Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
118.2 g (5.1 mmol) of sodium are added slowly to 2.5 litres of ethanol. 350.0 g (5.1 mol) of imidazole and 570 ml (858.6 g, 5.1 mol) of ethyl bromoacetate are added dropwise at an internal temperature of 20-25° C. The mixture is stirred at RT for 24 h. The precipitated solid is filtered off, the ethanol is removed under reduced pressure and the mixture is filtered again. The residue is purified by column chromatography on silica gel (mobile phase ethyl acetate). Yield: 639.0 g (81% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:25][N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: CCOc1ccc(N/C(C)=C\C(=O)OC)cc1
Reactant: N#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOc1ccc(-n2nc(-c3ccccc3)c(C(=O)OC)c2C)cc1

Procedure:
According to AVV A, (Z-3-(4-ethoxyphenylamino)-but-2-enoic acid methylester (235.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The olive-green oily raw product (490.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 95:5→0:100). The desired product was obtained in the form of a white solid (291.0 mg, 0.87 mmol, 87%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N[C@@H](C1C=NC(C)=CC=1)CCO.C1(C)C=CC=CC=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: Cc1ccc([C@H](N)CCO)cn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2cccnc2c1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Methyl quinoline-7-carboxylate (5 g, 0.01 mol) was dissolved in tetrahydrofuran (40 mL) at −20° C. under an atmosphere of nitrogen. 60% REDAL (60:40, Red-Al(R):toluene, 6.53 mL, 0.0201 mol) was added and allowed to stir at −20° C. for 4 hours. After warming to room temperature, the reaction was quenched slowly with water, concentrated under reduced pressure, partitioned between EtOAc and water, and filtered through Celite. The aqueous phase was extracted with EtOAc. The combined organic layers were dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column to afford the title compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][S:9]([CH2:12]P(OCC)(OCC)=O)(=[O:11])=[O:10])[CH3:7].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([O:30][CH3:31])[CH:23]=1>C1COCC1>[CH2:6]([O:8][S:9]([CH:12]=[CH:26][C:25]1[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][C:24]=1[O:30][CH3:31])(=[O:10])=[O:11])[CH3:7]
Reactant: COc1cc(Cl)ccc1C=O
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=Cc1ccc(Cl)cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
A 2.5M solution of n-butyllithium in hexanes (6.15 mL, 15.37 mmol) was added dropwise to a stirred solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (4.0 g, 15.37 mmol) in THF (200 mL) at −78° C. The reaction mixture was stirred at −78° C. for 15 minutes. A solution of 4-chloro-2-methoxy-benzaldehyde (2.41 g, 14.10 mmol) in THF (20 mL) was then added dropwise. After the addition was complete the reaction mixture was warmed to RT, stirred for 1 h and quenched with brine. The reaction mixture was concentrated under reduced pressure and DCM (200 mL) was added. The organic layer was separated, washed with brine (3×100 mL) and dried over MgSO4. Removal of solvent under reduced pressure, followed by purification on silica gel using hexane/ethyl acetate, 4:1 to 2:1 afforded the title compound (3.90 g, quantitative) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27](=[O:29])[CH:26]=[C:25]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH2:26][C:27](=[O:29])[NH:20][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccs2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 59.5 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (69 mg, 0.243 mmol) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (54 mg, 0.257 mmol) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown solid (46 mg).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:19][CH:20]([CH3:24])[C@H:21]([NH2:23])[CH3:22]>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:23][C@@H:21]([CH:20]([CH3:24])[CH3:19])[CH3:22])=[O:5]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Reactant: CC(C)[C@@H](C)N
Product: CC(C)[C@@H](C)NC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 20 from 2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and (R)-3-methylbutan-2-amine. Yield 60%. 1H NMR (400 MHz, dMSO): δ 0.74-0.79 (m, 6H), 0.94-0.96 (d, 3H), 1.48-1.49 (d, 6H), 1.59-1.64 (m, 1H), 3.59-3.65 (m, 1H), 6.99-7.02 (d, 1H), 7.44-7.45 (d, 2H), 7.77-7.80 (d, 2H), 9.14 (s, 1H), 9.18 (s, 1H); MS+H (312.1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][CH:10]=[C:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]1=2)#[N:8].O1CCCC1.[OH-].[Na+]>O>[NH2:8][CH2:7][CH2:9][CH:10]=[C:11]1[C:12]2[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=2[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=2
Reactant: N#CCC=C1c2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
