Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:11]([OH:13])=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[CH3:16]O>>[OH:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:11]([O:13][CH3:16])=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: CO
Reactant: Cc1c(C(=O)O)sc2ccc(O)cc12
Agent: Cl
Product: COC(=O)c1sc2ccc(O)cc2c1C

Procedure:
Dry HCl gas is bubbled through a solution of 5-hydroxy-3-methylbenzo(b)thiophene-2-carboxylic acid (1.0 g, 4.81 mmol) in methanol (150 ml) for 1 hour at room temperature. The brown solution is refluxed for 2 hours and concentrated. Extraction with ether, washing with water, aqueous sodium bicarbonate, water and bring, drying (MgSO4) and concentration affords the crude product which is subjected to flash chromatography over silica gel. Elution with 33% ethyl acetate in hexane affords methyl 5-hydroxy-3-methylbenzo(b)thiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:30][CH2:29][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:30][CH2:29][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1N(c2ccc(CO)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[8-(2-Chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-benzoic acid (0.5 g) was dissolved in THF under an argon atmosphere and then treated at 0° C. with borane THF complex (1 molar, 6.68 ml) and stirred overnight at RT. Then 1M aqueous HCl (1 ml) was added and the mixture was stirred for 10 minutes. The solvent was evaporated off in vacuo, the residue was adsorbed on silica gel and chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 50%) to give the desired 8-(2-chloro-benzenesulfonyl)-2-(4-hydroxymethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as a white solid. MS (ESI): 435.3 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH:10]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)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]>[Si:1]([O:8][C@@H:9]1[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)[C@@H:10]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (6RS,7RS)-7-(tert-butyldimethylsilyloxy)-6-methyl-5-azaspiro[2.4]heptan-4-one (162 mg), 4-bromo-2-chlorobenzonitrile (157 mg), cesium carbonate (310 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 140 mg, 56%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:6]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:2](=[O:3])[O:4][CH3:5])=[CH:21][CH:22]=3)[N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(-c2noc(-c3ccccc3)n2)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2noc(-c3ccccc3)n2)cc1

Procedure:
1.4 g. (0.015 mole) of methyl chloroformate is added to a mixture of 2.4 g. (0.01 mole) of 5-phenyl-3-(4-aminophenyl)-1,2,4-oxadiazole, from part (b), and 2.1 g. of potassium carbonate in 50 cc. of dioxane. The resulting mixture is refluxed for 0.5 hours. It is then concentrated to dryness and the residue is crystallized from benzene to yield [4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]carbamic acid, methyl ester.
Reaction SMILES: Cl[C:2]1([F:12])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.ClC1CCC(C(OC)=O)CC1.COC(=O)C1C=CC(F)=CC=1>[Pd].ClC1C=CC=CC=1Cl>[F:12][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCC(F)(Cl)CC1
Agent: [Pd]
Agent: COC(=O)C1CCC(Cl)CC1
Agent: COC(=O)c1ccc(F)cc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)C1CCC(F)CC1
Temperature: 300 °C
Yield: 85 %

Procedure:
A mixture of 1.2 parts of 1-chloro-1-fluoro-4-carbomethoxy-cyclohexane and 4.8 parts of o-dichlorobenzene were added to a bed of 2% palladium on carbon maintained at 300° C. A stream of nitrogen at 400 cc/min. swept the products into two cold traps at 0° C. and -80° C. to yield 3.84 parts of combined products. Analysis by gas chromatography and mass spectrometry indicated complete reaction to yield 85% 1-fluoro-4-carbomethoxy-cyclohexane, 5% 1-chloro-4-carbomethoxy-cyclohexane and 10% methyl-4-fluorobenzoate, excluding the solvent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1.[I-].[Na+].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[S:29][C:9]3=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)=[C:8]3[CH:7]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(CCCCBr)cc23)cc(OC)c1OC
Agent: [I-]
Agent: [Na+]
Product: COc1cc(Nc2c(C#N)cnc3sc(CCCCN4CCOCC4)cc23)cc(OC)c1OC

Procedure:
To a solution of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464 mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine (314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by flash column chromatography eluting with a gradient of 9:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate to provide crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile. The crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile is heated 70° C. in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67 mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a yellow oil; 1H NMR (DMSO-d6) δ 1.49 (quintet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J=7 Hz, 2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H), 9.46 (s, 1H); MS 483.5 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]3[N:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C4CCCCO4)=[O:27])=[N:22][CH:23]=3)[CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:36].CCOC(C)=O>CCO>[ClH:36].[ClH:36].[OH:29][NH:28][C:26](=[O:27])/[CH:25]=[CH:24]/[C:21]1[CH:20]=[N:19][C:18]([NH:17][C@@H:14]2[CH2:15][CH2:16][N:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:13]2)=[CH:23][N:22]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc4ccccc34)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc4ccccc34)C2)cn1)NO

