Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>ClC1C=CC=CC=1Cl>[CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccccc1C1CCCCCC1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: c1ccc(N2CCNCC2)c(C2CCCCCC2)c1
Temperature: 200 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of the 2-cycloheptylphenylamine (539 mg, 2.85 mmol) produced in Example (44b) in 1,2-dichlorobenzene (7 mL) was added bis(2-chloroethyl)amine hydrochloride (610 mg, 3.42 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 8 hours, the mixture was air-cooled to room temperature. To the reaction mixture were added aqueous solution of potassium carbonate, ethyl acetate and methanol, and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate, and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 540 mg of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[C:30]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][NH2:34])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCN)n(CC3CCOCC3)c12
Reaction time: 1 h
Yield: 31 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH method) to give the title compound as a beige solid (26 mg, 31%). LCMS (HpH) Rt 0.73 min, MH+ 451
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC>>[C:1]1([CH2:7][CH:8]2[O:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Solvent: CSC
Product: c1ccc(CC2OC2c2ccccc2)cc1
Yield: 80 %

Procedure:
Using the method of Example 36 with phenylacetaldehyde but using (1 mmol) of dimethyl sulfide gave the title compound in 80% yield as a clear oil. δH (CDCl3, 250 MHz): 7.3-7.1 (10H,m), 3.55 (1H,d,J=2.0 Hz), 3.05 (1H, dt,J=6.0 Hz,J=2.0 Hz), 2.80 (2H,d,J=6.0 Hz)ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-(2-nitrobenzenesulfonylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 73) (400 mg, 1.04 mmol) in DMF (10 mL) was added caesium carbonate (507 mg, 1.56 mmol) and the mixture stirred at rt for 40 min. Iodomethane (323 μL, 5.19 mmol) was added and the mixture stirred for 16 h. Solvent was removed in vacuo and the crude residue partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with 1M HCl (2×20 mL), water (20 mL), then brine (2×20 mL) before being dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow powder. δH (d6 DMSO): 8.43 (2H, m), 8.01 (2H, m), 4.00-3.89 (3H, m), 2.83-2.67 (5H, m), 1.54-1.43 (2H, m), 1.39 (9H, s), 1.34-1.24 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:14][CH2:13][C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[O:10][C:9]1[CH:20]=[CH:21][C:6]([CH2:4][OH:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(Oc2ccccc2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccc2CO)cc1
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A solution of 2-(4'-ethoxycarbonylphenoxy)benzoic acid (35 g) in dry tetrahydrofuran (120 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (9.3 g) in dry tetrahydrofuran (300 ml) at room temperature. After the addition, the mixture was refluxed with stirring for 4 hours, and then the excess of lithium aluminum hydride was destroyed by cautious addition of water. The mixture was concentrated and dilute hydrochloric acid was added to the residue. The resulting mixture was extracted with chloroform and the extracts were washed with water. Concentration of the dried extracts gave crude 4-(2'-hydroxymethylphenoxy)benzyl alcohol (25 g) as an oil, IRνmaxfilm cm-1 : 3300 (OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](N)[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:21][CH3:22])[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Solvent: CCO
Product: CCNc1cc(-c2c[nH]nc2-c2cccc(Cl)c2)ccn1
Yield: 46 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine (3.5 ml) and ethanol (5 ml) as heated at 150° C. in a sealed tube for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with 70 ethyl acetate/30 toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid, m.p. 186-187° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:26])[CH3:29]
Reactant: CCOC(=N)Cc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(Cc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0° C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes. The solids were removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (3×10 mL). The combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-(4-fluorophenyl)acetimidate (0.99 g, 52.7%) as an amorphous yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, J=8.5, 5.6 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.15 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[CH2:22][NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])=[CH:4][C:3]=1[F:29].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:22][NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])=[CH:4][C:3]=1[F:29]
Reactant: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Agent: Cl
Solvent: CCO
Product: COCC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (1.11 g) in ethanol (13 mL) was added 14.0 M hydrogen chloride-ethanol solution (12.0 ml), and the mixture was stirred at room temperature for 1 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-hexane to give the title compound (715 mg).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:36]#[C:37]Br>CO>[Br:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:37]#[N:36]
Reactant: N#CBr
Reactant: Cc1cc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(CN(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
N-(2-Bromo-4-methyl-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine (89 mg, 0.180 mmol) was dissolved in methanol (10 mL). To this solution was added sodium carbonate (53.9 mg, 0.396 mmol) followed by cyanogen bromide (5.0M solution in acetonitrile, 21.9 mg, 0.041 mL, 0.207 mmol). The solution stirred at room temperature for 20 hours then concentrated under reduced pressure to dryness. The residue was partitioned between water (10 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), the organics were combined and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (97.5%). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H) 7.72 (s, 2H) 7.54 (s, 1H) 7.51 (s, 1H) 4.34(s, 4H) 2.45(s, 3H). LC-MS calc. 519, found 520 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1(O)[CH2:11][CH2:10][CH:9]1[CH:12]1[CH2:14][CH2:13]1.S(=O)(=O)(O)O>C(O)C.[Pd]>[CH:12]1([CH:9]2[CH2:10][CH2:11][CH:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])[CH2:13][CH2:14]1
Reactant: Nc1ccccc1C1(O)CCC1C1CC1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1ccccc1C1CCC1C1CC1
Reaction time: 1 h