In a system protected by a drying tube and in which a nitrogen atmosphere is maintained, lithium aluminum hydride (380 mg., 0.01 mole) is suspended in 15 ml. of dry, peroxide-free tetrahydrofuran. The mixture is stirred and heated to refluxing for 4 hours. After cooling in an ice-bath, the mixture is stirred while a solution of 5-(2-cyanoethylidene)-5H-dibenzo[a,d]cycloheptene (1.21 g., 0.005 mole) in 20 ml. of tetrahydrofuran is added dropwise over 20 minutes. The deep red solution is stirred for 1 hour in the cold and then hydrolyzed by the successive dropwise addition of water, 0.4 ml., 20% sodium hydroxide, 0.4 ml., and water, 1.0 ml. The granular precipitate is filtered and washed with absolute ether. The combined filtrate and washings are evaporated to dryness under reduced pressure. The residual yellow oily base is dissolved in absolute alcohol and treated with a solution of maleic acid in absolute alcohol. Dilution with ether precipitates the hydrogen maleate as white crystals, m.p. 171°-173°C., dec. The yield of 5-(3-aminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrogen maleate is 0.45 g. (25%). Repeated crystallizations from mixtures of absolute alcohol-absolute ether gave an analytical sample melting at 176.5°- 177.5°C., dec.
Reaction SMILES: C(NCC)C.[C:6]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(O)C>[NH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:8])([CH3:7])[CH3:9])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: CCNCC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
25 ml of diethylamine was added to 250 ml of an ethanol solution of 1.88 g of 9H-fluoren-9-ylmethyl 3-t-butoxycarbonylaminopiperidine-1-carboxylate, and the mixture was stirred at room temperature for 18 hours. After the solution had been concentrated under reduced pressure, the residue was dissolved in a mixture consisting of 150 ml of toluene and 100 ml of 10% aqueous citric acid solution. The aqueous layer was made alkaline with a 5N aqueous sodium hydroxide solution, and then extracted twice with 100 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.79 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([NH:7][N:8]=[C:9]([C:11]1[C:15]([OH:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[S:13][CH:12]=1)[CH3:10])=[O:6].CC(C)([O-])C.[Na+].C1N=CN([C:40](N2C=NC=C2)=[S:41])C=1.Cl>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:14]2[S:13][CH:12]=[C:11]([C:9](=[N:8][NH:7][C:5]([C:4]3[CH:25]=[CH:26][C:27]4[NH:28][C:40](=[S:41])[NH:1][C:2]=4[CH:3]=3)=[O:6])[CH3:10])[C:15]=2[OH:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(=NNC(=O)c1ccc(N)c(N)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc2[nH]c(=S)[nH]c2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of 3,4-diamino-N′-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl}ethylidene]benzohydrazide(30 mg, 0.064 mmol, see the synthetic example 176) in tetrahydrofuran (3.0 mL) was added sodium tert-butoxide (12 mg, 0.13 mmol) and N,N′-thiocarbonyldiimidazole (23 mg, 0.13 mmol). The reaction mixture turned clear orange and was stirred at room temperature for 16 hours, and then was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. The precipitated solid was collected by filtration, washed with chloroform, washed with methanol and dried by means of a vacuum pump to give the desired product as a pale brown solid (yield 52%).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2([CH2:5][OH:16])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc(F)c(F)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4,5-difluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (96%): MS (ES+) m/z 344 (M−17), 384 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:14]1[CH:19]=[C:18]2[C:20]([C:22](O)([OH:25])[C:23](=[O:24])[C:17]2=[CH:16][CH:15]=1)=[O:21]>S(=O)(=O)(O)O>[OH:25][C:22]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:13])[CH2:11][CH3:12])[C:23](=[O:24])[C:17]2[C:18](=[CH:19][CH:14]=[CH:15][CH:16]=2)[C:20]1=[O:21]
Reactant: CCC(=O)Nc1ccc(C)c(C)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: CCC(=O)Nc1cc(C)c(C)cc1C1(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
N-(3,4-dimethylphenyl)propion amide (500 mg, 2.82 mmol) and ninhydrin (500 mg, 2.82 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred at room temperature for 1.5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 430 mg, 45%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>CC#N>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:22][CH2:21]1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCC(F)(F)CC1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCC(F)(F)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 68.4 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.155 g, 0.54 mmol), 4,4-difluorocyclohexylamine (0.11 g, 0.81 mmol) and TEA (0.082 g, 0.81 mmol) was dissolved in dry MeCN (3 ml) and heated in a microwave reactor at 130° C. for 10 mins. The reaction mixture was purified by silica gel column chromatography using a 85:15 mixture of hexane and EtOAc as eluant, to give the title compound (0.142 g, 68%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.49-7.42 (m, 3H), 5.23-5.16 (m, 1H), 4.41 (hep, 1H), 3.10-3.00 (m, 1H), 1.97-1.86 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (d, 6H), 1.49-1.37 (m, 2H), 1.37-1.21 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 158.6, 134.5, 131.8, 130.3, 129.0, 125.1, 123.9, 122.0, 120.0, 107.3, 49.9, 47.9, 32.1, 31.9, 31.7, 29.0, 28.9, 20.4; Mass Spectrum: M−H+ 385.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH2:19][O:20][CH3:21].[CH3:22]OC(C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)C>>[ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH:19]([O:20][CH3:21])[CH3:22]
Reactant: COCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: COC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Agent: Cl
Product: COC(C)c1c(OCc2ccccc2)c(=O)cc(C)n1C

