Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].[C:8]([O-:12])(=[O:11])[CH2:9]O.CCCCCCCCCCCCC[N+](CC1C=CC=CC=1)(C)C.[Cl-]>>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[C:8]([O-:12])(=[O:11])[CH3:9]
Reactant: CC(O)C(=O)[O-]
Reactant: O=C([O-])CO
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)C(=O)[O-]
Product: CC(=O)[O-]
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing sodium lactate (1.06M), at pH 7.5, and the solution cooled to 5° C. To the reactor was then added 5.0 g (wet weight) of Pichia pastoris transformant strain GS115-MSP 10 (5.54 IU/mL glycolate oxidase and 14,400 IU/mL catalase) which had been permeabilized by treatment with 0.1% benzalkonium chloride ("BARQUAT" MB-50), and the reactor purged with oxygen. The mixture was then stirred at 750 rpm, which bubbled oxygen through the mixture via the action of the turbine impeller, and at 5° C. under 70 psig of oxygen. The reaction was monitored by taking a 0.40 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC using 0.20M isobutyric acid added to the sample as internal standard. After 5 hours, the HPLC yields of pyruvate and acetate were 95.7% and 2.5%, respectively, and 1.9% lactate remained. The remaining permeabilized cell activity of glycolate oxidase and catalase were 116% and 107% of their initial values, respectively.
Reaction SMILES: [C:1]([NH:7][C:8]1[C:9](=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[C:10](O)=[O:11])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].ClC(OCC)=O.C(=O)=O.[OH-].[NH4+:28]>CN(C)C=O.O.C(N(CC)CC)C>[CH2:2]([C:1]1[NH:28][C:10](=[O:11])[C:9]2[C:8](=[CH:16][CH:15]=[C:14]([I:17])[CH:13]=2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Nc1ccc(I)cc1C(=O)O
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: O=C=O
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(I)cc2c(=O)[nH]1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To a mixture of 1500 g of N-valeryl-5-iodoanthranilic acid in 14.5 L of N,N-dimethylformamide is added under nitrogen, 660 mL of triethylamine. The resulting solution is cooled to 0° to 5° C. and 432 mL of ethyl chloroformate added over 10 minutes at a rate to maintain the temperature below 10° C. The reaction mixture is heated to 35° to 50° C. for 2 hours until the evolution of carbon dioxide ceases. Analysis of a small aliquot of the reaction mixture by GC/MS indicates 93.7% (area %) conversion. The reaction mixture is cooled to 10°-15° C. and 5.0 L of concentrated ammonium hydroxide added over 10 minutes. The resulting slurry is then heated at 60°-70° C. for 14 hours. To the reaction mixture is added 10 L of water and the resulting slurry cooled to ambient temperature and filtered. The recovered solid is washed with 3 L of a 1:1 water-N,N-dimethylformamide solution followed by two 3 L water washes. The solid is dried at 50° C. to give 803 g (56.7%) of the desired product. The purity is 100% as analyzed by GC/MS.
Reaction SMILES: [NH2:1]/[C:2](=[N:21]/O)/[CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C:25]([C:27]#[C:28][C:29]([O:31][CH3:32])=[O:30])=[O:26].[C:33]([O:41]C(=O)C1C=CC=CC=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[C:33]([O:41][C:27]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[N:1][C:2]([CH:3]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH2:4][O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:21][C:25]=1[OH:26])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)/C(N)=N\O
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(C(COCc2ccccc2)NC(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [(2E)-2-amino-1-[(benzyloxy)methyl]-2-(hydroxyimino)ethyl]carbamate prepared as described in Step 1 was dissolved in chloroform and treated with 1.2 eq. of dimethylacetylenedicarboxylate and the reaction was refluxed for 2.5 hours. After cooling at room temperature, the reaction mixture was concentrated and the solvent switched to xylene. The mixture was heated at 145° C. for 24 hours. After cooling at room temperature, solid material was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in dry CH2Cl2 then dry pyridine was added and finally benzoic anhydride (1.1 eq.). The mixture was stirred at room temperature overnight, then the solvent was removed by rotary evaporation and the residue taken in ethyl acetate was washed with 1 N HCl, sat. NaHCO3 and brine. Organic layer was separated, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, eluting with 60/40 v/v petroleum ether/ethyl acetate), collection and evaporation of appropriate fractions afforded title product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Sn](Cl)(Cl)(Cl)Cl.[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:18]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:18]1[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:5]
