Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[O:20]([C:22]#[N:23])[Na]>O.C(O)(=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH2:23])=[O:20])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: N#CO[Na]
Solvent: O
Solvent: CC(=O)O
Product: CCc1sc2ncnc(N)c2c1-c1ccc(NC(N)=O)cc1
Yield: 95.7 %

Procedure:
A mixture of Example 78A (0.27 g, 1 mmol) and NaOCN (0.13 g, 2 mmol) in water (1.5 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature and partitioned between water and ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 0.3 g of the desired product. MS (ESI(+)) m/e 314 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 2.63 (q, J=7.57 Hz, 2H); 5.94 (m, 2H); 7.24 (d, J=8.48 Hz, 2H); 7.56 (d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.75 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C=NC=C(C(F)(F)F)C=3)[CH2:13][CH2:12]2)[N:3]=1.Cl[C:28]1[N:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][C:29]=1[C:30]#[N:31]>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[N:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][C:29]=3[C:30]#[N:31])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-c2ccccc2)cnc1Cl
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc(C(F)(F)F)c3)CC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3ncc(-c4ccccc4)cc3C#N)CC2)n1

Procedure:
Following the procedure reported above for the compound of Example 262 but replacing 5-(trifluoromethyl)pyridine with 2-chloro-5-phenylnicotinonitrile the title product was synthesized. After the reaction work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 4:6, affording the title product (10%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:38][C:27]1[CH:26]=[C:25]([CH2:24][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:37]=[CH:36][C:28]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a solution of N-pentyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (70 mg, 0.23 mmol) in anhydrous MeCN (6 mL) under nitrogen at room temperature, was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (65.4 mg, 0.23 mmol) and N,N-diisopropyethylamine (39.6 μL, 0.23 mmol). The resultant solution was heated to reflux and stirred for 4 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (20 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:200–1:100 EtOAc:cyclohexane afforded the title compound as a colourless oil (66 mg).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[CH:15]=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (28.8 ml, 0.4 mol) was added dropwise to methanol (450 ml) at −10° C. temperature. To the obtained solution was added 3-(4-nitrophenyl)-acrylic acid (1) (38.63 g, 0.2 mol) and the reaction mixture was stirred at 0° C. for 3 hours, at ambient temperature for 24 hours and at 40° C. for 1 hour. The resulting precipitate was filtered, washed with methanol (2×10 ml) and dried affording the title compound in a form of yellow crystals (39.55 g, 96%). 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (2H, br s); 3.77 (3H, s); 6.87 (1H, d, J=16.0 Hz); 7.67-8.39 (5H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: c1ccc2c(C3CCCNC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the 3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole obtained in Example 28 and 10% palladium on carbon in a mixture of formic acid and methanol is stirred at room temperature for 3 days and filtered through celite. The celite is washed with methanol. The filtrates are combined and concentrated in vacuo to afford the title product, identified by HPLC and mass spectral analyses.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14](O)=[O:15])[S:2]1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19].[H-].[Na+]>CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14]([NH:21][S:18]([NH2:22])(=[O:20])=[O:19])=[O:15])[S:2]1
Reactant: O=C(O)CNC(=O)NCCCCC1CCSS1
Reactant: NS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)NC(=O)CNC(=O)NCCCCC1CCSS1
Yield: 29.7 %

Procedure:
The reaction was carried out as described in Example 73, but using 0.20 g of 3-[4-(1,2-dithiolan-3-yl)butyl]ureidoacetic acid (prepared as described in Example 48), 4 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole, 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of methanol and ethyl acetate, to obtain 76 mg of the title compound as yellow crystals, melting at 143 to 145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Cl:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:17])[C:3]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(Br)cccc1CBr
Temperature: 25 °C

