Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C([N:10](CC)CC)C.[F:15][CH:16]1[CH2:23][C@@:22]2(C(O)=O)[C@H:18]([C:19](=[O:35])[N:20]([C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])[CH2:21]2)[CH2:17]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[NH2:10][C@:22]12[CH2:23][CH:16]([F:15])[CH2:17][C@@H:18]1[C:19](=[O:35])[N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:21]2
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@@]2(N)CC(F)C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Toluene (10 mL) and triethylamine (565 μL, 4.05 mmol) were added to (1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (590 mg, 2.03 mmol). Then, diphenylphosphoryl azide (567 μL) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated to reflux for one hour and blended with a mixture of ethyl acetate-saturated sodium bicarbonate water. The organic layer was dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in dioxane (10 mL). 6N hydrochloric acid (10 mL) was added, and the mixture was heated with stirring at 70° C. for two hours. After washing with ether, the aqueous layer was made basic with a 10 M sodium hydroxide solution, followed by extraction with toluene five times. The extract was dried over magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure to give 476 mg (90%) of the title compound as a colorless oil. The product was used for the next step without purification.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[C:11]([F:20])=[C:12]2[C:18]([NH2:19])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH3:8]>N1C=CC=CC=1>[CH2:7]([O:9][C:10]1[C:11]([F:20])=[C:12]2[C:18]([NH:19][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH3:8]
Reactant: CCOc1cnc2[nH]cc(N)c2c1F
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Cyclopropanecarbonyl chloride (63.1 μL, 0.676 mmol) was added dropwise to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 0.615 mmol) in pyridine (5 mL) at 0° C. The reaction was stirred at about 0 to about 5° C. for 2 hours and then concentrated to dryness. Water (10 mL) was added and extracted with CHCl3/IPA (3:1). The combined organic phases were dried over MgSO4 and concentrated to yield N-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (90 mg, 55% yield) as a solid.
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)O[C:29](C)=O.[Na+].C=O>CO>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:11]=[CH:10][C:9]=3[N:8]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2C
Temperature: 120 °C
Yield: 15.4 %

Procedure:
To a microwave vial was added sequentially (4aSR*,5RS*,10bSR*)-5-cyclohexyl-9-(isopentyloxy)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (base of example 27) (200 mg, 0.56 mmol, 1 equiv.), methanol (2.5 mL) and NaBH(OAc)3 (237 mg, 1.12 mmol, 2 equiv.). The microwave vial was capped with a septum and formaldehyde (43 μL, 1.4 mmol, 2.5 equiv.) was added via syringe. The reaction mixture was heated under microwave heating at 120° C. for 10 min. The solvent was evaporated under reduced pressure and the crude taken up in CH2Cl2 and washed with sat. NaHCO3 solution. The combined organic fractions were dried over MgSO4 and the solvent removed under reduced pressure after filtration. The residue was purified by Combiflash column chromatography (SiO2, c-Hexane/AcOEt) to afford (4aSR*,5RS*,10bSR*)-5-cyclohexyl-9-(isopentyloxy)-6-methyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (32 mg, 15%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:25]1[CH:29]=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.Cl.[CH3:40][O:41]N.Cl>C(Cl)Cl>[CH3:40][O:41][N:25]([CH3:29])[C:15]([C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 102 %

Procedure:
To a solution of (1R*,3S*)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (M1, 3.00 g) as racemate synthesized according to the method described in Chemistry A European Journal, 2005, 11, pp. 6543-6551 in methylene chloride (30 mL), carbonyldiimidazole (2.60 g) was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, N,N-diisopropylethylamine (2.72 mL) and methoxyamine hydrochloride (1.56 g) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 1.0 mol/L aqueous hydrochloric acid and methylene chloride were added. The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layer and the extract were combined, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain oily tert-butyl ((1S*,3R*)-3-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate (M2, 3.60 g).
Reaction SMILES: [C:1]([S:5](F)(=[O:7])=[O:6])([F:4])([F:3])[F:2].[OH-:9].[K+:10]>>[C:1]([S:5]([O:7][K:10])(=[O:9])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(F)C(F)(F)F
Reactant: [OH-]
Reactant: [K+]
Product: O=S(=O)(O[K])C(F)(F)F

