Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])(=[O:4])[CH3:3].[N:12]([O-])=O.[Na+]>O>[ClH:1].[N:7]1[C:6]2[C:5](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([OH:4])=[CH:3][N:12]=1
Reactant: CC(=O)c1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1cnnc2ccccc12
Temperature: 65 °C
Yield: 77 %

Procedure:
560 ml of concentrated hydrochloric acid are introduced into a reactor. 111.6 g of 2-acetylaniline are added at ambient temperature. 62.8 g of sodium nitrite, in solution in 170 ml of water, are added to this orange-colored solution at −5° C. over 1 hour. The temperature is kept below 0° C. throughout the introduction. The reaction medium is heated at 65° C. for 3 hours. The mixture is subsequently cooled over 20 minutes and the product is then filtered off and washed with ether. The compound is dried over P2O5 at 45° C. overnight. 118.6 grams (77%) of the expected product are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17](=O)[O:18]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:17](=[O:18])([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[O:9][C:4]1([CH3:3])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC1(O)CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(OC(=O)Oc2ccccn2)CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (185 mg, 4.63 mmol) in THF (20 mL) was added 3-methyltetrahydrofuran-3-ol (394 mg, 3.86 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (834 mg, 3.86 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage (5-40% EtOAc:Hex) to afford the desired product 3-methyltetrahydrofuran-3-yl pyridin-2-yl carbonate (334 mg, 38.8% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.29 (m, 1H), 7.91-7.73 (m, 1H), 7.29-7.25 (m, 1H), 7.16-7.12 (m, 1H), 4.23 (d, J=10.3 Hz, 1H), 4.02 (td, J=8.5, 7.2 Hz, 1H), 3.95 (td, J=8.4, 4.5 Hz, 1H), 3.76 (d, J=10.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.11-2.02 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 61F (0.1000 g, 0.227 mmoles) in DMF (0.57 mL) was treated with NaH (0.0109 g, 0.27 mmoles, 60% dispersion). After 15 min, ethyl 4-bromobutyrate (0.039 mL, 0.27 mmoles) was added and the reaction was stirred overnight. The crude products were diluted with diethyl ether, washed with sat. NH4Cl, extracted with H2O (2×), washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane to 7:1 hexane:ethyl acetate) to provide the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Br:14])[C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Br:14])[C:12]=1[OH:13])[C:7]([O:9][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)cc(Br)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
To a stirred suspension of 3-acetyl-5-bromo-4-hydroxybenzoic acid (240 g, 926 mmol) in MeOH (2 L) was added dropwise sulfurous dichloride (68 mL, 926.5 mmol) under nitrogen and the mixture was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature concentrated, diluted with DCM. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford a crude compound, which was purified on silica, eluting with 70% of DCM in petroleum ether. The solvents were evaporated to dryness to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (108 g, 42.7%) as a white powder. Mass Spectrum: [M−H]− 229.
Reaction SMILES: C([O:4][C@H:5]1[C@H:12]([O:13]C(=O)C)[C@@H:11]([CH2:17][O:18]C(=O)C)[O:10][C@H:7]([O:8][CH3:9])[C@H:6]1[Cl:22])(=O)C.C[O-].[Na+].C(Cl)(Cl)Cl.CO>CO>[Cl:22][C@H:6]1[C@@H:5]([OH:4])[C@H:12]([OH:13])[C@@H:11]([CH2:17][OH:18])[O:10][C@@H:7]1[O:8][CH3:9]
Reactant: CO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1Cl
Yield: 90.8 %