Reactant: Cc1cn(N2C(=O)c3ccccc3C2=O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccccc2F)n(N2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.91 ml of 2-fluorobenzoyl chloride in 50 ml of dry DCM was cooled in an ice/salt bath. To the solution was added 0.86 ml (1.9 It g) of tin (IV) chloride. The mixture was stirred at -5° to 0° C. for 10 minutes after which was added 2.0 g of 2-(3-methyl-1H-indol-1-yl)-1H-isoindole-1,3-(2H)dione. The reaction mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature, cooled again in an ice bath, poured onto ice, extracted twice with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated to a green-yellow solid (2.67 g). The solid was chromatographed on silica gel, eluting with 15% acetone/heptane to provide 1.99 g of a solid, which was recrystallized from ethanol, m.p. 197°-199° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:30]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 67.1 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (85 mg, 0.197 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). (3-Methylphenyl)boronic acid (40.1 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (22.75 mg, 0.020 mmol) and potassium carbonate (54.4 mg, 0.394 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (58.6 mg). LCMS (A) m/z: 443 [M+1]+, Rt 1.53 min (acidic).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])[C:5]([F:8])([CH3:7])[CH3:6].[BH4-].[Na+].Cl>O1CCOCC1.O>[F:8][C:5]([CH3:7])([CH3:6])[CH:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])[CH2:3][OH:2]
Reactant: COC(=O)C(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21)C(C)(C)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(F)C(CO)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-3-methyl-butyric acid methyl ester (171 mg, 0.420 mmol) was dissolved in dioxane (3 mL) and water (2 mL). Sodium borohydride (63.6 mg, 1.681 mmol) was added slowly at 0° C. The reaction mixture was stirred at room temperature overnight, neutralized with 1 N HCl solution, then extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, filtered then concentrated. The residue was purified by column chromatography to give the title compound as a white foam. LCMS m/z=379.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45-0.50 (m, 1H), 1.23-1.30 (m, 1H), 1.47 (d, J=22.1 Hz, 3H), 1.53 (d, J=21.7 Hz, 3H), 2.22-2.30 (m, 1H), 2.33-2.40 (m, 1H), 2.78-2.85 (m, 1H), 2.88-3.05 (m, 2H), 3.90-4.00 (m, 2H), 4.11-4.25 (m, 1H), 7.22 (dd, J=5.3 and 1.8 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H), 7.97 (d, J=1.4 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2].C(OCC)(=O)C.C(O)C>C(O)(=O)C>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(O)c2ccccn2)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(O)c2ccccn2)ccc1N
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a solution of (3-ethoxy-4-nitrophenyl)(2-pyridyl)methanol (2.5 g) in acetic acid (50 ml), reduced iron (7.5 g) was added to the mixture and the mixture was stirred overnight. Ethyl acetate and ethanol were added to the mixture, and the unnecessary substances were filtered off. The filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate and neutralized with an aqueous solution of saturated sodium bicarbonate. The organic layer was separated and washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) and recrystallized from hexane-ethyl acetate, to give (4-amino-3-ethoxyphenyl)(2-pyridyl)methanol (340 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.C1(=O)O[CH2:17][CH2:16][O:15]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][CH2:17][CH2:16][OH:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: O=C1OCCO1
Product: COc1ccc2ccc(OCCO)cc2c1

Procedure:
*Prepared from 7-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(7-methoxy-naphthalen-2-yloxy)ethanol was obtained after column chromatography on silica gel using n-hexane/ethyl acetate (6:4) as eluent.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[CH3:17][O-:18].[Na+].[C-]#N.[Na+].C(Cl)Cl>CO>[Cl:7][C:5]1[N:6]=[C:2]([O:18][CH3:17])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Cl:8]
Reactant: C[O-]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Yield: 67 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.35 mmol), sodium methoxide (0.12 mL of a 25% solution in methanol, 0.53 mmol) and CuBr (0.010 g, 0.07 mmol) in methanol (0.5 mL) was heated at 100° C. for 6 h. Dilute aqueous NaCN and CH2Cl2 were added and the solution was stirred for a few minutes. The solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-40% EtOAc/hex) to afford the title compound (0.070 g, 67%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2H) 4.02 (s, 3H) 3.51-3.63 (m, 2H) 0.88-0.97 (m, 2H) −0.01 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[C:7]([I:22])=[C:8]([C:19](Cl)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1>CC(N(C)C)=O>[C:1]([CH2:4][NH:5][C:6]1[C:7]([I:22])=[C:8]([C:19]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=2)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CC(=O)O)cc2)c1I
Temperature: 60 °C
Reaction time: 30 h
Yield: 57 %

Procedure:
A mixture of MDTA-Cl X (2.18 g, 3.3 mmole) and p-aminophenylacetic acid (1.2 g, 8.27 mmole) in DMA (8 mL) was stirred at 60° C. for 30 h. The solvent was removed and the residue was treated with hot EtOAc (600 mL) containing EtOH (25 mL). The solution was filtered and the filtrate was freed of the solvent. The solid was recrystallized from EtOAc--EtOH to afford the title compound as a white amorphous solid (1.54 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
