Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.ClCCCl.[CH3:38][C:39]([CH3:41])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@H:6]4[C@H:7]([O:8][C:9]([CH3:12])([CH3:11])[O:10]4)[C@@H:3]([CH2:2][NH:1][CH:39]([CH3:41])[CH3:38])[CH2:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 7((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7.50 g, 16.5 mmol) in 1,2-Dichloroethane (140 mL, 1800 mmol) was treated with Acetone (1.34 mL, 18.2 mmol;) and Acetic acid (0.94 mL, 16 mmol) dropwise followed by Sodium triacetoxyborohydride (4.20 g, 19.8 mmol) and the mixture was stirred at RT for 4 h. HPLC analysis indicated the reaction was complete. The reaction mixture was diluted with 200 mL CH2Cl2 and washed with 150 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a an oil that produced a stiff foam when placed under high vac. The crude material (9.3 g) was carried on directly to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][C@@H:52]1[CH2:56][CH2:55][N:54]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:27])[CH2:53]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CC[C@@H](O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (55 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (R)-3-hydroxypyrrolidine (26 mg, 0.30 mmol) and N,N-diisopropylethylamine (53 μL, 0.30 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-60% MeCN/water[10 mM Et2NH]) and then silica gel column (0-20% MeOH/CH2Cl2) to afford a white foam.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:29])[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:9]=2)[O:4]1.[H][H]>C(O)C.[Pd]>[ClH:1].[CH3:2][C:3]1([CH3:29])[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:8][CH:9]=2)[O:4]1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(C(F)(F)F)c1
Yield: 74.2 %

Procedure:
To a solution of 2,2-dimethyl-7-dimethylaminoethyloxy-4-(3-trifluoromethylphenyl)-2H-chromene hydrochloride (4.96g) in ethanol (75 ml) was added 10% palladium on charcoal. The mixture was hydrogenated under hydrogen (1 atmosphere pressure) at ambient temperature (about 18° C) until no further hydrogen was taken up. The mixture was filtered and the solvent removed from the resulting filtrate under reduced pressure to yield the title compound (3.7g), m.p. 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[NH3:14]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:14])=[O:12])[CH:5]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: N
Solvent: C1COCCO1
Product: COC(=O)c1cccc(NC(N)=O)c1
Reaction time: 48 h