Procedure:
2.3 g (0.0113 mol) 1-(2-Aminophenyl)-2-cyclopropylcyclobutanol (prepared as described in Example 4) was dissolved in 40 ml of ethanol, 3.25 g sulphuric acid (96%) was added and after the addition of 500 mg of 10% Pd on charcoal, the mixture was hydrogenated for 1 hour at room temperature. After removal of the catalyst, ethanol was distilled off in a water jet vacuum and the residue purified by flash chromatography over silica gel (eluant: hexane/ethyl acetate 4:1). Yield: 1.88 g (89% of theory) of the cis isomer of 2-(2-cyclopropylcyclobutyl)phenylamine in form of a yellow oil (1HNMR (CDCl3): −0.1-0.05 ppm/m/2H, 0.19 ppm/m/1H, 0.27 ppm/m/1H, 0.55 ppm/m/1H, 1.65 ppm/m/1H, 2.15 ppm/m/3H, 2.52 ppm/m/1H, 3.55 ppm (broad)/2H −NH2, 6.68 ppm/d/1H, 6.80 ppm/t/1H, 7.08 ppm/t/1H, 7.18 ppm/d/1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:32][CH2:31][C:19]2([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][NH:21][C:20]2=[O:30])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][C:19]2([N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][NH:21][C:20]2=[O:30])[CH2:31][CH2:32]1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)ccc1O
Reactant: O=C1NCN(c2ccccc2)C12CCN(CCCCl)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(F)ccc1OCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
A mixture of 1.5 g of 2-allyl-4-fluorophenol, 3.1 g of 8-(3-chloropropyl)-1-phenyl-4-oxo-1,3,8-triazaspiro[4,5]decane, 0.7 g of potassium carbonate and 40 ml of toluene was heated under reflux for 10 hours. After cooling, the reaction mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 8-{3-(2-allyl-4-fluorophenoxy)propyl}-1-phenyl-4-oxo-1,3,8-triazaspiro[4,5]decane, m.p. 110° - 113° C; recrystallized from cyclohexane, m.p. 117° - 117.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:10])[C:6]([F:8])([F:7])[F:9]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(CCOC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2′-chloro-4′-[2-((RS)-tetra-hydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (352 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (48 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Ethyl bromoacetate (133 μl) was added to the reaction mixture, and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave ethyl N-[2-chloro-4-[2-((RS)-tetrahydropyran-2-yloxy)ethyl]phenyl]-N-trifluoroacetylamino-acetate (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([CH2:14][Br:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1C(=O)OC
Solvent: CC#N
Product: COC(=O)c1cccc(CBr)c1C(=O)OC
Temperature: 70 °C
Yield: 83.6 %

Procedure:
A stirred mixture of 3-methyl-phthalic dimethyl ester (12.1 g, 57.9 mmol) and N-bromosuccinimide (12.4 g, 69.5 mmol) in acetonitrile (150 mL) was heated at 70° C. (oil bath), while a 200 W light bulb situated 2 cm away was shining on the reaction mixture overnight. The resulting mixture was cooled and concentrated. The residue was dissolved in ethyl acetate (150 mL), washed with water (3×50 mL) and brine (50 mL), and dried (MgSO4). Solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, Hexane:EtOAc 8:2) to give 3-bromomethyl-phthalic dimethyl ester (13.9 g, 83%) as a solid: 1H NMR (CDCl3) δ 7.94-7.90 (dd, J=1.1 and 7.9 Hz, 1H), 7.65-7.62 (dd, J=1.0 and 6.9 Hz, 1H), 7.47 (t, J=7.8H, 1H), 4.54 (s, 2H), 3.97 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19].O>O1CCCC1>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CN
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methylamine in tetrahydrofuran (2M, 11 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (289 mg). The mixture was stirred at ambient temperature for 2 hours and poured into water. The precipitate was collected by filtration and dried to give 1-methylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (280 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CN(C=O)C>[N:9]([C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(N)ccn1
Temperature: 110 °C
Yield: 71.2 %