Procedure:
A solution of 1-bromo-2-chloro-3-methyl-benzene (3.90 g, 19.00 mmol), NBS (3.60 g, 20.20 mmol) and a catalytic amount of AIBN (50 mg) in CCl4 was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with pentane. The solvent was distilled off and the residue was purified by column chromatography using pentane as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 4.62 (s, 2H), 7.14 (t, J=7.62 Hz, 1H), 7.39 (dd, J=7.62 Hz, 1H), 7.60 (dd, J=7.91 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([I:12])[CH:7]=[CH:6][N:5]=1>O1CCCC1>[F:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([I:12])[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1c(I)ccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1c(I)ccnc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.72 g (19.2 mmol) of sodium borohydride is added to a solution of 4 g (16 mmol) of 2-fluoro-4-iodo-3-pyridinecarbaldehyde (described in J.O.C., 1993, 58, pp. 7832) in 100 ml of tetrahydrofuran. The mixture is stirred at room temperature for 4 hours and then hydrolysed. The reaction mixture is extracted with ethyl acetate. The organic phases are dried and concentrated to yield the expected product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C([Li])CCC.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)OCC1>C1COCC1.CCCCCC>[OH:22][C:19]1([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21][C:16](=[O:12])[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1cocn1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCC(O)(c2ncco2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1,3-oxazole (2.0 mL, 30.41 mmol) in THF (20 mL) was added 1.0 M solution of borane in THF (30.4 mL) at room temperature. The mixture was stirred for 1 hour before being cooled down to −78° C. To the above solution was added a 1.6 M solution of n-butyllithium in hexane (19 mL). After stirring at −78° C. for one hour, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.22 g, 33.45 mmol) in THF (10 mL) was added. After being stirred at −78° C. for 5 hours, the reaction was quenched by addition of a 3 M solution of HCl in water (40 mL). The resulting solution was stirred at room temperature overnight, neutralized with potassium carbonate and extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. Purification by flash chromatography on silica eluting with EtOAc afforded the desired product (3.9 g, 70%). LC-MS calculated for C9H11NO3: (M+H)+182; found 182.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Chloro-2-fluoro-benzenesulfonyl chloride (10.5 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g) were added to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded the title compound as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 14.14 g (75%).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:36][NH2:37]>>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][CH:13]([NH:37][CH3:36])[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Product: CNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1

Procedure:
N-((1-(Biphenylcarbonyl)-5-(methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and methyl amine. (ESI) 479 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][N:14]([C:21]([O:23]C(C)(C)C)=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][N:14]([C:21]([O:23][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:22])[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc(OCCN(C(=O)OCc2ccccc2)c2ccncc2)c1
Reaction time: 20 h
Yield: 62.2 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid methyl ester (0.950 g) in dichloromethane (16 ml) and trifluoroacetic acid (4 ml) was stored at room temperature for 1 h. The solution was concentrated in vacuo and residual trifluoroacetic acid removed by co-evaporation with further dichloromethane. The residue was dissolved in dichloromethane (20 ml) and the solution stirred with saturated aqueous sodium bicarbonate (25 ml). Benzyl chloroformate (0.394 ml) was added to the bi-phasic mixture and stirring continued for 20 h. The aqueous layer was removed and the organic layer washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (3:1 v/v), to give the title compound as a colourless gum (0.32 g).
Reaction SMILES: [I-:1].[I-].[I-].[CH2:4]([N:7]([C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[S+:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2)[CH2:8][CH2:9][CH3:10])[CH2:5][CH3:6].[CH2:25]([N:28](C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)[CH2:29]CC)CC.C(N(C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)CCC)CC.Cl.CNC>>[I-:1].[CH3:25][N:28]([C:19]1[CH:18]=[CH:17][C:16]2[C:21]([CH:20]=1)=[S+:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([N:7]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6])[CH:24]=1)[N:15]=2)[CH3:29]
Reactant: CCCN(CCC)c1ccc2nc3ccccc3[s+]c2c1
Agent: CNC
Agent: Cl
Agent: [I-]
Product: CCCN(CCC)c1ccc2nc3ccc(N(C)C)cc3[s+]c2c1