Procedure:
A solution of (5) (1 g) in dry methanol (50 ml) was treated with a catalytic amount of sodium methoxide at room temperature for 24 h. T.l.c. (chloroform-methanol, 6:1) showed one product. The solution was deionised by shaking with Amberlyst--15 resin (Trade Mark) and concentrated to give (6) (0.57 g, 90%) as a syrup [α]D +59.9 (c 1.05, water).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33](/[CH:36]=[CH:37]/[CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33](/[CH:36]=[CH:37]/[CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:10]([F:11])[C:2]=3[F:1])=[CH:44][CH:45]=2)[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OC/C=C/[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 2,3-difluoro-4-dodecyloxybenzoic acid, 1.8 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]phenol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 50 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 1.4 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate and concentrated. The crude product obtained was purified by chromatography on silica gel with toluene. The 2,3-difluoro-4-dodecyloxybenzoic acid 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]phenyl ester obtained was recrystallized from ethanol; m.p. (C-SC) 73° C., SC -N 124° C., cl.p. (N-I) 137° C..
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH:31]([OH:34])[CH2:32][CH3:33])=[CH:26][C:25]=2[CH3:35])[C:21]=1[CH2:22][CH3:23])[CH3:4].I[CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:25]([CH3:35])=[CH:26][C:27]([CH:31]([O:34][CH2:39][CH3:40])[CH2:32][CH3:33])=[CH:28][C:29]=2[CH3:30])[C:21]=1[CH2:22][CH3:23])[CH3:4]
Reactant: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(O)CC)cc2C)c1CC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(CC)OCC)cc2C)c1CC
Reaction time: 0.08 h
Yield: 146.5 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.031 g, 0.78 mmol) was added portionwise to a solution of 1-{4-[4-(2-ethoxy-naphthalen-1-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-3,5-dimethylphenyl}-propan-1-ol (0.123 g, 0.26 mmol) in 0.5 ml anhydrous tetrahydrofuran. After stirring 5 minutes, iodoethane (0.104 ml, 1.3 mmol) was added and the resulting mixture was stirred for 16 hours at ambient temperature. A second portion of sodium hydride (0.031 g of a 60% sodium hydride mineral oil dispersion; 0.78 mmol) was added, followed by a second portion of iodoethane (0.104 ml, 1.3 mmol). After stirring at ambient temperature for 4 hours, the reaction mixture was well-mixed with methylene chloride/aqueous sodium bicarbonate (10 ml of each). The aqueous phase was then twice extracted with 10 ml portions of fresh methylene chloride. The combined organic extracts were then dried over anhydrous sodium sulfate and concentrated in vacuo to afford a 190 mg residue. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes=1:4 in volume) afforded the title compound (45 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH:26]=[CH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:29]([NH:28][CH2:25][CH:26]=[CH2:27])=[O:30])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: C=CCN=C=O
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 44 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.2 eq of allyl isocyanate in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica, 3:7 ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, and then from methanol:water gives pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(2-propenylamino) carbonyl]-1H-indole-3-methanamine (44%); mp 148°-149° C.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].[H-].[Na+].C1COCC1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OC)=[O:18]>O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=[O:18])[CH2:1][S:2]([CH3:4])=[O:3]
Reactant: COC(=O)c1ccco1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DMSO (35 ml., dry, distilled from CaH2) and NaH (3.08 g., 0.076 mol as a 60% suspension in oil) was heated under nitrogen until evolution of H2 was complete, cooled to 0° C., and diluted with 35 ml. THF. Methyl furan-2-carboxylate (5 ml., 5.89 g., 0.047 mol) was added, the mixture warmed to ambient temperature, stirred 2 hours, poured into an equal volume of water, and extracted with one half volume of ether. The aqueous layer was adjusted to pH3 with 6N HCl and extracted 3×150 ml. CHCl3. The CHCl3 extracts were combined, dried and evaporated to an oil which crystallized on standing in vacuum. The latter was slurried in minimal 1:1 CHCl3 :hexane and recovered by filtration, 2.84 g.; tlc Rf 0.7 (3:1 ethyl acetate: methanol); 1H-nmr 2.75 (s, 3H), 4.21 (ABq, 2H), 6.58 (dd, 1H), 7.32 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[NH2:14][C:15]1[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:18]=[C:17]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])[CH:16]=1>CN(C=O)C>[Si:6]([O:34][CH2:33][C@H:32]([NH:31][C:17]1[CH:16]=[C:15]([NH2:14])[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:18]=1)[CH3:35])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Reaction time: 20 h