Procedure:
To a solution of 2-chloropyridin-4-amine (2.0 g, 15.6 mmol) in DMF (20 mL) under nitrogen was added NaN3 (2.0 g, 31.2 mmol) and NH4Cl (1.7 g, 31.2 mmol). The mixture was heated to 110° C. for 10 hours and then quenched with saturated Na2CO3. The reaction was filtered and then the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 2-azidopyridin-4-amine (1.5 g, yield: 83%). LCMS (ESI) m/z: 136.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:13]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:13]=1
Reactant: COC(=O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
To a stirred solution of (E)-methyl 3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylate (6.0 g, 20 mmol) in MeOH (100 mL) and H2O (20 mL) was added lithium hydroxide (1.5 g, 61 mmol). The resulting mixture was stirred at room temperature for 24 hours and then partially concentrated under reduced pressure. The pH of the residue was adjusted to 5 by the addition of 2N HCl and the aqueous phase extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 0-20% gradient of MeOH in DCM to give the desired product as a white solid (5.4 g, 94% yield). LCMS (ESI) m/z: 284.0 [M+H+].
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:28][CH:29]([CH3:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=1.O1CCOCC1>CN1CCCC1=O>[OH:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:29]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)[CH3:39])=[CH:32][CH:33]=1
Reactant: CC(N)Cc1ccc(CO)cc1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1

Procedure:
1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (1.1 g, 2.9 mmol) and [4-(2-amino-propyl)-phenyl]-methanol (0.96 g, 5.8 mmol) in 1:1 dioxane: 1-methyl-2-pyrrolidinone (16 mL) was heated to 100° C. for 20 h. The mixture was partitioned between water (30 mL) and ethyl acetate (60 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-8% 2M NH3 MeOH/CH2Cl2 to afford a white solid. M+1=469. 1NMR (CDCl3) d (3H, 1.21 ppm), s (1H, 1.79 ppm), m (2H, 2.22 ppm), m(1H, 2.79 ppm), m (1H, 2.98 ppm), m (4H, 4.11 ppm), m (1H, 4.13 ppm), b(3H, 4.68 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.29 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1cc(Cl)ccc1N
Product: N#Cc1cc(Cl)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-chlorobenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) 7.3 (S, 2H), 7.54-7.56 (d J=9.2 Hz, 1H). 7.74-7.77 (dd J=8.4 Hz, 2 Hz, 1H), 9.67 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[CH3:19].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH3:19][C:3]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:7][C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Temperature: 116 °C

Procedure:
To a reaction vessel under argon containing 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione (85 mg, 0.27 mmol), 2-(tributylstannyl)pyridine (123 mg, 0.32 mmol), Pd(PPh3)4(31 mg, 0.027 mmol) is added anhydrous toluene (0.7 ml). The mixture is heated to 116° C. with an oil bath for 18 hours, cooled to room temperature, diluted with ethyl acetate and filtered through a celite pad to remove any solids. The filtrate is concentrated to afford 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione as a brown solid (LC-MS m/z: 316.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[N:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[C:16]([CH3:23])[N:17]=[CH:18]2)=[C:11]=[O:12]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11]([NH:10][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[C:16]([CH3:23])[N:17]=[CH:18]2)=[O:12]
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Solvent: CCOCC
Product: Cc1cc2c(NC(=O)NCc3cccc(Cl)c3)cccc2cn1

Procedure:
3-chlorobenzylamine (141 mg, 1.0 mmol) in ether (20 mL) was treated with an ethereal solution of 5-isocyanato-3-methylisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=8.2 Hz), 7.51 (t, 1H, J=7.8 Hz), 7.31-7.43 (m, 4H), 7.10 (m, 1H), 4.38 (d, 2H, J=5.7 Hz), 2.65 (s, 3H); MS (ESI+) m/z 326/328 (M+H, 35Cl/37Cl).