Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].Cl.[F:19][C:20]([F:28])([F:27])[C:21]([NH:23][CH2:24][CH2:25][NH2:26])=[O:22].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[C:20]([F:28])([F:27])[F:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCNC(=O)C(F)(F)F
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 65.2 %

Procedure:
1.55 g (0.01 mol) of 2-fluoro-5-nitrotoluene, 2.65 g (0.025 mol) of sodium carbonate, 2.11 g (0.011 mol) of 2-(trifluoroacetamido)ethylamine hydrochloride and 10 ml of N-methyl-pyrrolidone were introduced into a three-necked flask under nitrogen. The mixture was heated to 90° C. After reaction for 48 hours, the reaction mixture was cooled and 30 ml of distilled water were then added slowly with vigorous stirring. A yellow precipitate appeared. This precipitate was filtered off, washed several times with water and then with pentane, and dried under vacuum. 1.9 g of expected nitro derivative (1) were obtained in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:29])[CH2:27][CH3:28]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:26][CH2:27][CH3:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCN
Solvent: c1ccccc1
Product: CCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30953.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), propylamine (0.190 g, 3.21 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 6 hours at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propyl-3,4,5,6-tetrahydrophthalamide as white crystals (0,360 g, 30.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:16](OCC)=[O:17])#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>CO.C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCCCCC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1=Nc2cc(Cl)ccc2C(=O)C1

Procedure:
3-Chloroaniline (28.5 g, 200 mmol) and diethyl acetylenedicarboxylate (37.4 g, 220 mmol) are heated in MeOH (300 mL) for 3 h at reflux. The reaction mixture is concentrated to yield a yellow residue, which is heated in phenyl ether (400 mL), for ¾ h. The mixture is cooled to room temp. and diluted with hexane whereupon a white solid precipitates which is filtered off: 34.4 g.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:17]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:7](=[O:9])[CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][S:4][C:1](=[O:3])[CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred ice-cold solution of 2.85 g (12 mmoles) 3-acetylthio-2-benzylpropanoic acid in 20 ml THF are successively added a mixture of 4.04 g (12 mmoles) glycine benzyl ester p.tosylate and 1.71 ml triethylamine in 20 ml CHCl3, a solution of 1.83 g (12 mmoles) HOBT in 15 ml THF, and a solution of 2.63 g (12.8 mmoles) DCC in 10 ml CHCl3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C#CCn1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Yield: 65.5 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer)(1.9 g) in methylene chloride (19.0 ml) were added anisole (2.3 g) and trifluoroacetic acid (6.2 g) with stirring under ice-cooling and then the resulting mixture was stirred for an hour at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The organic layer was separated and adjusted to pH 7.0 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate (x2) and then concentrated. The concentrate was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and then dried over phosphorus pentoxide to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g).
Reaction SMILES: [Tl].[Tl].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13])=[O:11].[CH3:21][N:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25]Cl>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:25][CH:24]([CH3:27])[CH2:23][N:22]([CH3:28])[CH3:21])=[O:13])=[O:11]
Reactant: O=C(C(=O)c1ccccc1O)c1ccccc1O
Reactant: CC(CCl)CN(C)C
Agent: [Tl]
Solvent: Cc1ccccc1
Product: CC(COc1ccccc1C(=O)C(=O)c1ccccc1OCC(C)CN(C)C)CN(C)C