Procedure:
3-Isocyanato-benzoic acid methyl ester (500 mg, 2.82 mmol) was treated with 0.5 M NH3 in dioxane (20 mL). The mixture was agitated for 48 h, and the product, 3-ureido-benzoic acid methyl ester (200 mg, 1.03 mmol), was isolated by filtration as a white solid (404 mg, 73.7%). This intermediate was dissolved in methanol (2 mL) and Amberlyst A26® (OH− form) was added. The resulting mixture was agitated overnight. The resin was then filtered and washed with methanol (3×2 mL). The product was eluted with a solution of 20% formic acid in methanol (3×2 mL) and the resin was washed with methanol (1 mL) and DMF (2×2 mL). The combined eluant solvents were evaporated to provide 139 mg (75% yield) of the urea 3-ureido-benzoic acid. This reagent was then coupled with 3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide using the same coupling procedure described in Example 14 to provide the title compound; MS, electrospray, 446 (M+H)
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7]CN)([CH3:3])[CH3:2].[CH:17]([N:20](C(C)C)CC)(C)C.Cl.[O:27]=[C:28]1[NH:37][C:36]2[N:35]=[CH:34][C:33](/[CH:38]=[CH:39]/[C:40]([OH:42])=O)=[CH:32][C:31]=2[CH2:30][CH2:29]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]([C:4]1[C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][N:20]([CH3:17])[C:40](=[O:42])/[CH:39]=[CH:38]/[C:33]1[CH:34]=[N:35][C:36]2[NH:37][C:28](=[O:27])[CH2:29][CH2:30][C:31]=2[CH:32]=1)([CH3:2])[CH3:3]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCOc1c(CCN)cccc1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cccc1C(C)C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
A solution of (3-isopropyl-2-propoxybenzyl)methylamine (0.238 g, 1.07 mmol) and diisopropyl-ethylamine (0.51 mL, 2.9 mmol) in DMF (20 mL) under N2 was treated sequentially with (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (0.250 g, 0.981 mmol), 1-hydroxybenzotriazole hydrate (0.144 g, 1.07 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.205 g, 1.07 mmol). After stirring for 18 h, the reaction mixture was diluted with H2O (30 mL). The resulting solids were collected by filtration and when washed with Et2O (50 mL) were unexpectedly dissolved. The filtrate was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to a light yellow solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 99.5:0.5) gave the title compound (0.26 g, 63%) as a white solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 10.64-10.62 (m, 1H), 8.37-8.31 (m, 1H), 8.09-7.98 (m, 1H), 7.52-7.49 (m, 1H), 7.28-7.19 (m, 2H), 7.10-7.06 (m, 1H), 6.89-6.87 (m, 1H), 4.80-4.66 (m, 2H), 3.76-3.70 (m, 2H), 3.31-3.26 (m, 1H), 3.12-2.85 (m, 5H), 2.55-2.49 (m, 2H), 1.82-1.76 (m, 2H), 1.19-1.17 (m, 6H), 1.05-1.02 (m, 3H); MS (ESI) m/e 422 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](=[O:36])CO)[C@@H:10]([CH2:11][C@H:12]3[C@H:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:38].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:32][C@:31]2([C:33]([OH:36])=[O:38])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
A mixture of compound 8 (460 mg, 0.899 mmol) and NaOH 6N (1350 μl, 11.10 mmol) in THF (20 ml) and water (10 ml) is stirred at RT for 3 days. Water is added and the organic solvent is evaporated. The basic aqueous solution (pH 12) is washed with AcOEt. The aqueous phase is then treated with HCl 6N until pH 6 when a solid precipitated. The solid is recovered by filtration and the aqueous phase is extracted with AcOEt, washed with brine, dried over Na2SO4 and then evaporated. The two fractions of obtained solid are combined and triturated with AcOEt (containing 2% MeOH) to give the title compound (150 mg, 0.301 mmol, 33.5% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]1[CH:16]([C:17]([CH2:19]P(=O)(OC)OC)=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](=O)[C:41]([O:43]C)=[O:42])=[CH:31]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]1[CH:16]([C:17]([CH2:19][CH:40]([CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[C:41]([OH:43])=[O:42])=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6]
Reactant: COP(=O)(CC(=O)C1Cc2ccccc2CN1C(=O)c1cc(C)cc(C)c1)OC
Reactant: COC(=O)C(=O)Cc1c[nH]c2ccccc12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(C(=O)N2Cc3ccccc3CC2C(=O)CC(Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
A Wittig-Horner reaction according to example 78 between dimethyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarbonylmethylphosphonate [from methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate (prepared according to example 88) as described in example 78] and methyl 3-indolepyruvate followed by catalytic hydrogenation of the double bond in the presence of Wilkinson's catalyst according to example 78 and hydrolysis of the methyl ester moiety according to example 12 gives 3-[N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl]-2-(3-indolyl)methyl-propionic acid as a mixture of isomers; FAB-MS m/e 495 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33]C=C)[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([OH:40])=[O:39])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:42]([O:41][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:46])([O:4][CH2:1][CH:2]=[CH:3][CH2:32][C@H:31]([CH3:33])[O:30][C:24]2[C:23]([CH2:22][O:21][CH2:20]3)=[CH:28][CH:27]=[C:26]([Cl:29])[CH:25]=2)[CH2:10][CH2:9]1)[C:38]([OH:40])=[O:39])([CH3:45])([CH3:44])[CH3:43]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4ccc(Cl)cc4O[C@@H](C)CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Solvent: ClCCCl
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(Cl)ccc1COC3
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 7.3 %