Procedure:
A solution of (2E)-3-[5-[{(3R)-1-(1-naphthylmethyl)-3-pyrrolidinyl}amino]-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (350 mg) and 2N—HCl solution in EtOH (10 mL) was stirred for 2 hours at ambient temperature. AcOEt (10 ml) and IPE (50 ml) was added to the reaction mixture. The resulting solid was collected by filtration to give (2E)-N-hydroxy-3-[5-[{(3R)-1-(1-naphthylmethyl)-3-pyrrolidinyl}amino]-2-pyrazinyl]acrylamide dihydrochloride (275 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[Sn]>Cl.O>[C:8]([C:7]1[C:6]([CH3:10])=[CH:5][C:4]([CH3:11])=[N:3][CH:2]=1)#[N:9]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: Cl
Agent: [Sn]
Solvent: O
Product: Cc1cc(C)c(C#N)cn1
Yield: 54 %

Procedure:
23 g of 2-chloro-3-cyano-4,6-dimethylpyridine are dissolved in 185 ml of concentrated hydrochloric acid and 240 ml of water. 25.4 g of tin metal are added and the mixture is brought to 100° C. The reaction is monitored by thin layer chromatography (TLC). When the reaction is complete, the mixture is allowed to return to room temperature and filtered and the filtrate is neutralized using sodium hydroxide solution. The mixture is extracted with methylene chloride and the combined organic phases are washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulphate. The solution is concentrated to give 5-cyano-2,4-dimethylpyridine in the form of a yellow precipitate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212° C. 1H NMR (CDCl3/300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2: C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)[N:29]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nc(-c2ccncc2)cs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccncc4)cs3)(CC1)CC2
Yield: 20.4 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(4-pyridyl)thiazole (60.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(4-pyridyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.2 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:8]([C:7]1[C:2]([Cl:1])=[C:3]([CH3:11])[CH:4]=[CH:5][CH:6]=1)=[O:9]
Reactant: c1ccsc1
Reactant: Cc1cccc(C(=O)Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cccs2)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred and cooled mixture of 28.4 parts of 2-chloro-m-toluoyl chloride, 12.6 parts of thiophene and 80 parts of methylene chloride is added dropwise a mixture of 39 parts of stannic chloride in 40 parts of methylene chloride at 10° C. Upon completion, stirring is continued first for 2 hours a 20° C and further for 3 hours at reflux. The reaction mixture is poured onto a mixture of ice-water and concentrated hydrochloric acid solution. The methylene chloride solution is separated, washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding 2-chloro-m-tolyl 2-thienyl ketone; bp. 197° -199° C at 12 mm. pressure.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].C1COCC1.C1CCC(N=C=NC2CCCCC2)CC1.[C:33](O)([CH3:36])([CH3:35])[CH3:34]>CCOC(C)=O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
To a stirred ice cooled solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (16.0 g, 94.117 mmol) in THF (160 ml) DMAP (1.148 g, 9.409 mmol) and DCC (23.265 g, 112.93 mmol) were added, followed by t-butyl alcohol (27.63 ml, 282.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a celite bed and washed with EtOAc. The filtrate was as such concentrated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as a solid. Wt: 15.0 g: Yield: 70%; 1H NMR (300 MHz, CDCl3): δ 2.86-2.74 (m, 1H), 2.70-2.50 (m, 2H), 2.04 (s, 3H), 1.89-1.78 (m, 1H), 1.42, 1.40 (2s, 12H), 0.91 (s, 3H); Mass: [M+Na]+ 249 (100%).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.CS[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][N:15]=1.[CH3:32][NH:33][CH3:34].O>O1CCCC1>[CH3:32][N:33]([CH3:34])[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][N:15]=1
Reactant: CNC
Reactant: CSc1ncc(-c2nc3cccc(C(=O)O)c3o2)cn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ncc(-c2nc3cccc(C(=O)O)c3o2)cn1
Reaction time: 0.25 h
Yield: 83 %

