Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:11][C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1
Reactant: COc1nc(C)c(F)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1nc(C)c(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of (5-fluoro-2-methoxy-6-methylpyridin-3-yl)methanol (20) (0.2 g, 1.16 mmol) in DCM was added thionyl chloride (0.278 g, 2.33 mmol). The reaction mixture was stirred for 2 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield to afford 3-(chloromethyl)-5-fluoro-2-methoxy-6-methylpyridine (21) as a pale yellow liquid (0.2 g) 90%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.C(N(CC)CC)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[Na+]>CN1CCCC1=O.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:12])=[N:4][N:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(Cl)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2.09 g (10.5 mmol) of commercially available 1,4-dichlorophthalazine in 20 ml of N-methylpyrrolidone were added 7.32 ml (52.5 mmol) of triethylamine and 2.35 g (12.6 mmol) of N-tert-butoxycarbonylpiperazine, followed by heating at 70° C. with stirring in an atmosphere of argon for 2 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give 2.77 g (76%) of 4-(4-chloro-1-phthalazinyl)-1-piperazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)([O-])=O.Cl.[H-].[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
An amount of 20.0 g of 2-(trans-3-nitrostyryl) quinoline was dissolved in 1000 ml of ethanol and 100 ml of conc. hydrochloric acid solution containing 49.0 g of stannous chloride.2 hydride was added thereto at room temperature, and the resulting mixture was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, a 30% aqueous sodium hydroxide solution was added to regulate pH value to 13 and then the precipitated solid was collected by filtration and washed with water. After drying under reduced pressure, the precipitate was recrystallized from toluene to give 15.0 g (yield 84%) of the captioned compound as a pale yellowish white substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([I:17])[N:11]3[N:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(Nc2nn3ccnc3s2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(Nc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
(4-Fluoro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl-amine (0.117 g, 0.50 mmol) was suspended in N,N-dimethylformamide (3 mL) and N-iodosuccinimide (0.124 g, 0.55 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2 hours in the absence of light. The mixture was evaporated and the residue was purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.4:9.6 to 1:9) to give 0.13 g of (4-fluoro-phenyl)-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine as an off-white solid (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:23][CH:22]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccc(F)cc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.8 g) in dimethyl sulfoxide (30 mL) were added 4-fluorophenylalanine (2.54 g) and cesium carbonate (4.90 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 3.69 g, 100%).
Reaction SMILES: [NH2:1][C:2]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40].ClCCl.CO>CN(C)C=O>[NH2:1][C:2]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([S:39]([C:32]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=2[O:30][CH3:29])(=[O:41])=[O:40])[C:3]1=[O:13]
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 0 °C
Yield: 78.5 %

Procedure:
3.54 g (12.03 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were dissolved in 80 ml of anhydrous dimethylformamide (dried over molecular sieve). Under an atmosphere of nitrogen and with cooling using an ice-bath, 1.49 g (13.23 mmol) of potassium tert-butoxide were added a little at a time. The colour of the reaction mixture changed, and the brown solution was stirred at 0° C. for another hour to ensure that the deprotonation proceeded to completion. At low temperature, 3.16 g (13.23 mmol) 2,4-dimethoxybenzenesulphonyl chloride were added, and the mixture was stirred at 0° C. for another two hours. The course of the reaction was monitored by TLC (silica gel, dichloromethane/methanol in a ratio of 9:1). The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was evaporated. The residue was suspended in diethyl ether and stirred until the product precipitated as a solid and could be removed by filtration. After removal of the solvent, the mother liquor was once more treated with diethyl ether (2×) until finally, after drying, 4.67 g (9.44 mmol, 79%) of the desired 3-amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were obtained as a solid substance.