Procedure:
To a solution of (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-chloro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (41.4 mg, 0.063 mmol) in DCE (2 mL) were added Hoveyda-Grubbs catalyst 2nd generation (9.90 mg, 0.016 mmol) and copper(I) iodide (12.03 mg, 0.063 mmol) and the mixture was stirred at 90° C. After 1.5 h, the mixture was cooled to rt and filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-16-chloro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (2.9 mg, 4.62 μmol, 7.32% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.31 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.94 (d, J=7.0 Hz, 1H), 6.48 (s, 1H), 6.34 (d, J=5.9 Hz, 1H), 5.65 (br. s., 1H), 4.75 (d, J=11.7 Hz, 1H), 4.67-4.47 (m, 5H), 4.34-4.22 (m, 1H), 3.64 (d, J=12.8 Hz, 1H), 3.39-3.27 (m, 6H), 2.49 (s, 3H), 2.41 (d, J=3.3 Hz, 1H), 2.27-2.15 (m, 1H), 1.82 (d, J=5.5 Hz, 3H), 1.68-1.55 (m, 1H), 1.32 (s, 3H), 1.20 (s, 12H). LCMS (M+H) calcd for C33H44ClN4O6: 627.29. found: 627.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]C(O)=O)[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13](Cl)(=[O:15])C.C[OH:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([OH:8])[CH:7]=1)[C:9]([O:15][CH3:13])=[O:18]
Reactant: CC(=O)Cl
Reactant: CO
Reactant: O=C(O)Cc1cc(O)cc(Br)c1
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 55 step (v) (3.24 g) was added to a preformed solution of methanol (200 ml) and acetyl chloride (20 ml) and stirred at RT overnight. The mixture was evaporated under reduced pressure to give an oil. The oil was purified by flash column chromatography (eluent 1:1 ether/isohexane) to give the subtitle compound (3.16 g).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]([C@:8]1([OH:29])[C@@:12]2([CH3:28])[CH2:13][C@H:14](O)[C@@H:15]3[C@:25]4([CH3:26])[C:19](=[CH:20][C:21]([CH2:23][CH2:24]4)=[O:22])[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:7])=[O:3].CN(C)C=O.N1C=CC=CC=1.CS(Cl)(=O)=O>CO>[C:2]([O:4][CH2:5][C:6]([C@:8]1([OH:29])[C@:12]2([CH3:28])[CH:11]([CH:16]3[C:15](=[CH:14][CH2:13]2)[C@:25]2([CH3:26])[C:19](=[CH:20][C:21](=[O:22])[CH2:23][CH2:24]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@@]1(O)CCC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 82.5 °C

Procedure:
The title compound can be synthesized from hydrocortisone acetate according to the procedure disclosed in EP 0097328.405 g (1 mol) of hydrocortisone acetate is added to a mixture of 2 liters of N,N-dimethylformamide and 350 ml of pyridine, and with stifling at room temperature, 260 g of methanesulfonyl chloride is added. The reaction mixture is heated, maintained at 80 to 85° C. for 1 hour, and then cooled to room temperature. Methanol (7 liters) is added. The precipitated crystals are separated by filtration, washed with methanol and water, and dried under reduced pressure to give the title compound.
Reaction SMILES: CS(O[CH:6]([CH3:20])[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].O.Cl>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH:6]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH3:20])[CH:19]=[CH:18][C:14]1=2
Reactant: CC(COCCc1ccc2sccc2c1)OS(C)(=O)=O
Reactant: CCNCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)C(C)COCCc1ccc2sccc2c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
In 10 mL of N,N-dimethylformamide is dissolved 1.00 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-methylethyl methanesulfonate, to which is added 3.3 mL of diethylamine. The mixture thus obtained is stirred in an ampoule at 100° C. for 15 hours. After cooling, the reaction mixture is introduced into a mixture of water and ethyl acetate, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the aqueous layer is separated. Ethyl acetate is added to the aqueous layer, pH is adjusted to 9.5 with 5 mol/AL aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=20:1 to 10:1). Thus, 0.63 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)-1-methylethyl]-N,N-diethylamine is obtained as an oily product.
Reaction SMILES: [C:1]([OH:13])#[C:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:16])[CH3:15].[CH2:23](N=C=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:40]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23].[CH2:12]([OH:43])[CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:13]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CCOC(=O)NC(C)C
Reactant: CCCCCCCCC#CC#CO
Product: CCCCCCCCCCCCCCCCCCN(C(=O)OCC)C(C)C
Product: OCCCCC#CC#CCCCCO

Procedure:
Following the general procedure of Example 1, the above-formed dodecadiyn-ol-isopropylurethane was reacted with n-octadecylisocyanate to form 5,7-dodecadiyn-1,12-diol n-octadecylisopropylurethane (VII) which had a melting point of 105°-108° C. The material was recrystallized from acetone to yield a blue powder with melting point 110°-111° C. The brown-black powder, which was obtained by irradiating the n-octadecylisopropylurethane of 5,7-dodecadiyn-1,12-diol with 50 Mrads of γ-radiation, exhibited thermochromic behavior after the as-polymerized material was extracted with acetone. The thermochromic behavior was evidenced on a Fisher-Johns melting point apparatus in which the thermochromic transition from a brown-black to a dark red was observed at 180°-205° C. This color change was reversible over many cycles observed for the polymer.
Reaction SMILES: [F:1][C:2]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[C:5]([F:13])=[C:4]([CH3:14])[C:3]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1.[F-].[Cs+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[C:6]([F:12])[C:5]([F:13])=[C:4]([CH3:14])[C:3]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1
Reactant: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C1=NC(C)(C)CO1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C1=NC(C)(C)CO1
Yield: 98.5 %