Procedure:
77% m-Chloroperbenzoic acid (476 mg, 2.12 mmol) was added to a suspension of methyl ester of 2-(2-methylthiopyrimidin-5-yl)benzoxazole-7-carboxylic acid (400 mg, 1.33 mmol) in tetrahydrofuran (10 ml) under ice cooling and the mixture was stirred for 15 min. and then at room temperature for 3 hrs. To the reaction mixture was added dropwise 50% aqueous solution of dimethylamine at room temperature and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled with ice and water (25 ml) was added thereto. The mixture was stirred for 15 min. and extracted with ethyl acetate. The organic layer was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=4) to give methyl ester of 2-(2-dimethylaminopyrimidin-5-yl)benzoxazole-7-carboxylic acid (328 mg, 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=O)[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl.[NH2:27][OH:28].C(=O)(O)[O-].[Na+]>C(O)C.C(O)C.ClCCl>[Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=[N:27][OH:28])[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: O=C1CC[C@@H](NC(=O)c2noc(-c3ccc(C(F)(F)F)cc3)c2Cl)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(N[C@@H]1CCC(=NO)C1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl

Procedure:
A suspension of (R)-4-chloro-N-(3-oxocyclopentyl)-5-(4-(trifluoromethyl)phenyl) isoxazole-3-carboxamide (20 mg, 0.054 mmol), hydroxylamine hydrochloride (5 mg, 0.064 mmol), and sodium bicarbonate (7 mg, 0.083 mmol) in ethanol (2 mL) was heated to reflux overnight. The reaction mixture was diluted with ethanol/dichloromethane, filtered through a cotton plug and evaporated in vacuo. Purification by silica gel chromatography, eluting with 8% methanol in dichloromethane gave the title compound as a mixture of cis and trans isomers (10.5 mg, 0.027 mmol). MS (ESI) m/z (M+H+): 388.2/390.3
Reaction SMILES: C([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)(O)=O.[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(O)(=O)CC>[C:7]1([C:8]2[C:16]3[NH:12][C:13]([C:8]([C:7]4[CH:6]=[CH:5][CH:4]=[CH:11][CH:10]=4)=[C:13]4[N:12]=[C:16]([C:8]([C:7]5[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=5)=[C:16]5[NH:12][C:13](=[C:8]([C:7]6[CH:6]=[CH:5][CH:4]=[CH:11][CH:10]=6)[C:13]6[CH:14]=[CH:15][C:16]=2[N:12]=6)[CH:14]=[CH:15]5)[CH:15]=[CH:14]4)=[CH:14][CH:15]=3)[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
The acid derivative of 5,10,15,20-tetrakis(phenyl)porphyrin was prepared according to the procedure of Longo, et al. J. Heterocyclic Chem., 6, 927 (1969). 1.50 g 4-Carboxy-benzaldehyde (0.01 mole) and 0.69 mL pyrrole (0.01 mole) were combined in 150 mL propionic acid. The mixture was refluxed for 2 to 4 hours, cooled to room temperature, and then filtered through a fine frit. The resulting solid was then extracted into methanol and filtered through a medium frit. The filtrate was placed in a round-bottom flask, and the methanol removed on a rotary evaporator, leaving a solid purple residue. The recovered solid was then dried overnight under vacuum.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)[nH]c2nccc1-2
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of 2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (3.2 g, 4.57 mmol) in 1,4-dioxane (200 ml) was added 1.0M potassium hydroxide (91 ml, 91 mmol) and the resulting reaction was stirred at 80 C for 6 hrs. The reaction was diluted with ethyl acetate (200 ml), washed with brine (200 ml), adsorded to silica gel and purified by LC (DCM to 5% MeOH/DCM) to provide 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (1.8 g, 72%). ESIMS (M+H)+=547. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.88 (m, 2 H) 2.07 (br. s., 6 H) 2.59-2.68 (m, 2 H) 2.74 (d, J=4.58 Hz, 3 H) 3.20 ) (s, 2 H) 3.66 (t, J=6.13 Hz, 2 H) 3.80 (s, 3 H) 6.25-6.28 (m, 1 H) 6.78 (s, 1 H) 6.88-6.98 (m, 2 H) 7.32-7.39 (m, 1 H) 7.45 (s, 1 H) 8.20 (d, J=8.42 Hz, 1 H) 8.38 (s, 1H) 8.46-8.59 (m, 1 H) 10.06 (s, 1 H) 11.32 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:12][CH2:13][CH:14]([CH2:17][O:18][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of Intermediate 14c (470 mg, 1.88 mmol) and Et3N (390 μL, 2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (607 μL, 2.26 mmol) and the mixture stirred at RT for 0.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound (565 mg, 74%). LCMS (Method 3): Rt 5.21 min, m/z 407 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[O:4]1[CH:5]=[CH:6][C:2]([NH:1][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:3]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccon1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Yield: 94.2 %

Procedure:
To a solution of 3-aminoisoxazole (0.878 ml, 11.9 mmol) and pyridine (1.13 ml, 14.3 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.97 ml, 14.3 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give 2.91 g (94.1%) of the desired product as a solid.