Reaction SMILES: C1C2C(CO[C:16](=O)[N:17]([C@@H:19]([C:31](=[O:50])[N:32]([C@H:34]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:35]([NH:37][N:38]([C:40](=[O:42])[CH3:41])[CH3:39])=[O:36])[CH3:33])[CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)C)C3C(=CC=CC=3)C=2C=CC=1.NCCN(CCN)CCN>C(Cl)Cl>[C:40]([N:38]([CH3:39])[NH:37][C:35](=[O:36])[C@H:34]([N:32]([CH3:33])[C:31](=[O:50])[C@H:19]([NH:17][CH3:16])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NN(C)C(C)=O
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid ((9H-fluoren-9-yl)methyl) ester (0.21 g, 0.31 mmol) in methylene chloride (4 ml) was added tris(2-aminoethyl)amine (4 ml) and the mixture was stirred for 60 min. Then methylene chloride (50 ml) was added and the mixture was washed with brine (2×20 ml), phosphate buffer (pH=6, 2×20 ml), water (20 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.13 g (92%) of (2R)-N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:12]([O:14][C:15]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 3-tert-butyl aniline (54 mg, 0.36 mmol), 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.36 mmol) and EDCI (200 mg, 1.08 mmol) in CH2Cl2 was stirred at room temperature overnight. Next morning the reaction mixture was partitioned between EtOAc and water. The organic layer was separated dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column with 20-50% Et2O in hexanes gradient to afford the product (31 mg; Yield: 21%). HRMS m/z calcd for C25H32N2O3 [M+H]+: 409.2486. Found: 409.2484.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](OCCOc1ccccc1)C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of methyl 4-[(1S)-1-[[(2R)-3-methyl-2-(2-phenoxyethoxy)butanoyl]amino]ethyl]benzoate (2.0 g, 5.01 mmol) in MeOH (25 mL) and THF (25 mL) is added 5N NaOH (10 mL, 50 mmol). The mixture is stirred at room temperature for 1.5 h, treated with 5N HCl (10 mL), and concentrated to remove organic solvents. The aqueous residue is extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers are dried with MgSO4, filtered, and concentrated. The crude material (1.36 g) is dissolved in ethyl acetate and washed with 1N NaOH (25 mL). The aqueous layer is extracted with ethyl acetate (25 mL), acidified with 1N HCl (25 mL), and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate layers are dried with MgSO4, filtered, and concentrated to a waxy solid. This material is co-evaporated with MeOH (3×) to provide the title compound as a white solid (925 mg, 48%). MS (m/z): 386.2 (M+1).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:9]([C:12]1[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)(=[O:11])=[O:10]>O>[CH:1]1([NH:7][S:9]([C:12]2[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Reactant: NC1CCCCC1
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
250 ml of water and 300 ml of cyclohexylamine were put into a 1-liter balloon flask. 139 g of moist 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added by fractions, the temperature being maintained at from 20°-30° C. The mixture was stirred at room temperature for three hours and then the solution was treated with 30 g of black carbon 3 S. After filtration, 300 ml of hydrochloric acid (d=1.18) were added. The precipitate was recrystallized, washed with water and dried. 92 g of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 150° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(OCc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 126-127° C.; 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 3.01 (t, 2 H), 5.20 (s, 2 H), 6.81 (s, 1 H), 7.22 (m, 6 H), 7.41 (m, 7 H).