Procedure:
The title compound was prepared by the method outlined for 1,6-dimethyl-2-methoxymethyl-3-benyloxy-pyridin-4(1H)-one hydrochloride, using 3.56 g (13 mmol, 1 eq.) of 2-(1-methoxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one to yield the pure product 2.64 g (62.8%) after recrystallisation from methanol/diethyl ether, as a white crystalline solid m.p 17-19° C.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:13]2[CH2:18][CH2:17][CH2:16][N:15](S(CC[Si](C)(C)C)(=O)=O)[CH2:14]2)[CH2:3][CH2:2]1.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:28][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]#[C:4][CH:1]1[CH2:2][CH2:3]1)[CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: COCCCOC(c1ccccc1C#CC1CC1)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: COCCCOC(c1ccccc1C#CC1CC1)C1CCCNC1
Temperature: 65 °C
Yield: 95.4 %

Procedure:
A 50-mL round bottom flask was charged with 3-((2-(cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine (63 mg, 0.128 mmol, 1.0 equiv), tetraethylammonium fluoride (63 mg, 0.422 mmol, 3.4 equiv) and acetonitrile (5 mL). The mixture was heated to 65° C. for 17 h. Analysis of the yellow reaction mixture by LC-MS showed consumption of the protected piperidine and formation of a new signal containing the mass of the desired product. The acetonitrile was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The layers were separated and the aqueous layer was extracted twice with additional CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated, yielding 3-((3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)piperidine (40 mg, 95%). No additional purification was attempted. MS ESI +ve m/z 328 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8](C(O)=O)=[C:7]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3c(Br)cccc23)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CNc2ccnc3c(Br)cccc23)cc1
Yield: 101.6 %

Procedure:
A solution of 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylic acid (1.0 g, 2.58 mmol) in diphenyl ether (5 mL) was heated at 240° C. for 30 min. Then petroleum ether was added to the reaction mixture at rt and the precipitated solid was filtered and dried to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.38 (d, J=5.4 Hz, 1H), 8.34-8.31 (d, J=9.0 Hz, 1H), 8.06 (t, 1H), 8.02-7.99 (d, J=7.5 Hz, 1H), 7.37-7.29 (m, 3H), 6.90-6.87 (d, J=8.4 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([OH:23])[CH2:5]2.C=O.O.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])[CH2:34][O:23][C:6]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5]2
Reactant: O=C(NN=C1c2ccc(F)cc2CC1(O)c1ccc(F)cc1)Nc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(Br)cc1)N1COC2(c3ccc(F)cc3)Cc3cc(F)ccc3C2=N1
Yield: 447.8 %

Procedure:
A mixture of 0.80 g (0.0017 moles) of the product obtained in Step C, 0.25 g (0.0027 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 45 mL of acetonitrile was refluxed for 30 minutes. The resulting mixture was partitioned between chloroform and saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated to give a yellow solid. The solid was triturated with methanol/water, and dried under vacuum to afford 0.57 g of a yellow solid, m.p. 208°-209° C.
Reaction SMILES: FC1C=C(B(O)O)C(OC)=NC=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[C:17]([O:24]C)[N:16]=1>>[CH3:13][O:14][C:15]1[NH:16][C:17](=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(B(O)O)c(OC)n1
Agent: COc1ncc(F)cc1B(O)O
Product: COc1cccc(=O)[nH]1

Procedure:
I-236 was prepared analogously except in step 4, 5-fluoro-2-methoxy-pyridin-3-yl boronic acid was replaced with 2,6-dimethoxy-pyridin-3-yl boronic acid. The crude material was purified by trituration in 10% methanol in ethyl acetate (10 mL). The solid was filtered and dried to give the 6-methoxy pyridone.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[N:21]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(N=[N+]=[N-])CC1F
Temperature: 100 °C

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexyl methanesulfonate (570 mg, 1.75 mmol) in DMF (10 mL) was added sodium azide (340 mg, 5.24 mmol). The reaction mixture was heated to 100° C. overnight, diluted with EtOAc, and washed with water. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:10])=[O:11]
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 77.5 %

Procedure:
Ethyl (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-methanol (10 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.50 g) in water (5 mL)) was added to this solution, and the mixture was stirred at room temperature for 7 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-brown oil was crystallized from ethyl acetate-hexane to give the title compound (730 mg, yield: 78%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH2:18][O:19]CC2C=CC=CC=2)=[CH:12][CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][OH:19])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(NC(=O)CO)cc1
Reaction time: 5 h
Yield: 65.1 %

Procedure:
6-[4-(2-Benzyloxyacetylamino)phenoxy]hexanoic acid methyl ester 70 (1 g, 2.6 mmol) was dissolved in methanol (10 ml) in a pressure vessel, pd on carbon (5%, 250 mg) added and the mixture stirred under a hydrogen atm. (2 Kg) for 5 hrs. Catalyst was removed by filtration and methanol was distilled off. Crude 71 was recrystallised in chloroform:hexane (1:6) to get pure 71 (0.5 g, 65.3%) as a white powder. M.p: 91.5-94° C.