOCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(Cl)cc2)CCCOC1
Reaction time: 12 h

Procedure:
A mixture of 2-(4-chlorophenyl)acetonitrile (73 g, 483 mmol) and 1-chloro-3-(chloromethoxy)propane (69.1 g, 483 mmol) in ethoxyethane (242 mL, 483 mmol) was added dropwise to a mixture of NaH (57 g, 1437 mmol) in 1-methylpyrrolidin-2-one (1208 mL, 483 mmol) at −20° C. The reaction was stirred for 12 hours and then slowly quenched with H2O. The reaction mixture was extracted with ether (5×), and the combined organic layers were washed with H2O (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo to give the desired nitrile as a yellow oil. MS m/e=223.2 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].Cl[CH2:6][O:7][C:8]([O:10][CH:11]([CH3:19])[CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9]>C1COCC1>[C:1]([O:4][CH2:6][O:7][C:8]([O:10][CH:11]([CH3:19])[CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)NCC(C)OC(=O)OCCl
Reactant: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCC(C)OC(=O)OCOC(C)=O
Reaction time: 120 h
Yield: 46.9 %

Procedure:
A THF solution (30 ml) of TBA acetate (1.21 g, 4 mmol), prepared by freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid, was added to a stirred solution of N-(2-chloromethoxycarbonyloxypropyl) methacrylamide (0.943 g, 4 mmol) from Example 16 above in THF (10 ml) at room temperature. Following stirring for 5 days the solvent was removed under reduced pressure and the residue was dissolved in chloroform (50 ml) and washed with water (5×10 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography (silicagel, hexane/ethyl acetate (3:4)) gave 0.486 g (47%) of the title product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([N:14]=[C:15]=[S:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:11]=[CH:12][CH:13]=1
Reactant: NCC(N)=O
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of glycinamide hydrochloride (6.1 g), 3-chloro-2-methylphenylisothiocyanate (10.1 g), triethyl amine (5.6 g), and chloroform (200 mL) was heated at reflux for 3 hours then cooled to ambient temperature. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide (12.5 g), m.p. 162°-164° C. (dec.). This compound was used without further purification for the preparation of the title compound of step 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Yield: 95.7 %

Procedure:
A mixture of 22.52 g (47.05 mmol) (S)-3-(2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester, 1 g 20% Pd on charcoal, 250 mL tetrahydrofuran and 250 mL ethanol was shaken under a 50 psig. hydrogen atmosphere for 26 h. The mixture was filtered through a pad of celite and concentrated. The residue was passed through a 100 g plug of silica eluting with 6:4 ethyl acetate:hexanes to give 17.5 g (45.05 mmol, 95.7%) of (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a thick colorless oil. MS (APCI) m/z 387.0 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][F:5])=[CH:19][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FCCCBr
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
3-Bromo-1-fluoro propane (1.6 g, 11 mmol) was added to a mixture of (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (compound 17c) (2.0 g, 3.7 mmol) and cesium carbonate (3.6 g, 11 mmol) in DMF (60 mL). The suspension was stirred overnight at room temperature. The reaction mixture was diluted in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 1.89 g (85.1%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2C[CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: CN(C=O)C.[SH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[F:21][C:22](I)([F:45])[C:23]([F:44])([F:43])[C:24]([F:42])([F:41])[C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]>O>[F:45][C:22]([F:21])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:23]([F:43])([F:44])[C:24]([F:41])([F:42])[C:25]([F:39])([F:40])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Sc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Yield: 63.5 %

Procedure:
To a solution composed of 40 ml of DMF and 4.66 g (25 mmol) of 2-mercaptobiphenyl was added 1.00 g (25 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 13.6 g (25 mmol) of perfluorooctyl iodide was added. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 hours. Water was addd to the reaction mixture, and the mixture was extracted with hexane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography using hexane as an eluent to give 9.60 g (64%) of 2-(perfluorooctylthio)biphenyl as a colorless oil. The properties of the product were as shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:15]#[N:16].[OH-:30].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:4][C:3]=1[CH:14]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:15]([NH2:16])=[O:30]
Reactant: [OH-]
Reactant: COc1cc(Br)c(C(C#N)CCCc2ccc(OC(C)C)cc2)cc1OC(C)C
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(Br)c(C(CCCc2ccc(OC(C)C)cc2)C(N)=O)cc1OC(C)C
Reaction time: 6 h

Procedure:
α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)benzene pentane nitrile (30.0 g, 65.2 mmol) in ethanol (600 ml) is mixed with potassium hydroxide (60.0 g, 1.07 mol) in water (100 ml) and stirred for 6 hours at boiling temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])OC1C1C=CC(OC)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][Cl:34].O1CCCC1.S([O-])(O)(=O)=O.[K+]>CCCCCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14](=[O:23])[CH2:33][Cl:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCBr
Reactant: COc1ccc(C2OC(=O)[C@H](Cc3ccccc3)N2C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.55 h
Yield: 62 %

Procedure:
(4S)-N-benzyloxycarbonyl-2-(p-methoxyphenyl)-4-phenylmethyloxazolidin-5-one (Tetrahedron Lett. 1995, 36, 42, 7761) (700 mg) and bromochloromethane (0.142 ml) were added to dehydrated tetrahydrofuran (16.8 ml), and they were cooled to −78° C. 1.54 Mn-butyllithium solution (1.42 ml) in hexane was added to the obtained mixture, and they were stirred for 33 minutes. 5% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. After the extraction with ethyl acetate at room temperature twice followed by drying over anhydrous magnesium sulfate, magnesium sulfate was removed. The obtained solution in ethyl acetate was analyzed by HPLC to find that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (347 mg) was obtained in a yield of 62%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C#Cc1ccc(CO)cc1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(CO)cc3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethynyl-4-(hydroxymethyl)benzene (169 mg, 1.28 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (364 mg, 0.638 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature overnight, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as brown oil.