Procedure:
That is, CH3SO2F is subjected to electrolytic fluorination using HF to obtain CF3SO2F. The resultant CF3SO2F is subjected to hydrolysis using KOH to obtain CF3SO3K. The CF3SO3K obtained is subjected to acid decomposition with the use of concentrated H2SO4 and if necessary, additionally fuming sulfuric acid at elevated temperature and under reduced pressure to obtain a CF3SO3H-containing reaction product. The reaction product obtained is subjected to simple distillation at a temperature of from 120° to 200° C. and under condition of reduced pressure of from 50 to 10 Torr to obtain a distillate of CF3SO3H. Thus, there is obtained a crude product of CF3SO3H. This CF3SO3H product still contains a certain amount of those impurities as above described.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=[CH:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[CH:16][C:17]#[N:18])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2cccc(OCc3ccccc3)c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(O)c2)c1
Yield: 63.5 %

Procedure:
3-(3-Benzyloxyphenyl)-3-(3,5-dimethoxyphenyl)acrylonitrile (3.45 g), 20% palladium hydroxide on charcoal (0.103 g, 3% w.t.), cyclohexene (12 ml), and ethanol (24 ml) were heated to reflux overnight. The black suspension was cooled, filtered through a Celite pad, and concentrated to an oil, which was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) to give 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile as an off-white solid (1.66 g, 64%): mp, 127-129° C.; 1HNMR (DMSO-d6) δ 9.73 (s, 0.67H, OH of one isomer), 9.65 (s, 0.26H, OH of the other isomer), 7.33-7.23 (m, 1H, Ar), 6.92-6.62 (m, 4H, Ar), 6.46 (d, J=2 Hz, 2H, Ar), 6.32 (s, 0.73H, double bond proton of one isomer), 6.27 (s, 0.27H, double bond proton of the other isomer), 3.77 (s, 1.85H, 2OCH3 of one isomer), 3.73 (s, 4.29H, 2OCH3 of the other isomer), isomer ratio 27.6%:72.4%; 13C NMR (DMSO-d6) δ 161.5, 160.4, 157.4, 157.2, 139.9, 138.7, 138.1, 129.7, 119.7, 118.7, 118.0, 117.5, 116.7, 115.7, 115.0, 107.1, 106.6, 101.8, 101.0, 96.3, 96.0, 55.4; Anal. Calcd. For C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.40; H, 5.26; N, 4.85.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(N(CC)CC)C.[CH2:25](Cl)[CH:26]=[CH2:27]>O>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:27]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:8]([F:16])([F:17])[F:7])[CH:10]=1)[CH:26]=[CH2:25]
Reactant: C=CCCl
Agent: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCNc1cccc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
Sodium carbonate (318 g; 3 moles), water (0.5 liter), meta-trifluoromethylaniline (966 g; 6 moles) and triethylamine (20 g; 0.2 mole) were introduced, in an inert atmosphere, into a 2 liter round flask. The reaction medium was heated to a temperature of 50° C. with good stirring. Allyl chloride (230 g; 3 moles) was then introduced over approximately a 4 hour period. The temperature increased from 50° C. to 70° C. during the addition of allyl chloride. The reaction mass was then heated to a temperature of 100° C. for 1 hour before being cooled to about 50° C. After washing with water and phase separation, the organic phase was distilled under vacuum (5,000 Pa). This resulted in the separation of unconverted m-trifluoromethylaniline (540 g; 3.35 moles) from N-allyl-meta-trifluoromethylaniline (367 g; 1.83 moles), which corresponds to a 61% yield based on allyl chloride and a 70% yield based on meta-trifluoromethylaniline. The mass/volume output was 245 gel of reaction medium.
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([CH2:22][NH2:23])[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.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]>ClCCl>[C:31]([C:33]1[CH:34]=[C:35]([S:39]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 3-cyanobenzenesulfonylchloride (100 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with water. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound. 1H NMR (400 MHz, CDCl3) δ7.97 (s, 1H), 7.93-7.91 (d, 1H), 7.83-7.81 (d, 1H), 7.62-7.58 (m, 1H), 7.11-7.09 (d, 2H), 6.89-6.86 (d, 2H), 4.06-4.03 (m, 3H), 3.77-3.72 (m, 2H), 3.56-3.51 (m, 2H), 3.08 (br s, 2H), 2.70-2.67 (m, 2H), 3.08 (br s, 4H), 2.08-2.01 (m, 4H), 1.85-1.82 (m, 6H).
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][C:20]=1F.Cl.CN(C)C=[O:30]>O>[CH3:13][C:6]1[CH:5]=[CH:4][C:12]([O:30][C:20]2[CH:19]=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[Cl:14])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)O