93 mg (0.3 mmol) of 4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-amine and 46 mg (0.36 mmol, 1.2 eq) of Huenigs base are dissolved in 2 mL tetrahydrofuran. To this are added 63 mg of cyclopropanecarbonyl chloride (0.6 mmol, 2 eq) and the reaction mixture is stirred for 16 hrs at room temperature. Next, the volatile components are removed under vacuum and the crude material treated with 3 mL NH3 in methanol (7 molar). The mixture is stirred for 16 hrs at room temperature and then evaporated. The crude product is purified by preparative HPLC (Phenomenex AMA Gemini C18; 110 A; 10 μm 100×30 mm, gradient: 0-2.0 mins 80% water, 20% acetonitrile, 2.0-12.0 mins linear gradient up to 25% water, 75% acetonitrile, 12.0-16.0 mins 5% water, 95% acetonitrile, modifier 15% NH4OH in H2O, addition of the modifier at 1.0 mL/min throughout the separation). 38.2 mg (33%) of N-{4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-yl}cyclo-propanecarboxamide are obtained as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCl>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[C:5]([C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[N+:15]([O-:17])=[O:16])=[O:21])[CH:6]=[CH:7][C:8]1=2
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3[N+](=O)[O-])ccc21
Yield: 42 %

Procedure:
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (10.09, 53.2 mmol) and o-nitrobenzoic acid chloride (9.4 g, 50.5 mmol) were dissolved in dichloromethane (50 ml), and the mixture was added with AlCl3 (14.3 g) portionwise and then heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured into water and extracted with dichloromethane and dried, and then the solvent was evaporated to give a crude product (21.59 g). This product was purified by silica gel column chromatography (AcOEt:n-hexane=1:10) to give (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl-2-nitrobenzene (Compound 37, 7.5 9, 42%). This product was further recrystallized from n-hexane.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(OCC)(=O)C>[CH2:5]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-hexyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:22](#[N:25])[CH:23]=[CH2:24].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:24][CH2:23][C:22]#[N:25])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: C=CC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccccc1CCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To 100 ml of a solution of 6.0 g of N-(p-chlorobenzoyl)phenylglycine methyl ester in dichloromethane were added 1.6 g of acrylonitrile and 3.6 g of 1,8-diazabicyclo[5.4.0]-7-undecene followed by stirring at room temperature for 16 hours. The solvent was distilled off and 100 ml of ethyl ether were added to the resulting residue. The mixture was washed with two 100 ml portions of water, and the organic layer was separated off and dried over magnesium sulphate. The solvent was distilled off and the residue was recrystallized from diethyl ether, to give 5.8 g of the desired product as a colourless powder melting at 127°-128° C.
Reaction SMILES: CO[C:3]([C:5]1([CH3:27])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[NH:6]1)=[O:4].[Br:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33]>CC(=O)CC>[Br:28][CH2:29][CH2:30][N:31]1[C:32](=[O:33])[N:6]2[CH:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:27])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=4
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCBr
Solvent: CCC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3.17 g (1RS,3SR)-1-(3-Hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 35 ml 2-butanon are added 860 μl bromoethyl isocyanate. The mixture is heated to reflux for 7 h and is stirred at room temperature over night. The precipitated compound is filtered and washed with 2-butanon. 3.09 g (74%) of the title compound are obtained. m.p.: 299-302° C., MS: m/z (MH+)=484.0/486.0
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([F:21])([CH3:20])[CH3:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>N1CCCCC1.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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:31]#[C:30][C@:28]([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:10]=3)[C:6]([C:18]([F:21])([CH3:20])[CH3:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(F)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(C)(C)F)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C

Procedure:
To a solution of 4-[6-bromo-3-(2-fluoropropan-2-yl)-1H-indazol-1-yl]pyrimidin-2-amine (95 mg, 0.26 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (79 mg, 0.52 mmol). The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Biotage, eluent:DCM containing a 1-10% MeOH gradient). Further purification by reverse phase preparative HPLC furnished the title compound as an orange solid: 1H NMR (500 MHz, DMSO) delta 1.76-2.00 (9H, m), 2.62 (3H, s), 6.82 (1H, s), 6.95-7.15 (3H, m), 7.39 (1H, d, J=9.93 Hz), 7.95 (1H, d, J=9.93 Hz), 8.33 (1H, br. s.), 8.94 (1H, s); LC-MS: m/z=+422.05 (M+H)+.