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:33]=[N:34][C:35]([NH:47][C:48](=[O:52])[NH:49][CH2:50][CH3:51])=[CH:36][C:37]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=3)=[CH:29][N:30]=2)[C:25](=[O:53])[C:24]([C:54]([O:56]CC)=[O:55])=[CH:23]1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[K+]>[CH2:12]([O:11][P:9]([O:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:33]=[N:34][C:35]([NH:47][C:48](=[O:52])[NH:49][CH2:50][CH3:51])=[CH:36][C:37]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=3)=[CH:29][N:30]=2)[C:25](=[O:53])[C:24]([C:54]([OH:56])=[O:55])=[CH:23]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3CCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn1
Temperature: 60 °C
Yield: 73.9 %

Procedure:
To a stirred suspension of ethyl 1-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 30, 210 mg, 0.2511 mmol) in ethanol (20 mL), 10% potassium hydroxide (0.2 mL) was added. The reaction mixture was heated to 60° C. for 30 min. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to a residue. The residue was diluted with water and acidified with 2N hydrochloric acid solution to pH 4 to obtain solid which was filtered, washed with water and dried to afford 1-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 150 mg (84%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+].CO>>[C:30]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:7])[N:9]=1)#[N:31]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccc(Oc3ccc4c(C#N)nc(C(=O)NCC(=O)O)c(O)c4c3)cc2o1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (81 mg, 0.19 mmol), glycine (292 mg, 3.89 mmol), and 0.5 M sodium methoxide/methanol (7.4 mL) was refluxed for twenty-six hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted with dichloromethane (2×35 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (5.5 mL). The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (72 mg): MS: (+) m/z 419.30 (M+1); (−) m/z 417.28 (M−1).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-].[K+]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@:3]([OH:4])([CH2:2][OH:1])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [K+]
Agent: [OH-]
Product: OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
An aqueous solution containing 80 g. of dextrose (d.b.) and 13.3 mg. of Mg(OH)2 per 100 ml. was prepared. The solution was stirred for at least one hour (preferably overnight) to equilibrate. The pH was adjusted to 8.5 at room temperature with 3 N KOH. 193.9 g. of substrate (about 150 ml.) was added to a 1-liter stainless steel beaker covered with a center-holed watch glass containing an additional hole near the edge. The sample was placed in a 60°C water bath, and stirred for 15 minutes, while maintaining a pH of 8.0 with 3 N KOH. The substrate was sparged with nitrogen at a moderate rate using a gas dispersion tube placed through the peripheral hole of the watch glass. A pre-weighed amount of xylose isomerase-basic magnesium complex containing from 1,000 to 3,000 units of bound isomerase was added using 50 ml. of 60°C water to transfer the material to the stainless steel beaker. This yielded a reaction mixture containing 60 g. of dextrose and 10 mg. of Mg(OH)2 per 100 ml. and an isomerase dosage level of from 8.3 to 25.0 units per gram of dextrose. The reaction mixture was adjusted to pH 8.0, and digested for exactly two hours after enzyme addition. The material was filtered immediately by vacuum through an 11-cm. Whatman 541 paper and the pH of a 500 ml. portion of the filtrate was adjusted to about 2.5 with 1.0 N perchloric acid. The dry substance content of the inactivated sample was determined by refractive index measurement and the levulose concentration by using spectrophotometric or polarimetric procedures. From the amount of levulose produced, effective isomerase ("retained isomerase activity") activity was calculated using the following equation: ##EQU2## where: V = reaction volume, ml.;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:20])[CH2:23]1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by heating 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (70 mg, 0.244 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (57.0 mg, 0.244 mmol), XPhos (23.3 mg, 0.049 mmol), Pd2dba3 (22.4 mg, 0.024 mmol) and sodium tert butoxide (46.9 mg, 0.488 mmol) in toluene (2.0 mL) at 110° C. in a microwave reactor for 2 h. After this time the reaction was partitioned between EtOAc (70 mL) and water (30 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)quinoline. 1H NMR (500 MHz, chloroform-d) δ ppm 8.59 (1H, d, J=4.9 Hz), 7.84 (1H, dd, J=10.0, 2.7 Hz), 7.79 (1H, dd, J=9.3, 6.1 Hz), 7.66-7.70 (1H, m), 7.59 (1H, d, J=2.2 Hz), 7.27-7.32 (1H, m), 7.22 (1H, dd, J=5.0, 1.8 Hz), 5.81 (1H, d, J=2.4 Hz), 3.79-3.83 (2H, m), 3.72-3.78 (4H, m), 2.92-3.05 (4H, m), 2.47-2.52 (3H, m), 2.36 (3H, s), 1.57 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=484.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][CH2:17][CH2:18][CH3:19])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 82 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 66 mg of propylamine and 120 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. N4-(4-Methoxyphenyl)-N6-propylpyrimidine-4,6-diamine was obtained in the form of a colorless solid.