Procedure:
A mixture of sodium hydride (2.3 g, 50% dispersion in mineral oil, prewashed with petroleum, b.p. 40°-60°) and 4-hydroxy-2-methylbenzoic acid (3.4 g) in dry N,N-dimethylformamide (30 ml) was stirred for thirty minutes, then treated with 3-chloro-4-fluorobenzotrifluoride (4.5 g). The mixture was heated at 130° for five hours, cooled, diluted with water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water and brine, dried and evaporated. The residue was recrystallised from petroleum (b.p. 80°-100°) to give 2-methyl-5(2-chloro-4-trifluoromethylphenoxy)-benzoic acid (2.06 g, m.p. 113°). A suspension of this material (1.34 g) in thionyl chloride (5 ml) was heated under reflux for one hour and the excess reagent removed in vacuo. The residue was dissolved in acetonitrile and again evaporated to give crude acid chloride.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][N:51]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[N:56]1[CH:57]=[CH:58][CH:59]=[C:54]([CH2:53][N:51]2[CH:52]=[C:48]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[C:8]([C:11]5[CH:16]=[CH:15][C:14]([N:17]6[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]6)=[CH:13][CH:12]=5)[CH:9]=4)[N:4]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:3]=3)[CH:49]=[N:50]2)[CH:55]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccnc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 72.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (150 mg, 0.22 mmol) was coupled with 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64) (130 mg, 0.45 mmol) using sodium carbonate (70 mg, 0.66 mmol) and Pd(PPh3)2Cl2 (7.7 mg, 0.011 mmol) in toluene/ethanol/water (10/10/2 ml) to give 110 mg (70% yield) of the titled compound after purification by column (Silica gel 60/120) using 35% ethyl acetate in hexane as eluent.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.FC(F)(F)S(O[CH2:40][C:41]([F:44])(C)[CH3:42])(=O)=O>>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C@@:13]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:12]=2[CH:11]=[C:10]([O:22][CH2:23][C:41]([F:44])([CH3:42])[CH3:40])[CH:9]=1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
The title compound was synthesized by steps analogous to those described in method A8 above, but using intermediate 20B, pyridin-3-ylboronic acid and 2-fluoro-2-methylpropyl trifluoromethanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#Cc1cccc(OCCOC)c1
Yield: 70.1 %

Procedure:
3-Hydroxyphenylacetylene (237 mg, 2 mmol) was heated with 2-bromoethylmethylether (0.23 mL, 2.4 mmol) and potassium carbonate (322 mg, 2.4 mmol) in acetone (5 mL) to 110° C. in a microwave oven (CEM Discover) for 45 minutes. Water (1 mL) was added to the mixture and the whole was extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by column chromatography (SiO2, dichloromethane) to afford 3-(2-methoxyethoxy)phenylacetylene as a colourless oil (247mg, 70% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>CCCCCCC>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CCCCCCCCCCO
Solvent: CCCCCCC
Product: CCCCCCCCCCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Temperature: 25 °C

Procedure:
Ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5 mg) was added to a solution containing Mucor miehei lipase Lipozym IM (immobilised Mucor miehei lipase commercially available from Novo Nordisk) (10 mg), n-decanol 8 μl, heptane 0.5 ml and 4 Å molecular sieves. The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixtures were analysed by the gradient HPLC method 2 and by the chiral HPLC method.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[K+].CO.[C:18](=S)=[S:19]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:18]([SH:19])=[N:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Sc1nnc(-c2ccc3c(c2)OCO3)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzo[1,3]dioxole-5-carboxylic acid hydrazide (45.8 g, 254 mmol) was added to a mixture of potassium hydroxide (15.7 g, 280 mmol) and methanol (350 ml). The mixture was stirred for 30 minutes at room temperature. Carbon disulfide (38.7 g, 508 mmol) was added. The mixture was stirred at reflux for 20 hours, followed by another portion of carbon disulfide (12.7 g, 167 mmol) and reflux for 4 h. Water (300 ml) was added and the excess of carbon disulfide and methanol was evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid to pH 3-4. The product precipitated, filtered and was washed with water (50 ml). Yield 53.5 g (95%) as yellow powder.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)ncnc1OCC#CCO
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of DMPU was added 2.8 g sodium hydride in portions. After completion of the addition stirring was continued for 1.5 h followed by the addition of 2.78 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide. The mixture was heated to 90° C. and stirred for 65 h. The solvent was removed in vacuo, the residue was taken up in 250 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. Column chromatography of the crude product on silica gel eluting with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. Beige crystals were obtained for analytical purposes after crystallisation of a part of the isolated product from 2-propanol. LC-MS: tR=4.50 min, [M+1]+=485.27, [M−1]−=483.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH3:51])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH3:51])=[N:49][N:50]=2)=[O:43])=[C:18]([CH3:23])[CH:17]=1
Reactant: Cc1nnc(N)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C)s4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methyl-1,3,4-thiadiazole (49 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 40 mg of the title compound.