Procedure:
This compound was obtained following isolation of 3-(N,N-dipropylamino)-phenothiazin-5-ium triiodide and subsequent treatment with dimethylamine hydrochloride. Precipitation from dichloromethane by addition of diethyl ether yielded purple lustrous crystals. Mass spectrometry: C20H26N3OS requires m/z=340; found m/z=340 (I− not detected by mass spectrometry).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[Br:1])[CH2:6][CH3:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and benzyl chloroformate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CO>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: NCCCc1ccc(O)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanol solution (25 mL) of 4-(3-aminopropyl)phenol (1.83 g), tert-butyl acrylate (1.7 mL) was added dropwise thereto at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=3:1) to give the title compound (1.55 g) having the following physical properties. TLC: Rf 0.24 (ethyl acetate:methanol 5:1);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:17]1[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=1[Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(F)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 26.9 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 650 mg, 4.4 mmol), 2-chloro-5-fluorophenylboronic acid (Aldrich; 760 mg, 4.35 mmol), copper(II) acetate (807 mg, 4.4 mmol) and triethylamine (623 μL, 4.4 mmol) in 1,2-dichloroethane (4.5 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2-chloro-5-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (322 mg, 27%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(O)C>[OH:31][NH:30][C:22](=[NH:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:25]([F:28])([F:26])[F:27])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:24]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)NO)CC3)cc1
Yield: 414.8 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.100 g, 0.255 mmol), hydroxylamine hydrochloride (0.027 g, 0.382 mmol), and triethylamine (0.071 mL, 0.510 mmol) were dissolved in ethanol (10 mL). The reaction was refluxed overnight, concentrated, and purified by reverse HPLC and freeze-drying to afford the title compound (0.45 g, 42%): 1H NMR (CHCl3) δ 7.61 (bs, 0.5 H), 7.38 (d, j=8.5 Hz, 2H), 6.94 (d, j=8.8 Hz, 2H), 6.72 (bs, 0.5H), 3.82 (s, 3H), 3.68 (t, j=6.4 Hz, 2H), 3.48 (s, 2H), 3.01 (t, j=6.4 Hz, 2H), 3.35 (s, 3H), 1.56 (bs, 4H) ppm; Mass Spec 426.3(M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[N:13]=[C:14](Cl)[C:15]([NH2:21])=[N:16]2>CN(C=O)C>[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[N:13]=[C:14]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:15]([NH2:21])=[N:16]2
Reactant: Oc1ccccc1
Reactant: Nc1nc2cccc(Br)c2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2cccc(Br)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil; 0.193 g, 4.84 mmol) in 5 mL DMF at 0° C. under N2 was added phenol (0.455 g, 4.84 mmol). Gas evolution was observed. The reaction was warmed to RT. After 5 min, 5-bromo-3-chloroquinoxalin-2-amine (0.250 g, 0.967 mmol) was added, and the reaction was sealed and stirred overnight. The reaction was partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was sequentially washed with water (1×), and saturated aq. NaCl (1×), and then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 2 g silica gel and dried. The material was purified by silica gel chromatography using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford 5-bromo-3-phenoxyquinoxalin-2-amine (0.209 g, 0.661 mmol, 68% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.55 (1H, dt, J=7.6, 0.7 Hz), 7.37-7.51 (7H, m), 7.26-7.35 (2H, m). m/z (ESI, +ve) 316.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([N:64]1[CH2:71][C@@H:70]2[C@@H:66]([CH2:67][NH:68][CH2:69]2)[CH2:65]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:64]3[CH2:71][C@@H:70]4[C@@H:66]([CH2:67][NH:68][CH2:69]4)[CH2:65]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (3.35 g, 7.25 mmol) was dissolved in DMF (30 mL) and HATU (2.85 g, 9.42 mmol) was added. cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (2.0 g, 9.42 mmol) and DIPEA (1.63 mL, 9.42 mmol) were added and the mixture was stirred at room temperature for 17 hours. The volatiles were evaporated and the resultant residue azeotroped with toluene. The solid was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4) and evaporated. The residue was dissolved in DCM (10 mL) and TFA (10 mL) was added. The solution was stirred at room temperature for 4 hours and then evaporated. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The solvent was evaporated and the product was crystallised from MeOH/Et2O. The desired product was obtained as an off-white solid (3.7 g, 90%). LCMS (Method 5) [M+H]+=556.9, RT=2.83 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 9.38-9.22 (m, 2H), 8.69 (dd, 2H, J=1.7, 4.2 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.30 (dd, 2H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.4 Hz), 5.15 (s, 2H), 3.80-3.67 (m, 2H), 3.65-3.53 (m, 2H), 3.49-3.32 (m, 3H), 3.16-2.94 (m, 4H).