Procedure:
A suspension of 15 g. (0.023 M) of 2,2'-dihydroxybenzil dithallium salt in 500 ml. of dry toluene was stirred vigorously while adding dropwise a solution of 8.8 g. (0.05 M) of 3-dimethylamino-2-methyl propyl chloride in 91.5 ml. of toluene. The mixture was gradually heated to reflux during the addition, and the resulting mixture was stirred and refluxed for 12 hours before a color change was observed. After cooling to 25°, the pale yellow solid was filtered off and washed with toluene. The material was resuspended in toluene and filtered off again. The combined filtrates were washed with 10% sodium hydroxide solution, saturated brine solution, and finally dried over MgSO4. Evaporation of the dry toluene extract with heating up to 70° at 11 mm resulted in an oily residue. Various salts were prepared but failed to solidify. The free base was regenerated and the crude material began to crystallize. The product was recrystallized from hexane. After cooling to +5° overnight, the material was filtered off and dried in vacuo over P2O5 and paraffin wax to obtain 3.8 g. of the title compound; m.p. 69°-70°; λKbr/max 3.55, 5.88, 6.10, 6.55, 6.72 μ.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[NH:10][C:11](=[O:22])[CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][NH:10][C:11](=[O:22])[CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: [H][H]
Reactant: COc1ccc(C(O)C(=O)N/N=C/c2ccc(O)c(OC)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(O)C(=O)NNCc2ccc(O)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of hydroxy-(4-methoxy-phenyl)-acetic acid [1-(4-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide (21 g, 63 mmol) in 500 ml of ethanol is hydrogenated under atmospheric pressure with hydrogen and a mixture of 5% of palladium on charcoal (10.5 g) as catalyst. The reaction is stirred for 6 hours at room temperature. Subsequently, the mixture is filtered under argon and the solvent is evaporated to yield hydroxy-(4-methoxy-phenyl)-acetic acid N′-(4-hydroxy-3-methoxy-benzyl)-hydrazide as colourless tarr.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)#[CH:2].C(N(CC)C(C)C)(C)C.[CH2:23]([N:30]=[N+:31]=[N-:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH2:23]([N:30]1[CH:2]=[C:1]([C:3]2[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=2)[N:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-ethynyl-4-methylthiazole-5-carboxylate (0.19 g, 0.71 mmol) in tetrahydrofuran (5 mLl) was added copper(I) iodide (0.003 g, 0.014 mmol), N,N-diisopropylethylamine (0.15 mL, 0.74 mmol) and benzylazide (0.11 g, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a yellow solid (0.23 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.39-7.26 (m, 5H), 5.54 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); MS (ES+) m/z 329.3 (M+1).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>CO>[C:5]([N:9]=[N:10][C:11]([S:1][C:2]#[N:3])([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC(C)(C)SC#N
Reaction time: 0.25 h

Procedure:
To a stirred solution of 9.72 grams (0.12 moles) of sodium thiocyanate in 50 ml methanol in a 125 ml erlenmeyer flask was slowly added 16.25 grams (0.1 mole) of 2-t-butylazo-2-chloropropane while holding the reaction temperature at 5° C. with an ice bath. After the addition was complete, the reaction was stirred an additional 15 minutes and poured into 300 ml water. The solids which formed were filtered off and pulled semi-dry on the filter funnel. The crystals were dissolved in pentane, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure. The pale yellow solid residue weighed 8.0 grams (43% crude yield) and melted at 29°-31° C. The infrared spectrum of the product contained a sharp weak band at 2160 cm-1. There also was a weak doublet at 2020 and 2070 cm-1 indicating there was a trace of the isothiocyanato isomer present.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][N:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:21][CH:22]=[O:23])=[CH:3][N:2]=1
Reactant: O=Cc1cncc2ccccc12
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cncc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-isoquinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+].C1C=CC=CC=1>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:1]2[CH2:8][S:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Yield: 81.9 %

Procedure:
Dissolved in 100 ml of 1N sodium hydroxide were 6.65 g of L-thioproline, and 50 ml of water were further added to the solution. A solution of 9.10 g of 4-phenylbutanoyl chloride in 50 ml of benzene was added dropwise to the solution under stirring. Thereafter, 50 ml of 1N sodium hydroxide were further added, and the mixture was stirred for 24 hours. A benzene layer was removed, and a water layer was washed twice with 70 ml of ether. After 7% hydrochloric acid was further added to the water layer to acidify it, the water layer was extracted three times with 70 ml of ethyl acetate. The resulting extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the resultant oily residue was subjected to column chromatography on silica gel, thereby obtaining 11.4 g of N-(4-phenylbutanoyl)-L-thioproline as colorless crystals from a chloroform-methanol fraction.
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][C:27]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCc4ccc(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 2,4-difluorobenzylamine (22 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 32 mg (yield 41%) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[ClH:28].CCOC(C)=O>C1COCC1>[ClH:28].[ClH:28].[N:13]1([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N3CCOCC3)nc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: c1nc(N2CCOCC2)ncc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-[2-(morpholin-4-yl)pyrimidin-5-yl]piperazine-1-carboxylate (1.42 g) was mixed with MeOH (20 ml) and THF (20 ml), and a 4M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature overnight and then stirring for 30 minutes under ice-cooling. The precipitated solid was collected by filtration and washed with EtOAc to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine dihydrochloride (1.15 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:14]1[CH:13]=[CH:12][C:11]2[C:10]3[C:18](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:17](=[O:19])[C:16]=2[CH:15]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2ccc(I)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 266.6 %