Procedure:
A solution of 12.0 g (38.0 mmol) of 2-[2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)phenyl]-4,4-dimethyl-2-oxazoline, 5.85 g (38.5 mmol) of cesium fluoride, 110 ml of dimethylformamide, and 15 ml of water was stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate; the organic phase was washed with water, dried over magnesium sulfate, and concentrated to give 9.1 g of liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:10]=1[O:11][C:12]1[N:17]=[C:16]([S:18][CH3:19])[N:15]=[C:14](Cl)[C:13]=1[N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:10]=1[O:11][C:12]1[N:17]=[C:16]([S:18][CH3:19])[N:15]=[C:14]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:13]=1[N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Temperature: 50 °C
Yield: 65 %

Procedure:
To 6-(2-benzyloxy-5-cyanophenoxy)-4-chloro-5-nitro-2-methylthiopyrimidine (2.5 g, 5.83 mmol) in 50 mL acetonitrile at 0° C. was added cesium carbonate (2.47 g, 7.58 mmol) followed by benzylamine (0.64 mL) and the reaction mixture was heated at 50° C. for 4 hours. The reaction was filtered, the filtrate evaporated and the residue chromatographed on silica gel (ethyl acetate:hexane) to afford 1.82 g (65%) of 6-(2-benzyloxy-5-cyanophenoxy)-4-(benzyl)amino-5-nitro-2-methylthiopyrimidine, a compound of formula (E).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O1CCOCC1.CC(C)=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:30](=[O:32])[CH3:31])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A mixture of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (100 mg, 0.250 mmol), acetic anhydride (0.09 mL, 1.00 mmol) and 10% Pd/C (9.0 mg) in a mixture of dioxane (2.5 mL) and acetone (1.5 mL) was stirred at room temperature for 24 h. Then, 4.0 equivalents of acetic anhydride was added and stirring was continued for 2 days. After filtration, the reaction solution was quenched with saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic phase was dried with anhydrous Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography using a 30% to 100% gradient of EtOAc in heptane gave the title compound (57 mg, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.23 (d, J=6.6 Hz, 3.3H), 1.24 (d, J=6.6 Hz, 2.7H), 1.93 (m, 2H), 2.11 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.71 (t, J=6.1 Hz, 0.9H), 2.80 (t, J=6.1 Hz, 1.1H), 2.95 (m, 2H), 3.34 (m, 2H), 3.79 (t, J=5.9 Hz, 1.1H), 3.84 (t, J=6.1 Hz, 0.9H), 4.15 (m, 1H), 4.44 (tt, J=7.5, 3.7 Hz, 1H), 4.53 (s, 0.9H), 4.54 (s, 1.1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.00.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[C:8]([C:10]2[S:14][C:13](CCCCCC)=[CH:12][CH:11]=2)[C:7]([S:21](C)=O)=[CH:6][C:5]=1[C:24]1SC(CCCCCC)=[CH:26][CH:25]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.F[C:50](F)(F)[S:51](O)(=O)=O>>[S:14]1[C:10]2[C:8]3[CH:9]=[C:4]4[S:2][C:25]5[CH:26]=[CH:50][S:51][C:24]=5[C:5]4=[CH:6][C:7]=3[S:21][C:11]=2[CH:12]=[CH:13]1
Reactant: CCCCCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCCCCC)s3)cc2S(C)=O)s1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: c1cc2sc3cc4c(cc3c2s1)sc1ccsc14
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 10 ml round bottomed flask was filled with 5,5′-(2,5-bis(methylsulfinyl)-1,4-phenylene)bis(2-hexylthiophene) (2b) (200 mg, 0.53 mmol), phosphorus pentoxide (28 mg, 0.2 mmol) and trifluoromethanesulfonic acid (6 ml). The mixture was stirred for 72 h at room temperature to give a dark brown solution, which was then poured into ice-water (100 ml). The yellow precipitate was collected by suction filtration and dried under vacuum. The structure of this compound, which was insoluble in apolar organic solvents, was assumed to be the sulfonium salt. Demethylation of the solid was achieved by refluxing it in pyridine (40 ml) for 12 h. When the suspension was cooled to room temperature, a large volume of CH2Cl2 was added to extract the product. Dithieno[2,3-d:2′,3′-d′]benzo[1,2-b:4,5-b′]dithiophene (1b) was thus obtained as off-white powder by Hexane as an eluent (120 mg, 70%).