Procedure:
Imidazole (1.2 g) was added to a solution of tert-butyldimethylsilyl chloride (2.83 g) and the subtitle product of step iii) (1.8 g) in DMF (10 ml). The reaction was stirred for 20 h before partitioning between EtOAc (100 ml) and H2O (200 ml). The aqueous was extracted further with EtOAc (2×100 ml), the organics combined, washed with H2O (100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to a crude solid. This material was purified by column chromatography (50% Et2O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.80 g.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in dichloromethane (3 mL) and triethylamine (20.3 mg, 0.201 mmol, 28.2 μL, 3.0 eq) was added followed by methanesulfonyl chloride (8.4 mg, 0.0734 mmol, 5.7 μL, 1.1 eq). The reaction was stirred for 5 minutes and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-8% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow foam (31 mg, 88%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.99 (s, 1H), 8.60 (d, 1H, J=7.8 Hz), 8.10 (s, 1H), 7.55-7.40 (m, 3H), 7.30-7.20 (m, 1H), 7.15-7.02 (m, 2H), 6.92 (s, 1H), 6.23 (bs, 1H), 3.87-3.77 (m, 2H), 3.20-3.05 (m, 4H), 3.03 (d, 3H, J=4.9 Hz), 2.47 (s, 3H), 2.20 (d, 2H, J=8.8 Hz), 1.81-1.70 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccncc1OCOC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1OCOC
Temperature: 55 °C

Procedure:
To an ethanol solution (0.1 M) of cis-1-(1,1-dimethylethyl) 3-ethyl 4-(3-{[(methyloxy)methyl]oxy}-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added freshly prepared sodium ethoxide (1.2 eq.). The resulting yellow-orange solution was heated at 55° C. for 16 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 95:5 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1

Procedure:
A solution of 2300 mg (5.87 mmol) of ethyl E-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate in 160 ml of dry acetonitrile is mixed with 1600 mg (7.05 mmol) of 4-(tert-butyl)benzyl bromide and 1220 mg (8.81 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulfate and the organic phase concentrated. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 2800 mg (5.21 mmol, 88% of theory) of a solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid (3.1 g, 13.2 mmol) in tetrahydrofuran (30 ml) was added a 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (13.8 ml, 13.8 mmol) at 0° C. with stirring, and the resulting mixture was stirred at the same temperature for 20 minutes, and after raising the reaction temperature to room temperature, the reaction mixture was furthermore stirred for 4 hours. After stirring, water (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9 to 7:3) as the eluent to afford the title compound (2.8 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6](=[CH:13][C:14]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Pd:24]>>[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[Pd:24].[Pd:24]
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Temperature: 55 °C

Procedure:
An example of such a catalyst complex has the structure Pd2DBA3.CHCl3, in which DBA is dibenzylideneacetone. This complex is formed by the addition of palladium (II) chloride to a methanol solution containing sodium acetate and dibenzylideneacetone. The reaction mixture was warmed to 55° C. for one hour to form a precipitate, noting that excessive heating causes decomposition of the complex to palladium metal. The precipitate and catalyst precursor is filtered from the methanol and redissolved in chloroform to produce a dark purple solution, which is stripped under reduced pressure to produce a dark purple-black solid of Pd2DBA3.CHC3. This solid is redissolved and added to a solution of diene polymer or copolymer.
Reaction SMILES: [K].O[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].C(O)C.O.[NH2:15][NH2:16]>O>[C:6]([C:5]1[CH:4]=[CH:3][NH:16][N:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)C=CO
Reactant: NN
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc[nH]n1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
Under nitrogen atmosphere, mixture of 50.00 g of pinacolone and 42.00 g of methyl formate was cooled to 0° C., and then 56.00 g of potassium t-butoxide was added to the mixture over the period for 3 hours. During that, the temperature of the mixture was kept below 20° C. After that, the reaction mixture was stirred at 30° C. for 5 hours. Diethyl ether was added to the reaction mixture which was cooled to room temperature, as a result, solid was produced. The solid was collected by filtration, and dried under reduced pressure to give 32.12 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt. 21.61 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt was suspended to 150 ml of ethanol. 6.52 g of hydrazine hydrate was added to the suspension, and then refluxed for 7 hours. 50 ml of water was added to the reaction mixture which was cooled to room temperature, and the mixture was concentrated to 40 ml under reduced pressure. The concentrated solution was extracted by ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.83 g of 3-t-butyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.