Procedure:
Add acetic acid (45 mL), concentrated sulfuric acid (5.4 grams, 0.055 moles), water (10 mL), 9-fluoreneone (9.01 grams, 0.05 moles), iodine (6.0 grams, 0.0237 moles), and periodic acid (2.85 grams, 0.0125 moles) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the reaction mixture to 45° C. and stir 1 hour, then warm to 50° C. and stir an additional 2.5 hrs. Warm the mixture to 60° C. and add additional acetic acid (45 mL). Stir the reaction mixture for an additional 10 hours, cool to room temperature and stir the reaction mixture at room temperature for about 8 hours. Collect the precipitate by filtration. Transfer the filter cake and acetic acid (40 mL) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the mixture to 70° C. and add additional acetic acid with continued warming until a clear solution is observed. Reduce the reaction mixture to 50° C. and stir at 50° C. for 2 hours. Slowly cool the reaction mixture to 25° C. and stir 1 hour. Recover the precipitate by vacuum filtration. Air-dried the resulting filter cake to provide the title compound (10.2 g, 66.6% yield). 1H NMR (CDCl3, 500.0 MHz): δ 7.95 (d, 1H, J=1.5); 7.81 (dd, 1H, J=2, 8); 7.64 (d, 1H, J=7.5); 7.50 (m, 2H); 7.33-7.24 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=N[CH:7]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].[C:21]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:11]=[C:9]1[CH2:10][C:4]2[C:5](=[CH:21][CH:7]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:3]=2)[NH:8]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: O=C1Cc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)CC(=O)N2
Yield: 162.4 %

Procedure:
A solution of 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g, 9.49 mmole), tert-butyl acrylate (1.8 g, 14.1 mmole), Pd(OAc)2 (0.32 g, 1.4 mmole), tri-ortho-tolylphosphine (0.57 g, 1.9 mmole), and diisopropylethylamine (4.9 mL, 28.2 mmole) in propionitrile (100 mL) and DMF (10 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (0.80 g, 33%) as a light yellow solid. MS (ES) m/e261 (M+H)+.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@H](C(N)=O)C1
Yield: 56.2 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 6.97 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.47-2.49 (m, 1H), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1O)[CH3:2].P(Cl)(Cl)(Cl)=O.[NH3:32]>C(#N)C>[CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1[NH2:32])[CH3:2]
Reactant: N
Reactant: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.800 g (5.138 mmol) of 6-ethyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 25 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 375 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 4 h at RT. Concentration on a rotary evaporator was carried out and the residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 157 mg (8% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[C:11]([CH2:24][NH:25][C:26]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][N:29]2[C:34](=[O:41])[C@H:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27])[CH:10]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:13][C:12]1[CH:22]=[CH:23][C:9]([Cl:8])=[CH:10][C:11]=1[CH2:24][NH:25][C:26]([C@@H:28]1[CH2:33][O:32][CH2:31][CH2:30][N:29]1[C:34](=[O:41])[C@H:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)[C@H](O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](O)C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (50% solution in CH2Cl2, 3 mL) was added to a solution of tert-Butyl 4-chloro-2-[{(S)-4-{(R)-2-hydroxy-3,3-dimethylbutanoyl}morpholine-3-carboxamido}-methyl]-benzylcarbamate (0.25 g, 0.50 mmol) in CH2Cl2 (1 mL) and the reaction was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure and residue was triturated with diethyl ether to afford the title compound as a white hygroscopic solid. 1HNMR (400 MHz, CD3CN): 8.37 (t, J=4.0 Hz, 1H), 8.05 (bs, 3H), 7.46-7.43 (m, 2H), 7.34 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 4.78 (d, J=4.0 Hz, 1H), 4.46 (dd, J=15.2, 6.0 Hz, 1H), 4.39-4.43 (m, 3H), 4.22 (d, J=2.8 Hz, 2H), 3.91 (d, J=12.4 Hz, 2H), 3.86 (dd, J=11.6, 2.4 Hz, 1H), 3.58 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 3.53-3.42 (m, 2H), 0.98 (s, 9H).